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Neurosci Biobehav Rev. Author manuscript; available in PMC 2008 April 30. Published in final edited form as: Published online 2007 November 29. doi: 10.1016/j.neubiorev.2007.10.008. | PMCID: PMC2360482 NIHMSID: NIHMS43363 |
Behavioral Genetic Contributions to the Study of Addiction-Related Amphetamine Effects Tamara J. Phillips,1,2,3* Helen M. Kamens,2,3* and Jeanna M. Wheeler2,3 1Veterans Affairs Medical Center, Oregon Health & Science University, Portland, OR 97239 USA 2Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, OR 97239 USA 3Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239 USA Amphetamines, including methamphetamine, pose a significant cost to society due to significant numbers of amphetamine-abusing individuals who suffer major health-related consequences. In addition, methamphetamine use is associated with heightened rates of violent and property-related crimes. The current paper reviews the existing literature addressing genetic differences in mice that impact behavioral responses thought to be relevant to the abuse of amphetamine and amphetamine-like drugs. Summarized are studies that used inbred strains, selected lines, single gene knockouts and transgenics, and quantitative trait locus (QTL) mapping populations. Acute sensitivity, neuroadaptive responses, rewarding and conditioned effects are among those reviewed. Some gene mapping work has been accomplished, and although no amphetamine-related complex trait genes have been definitively identified, translational work leading from results in the mouse to studies performed in humans is beginning to emerge. The majority of genetic investigations has utilized single-gene knockout mice and has concentrated on dopamine- and glutamate-related genes. Genes that code for cell support and signaling molecules are also well-represented. There is a large behavioral genetic literature on responsiveness to amphetamines, but a considerably smaller literature focused on genes that influence the development and acceleration of amphetamine use, withdrawal, relapse, and behavioral toxicity. Also missing are genetic investigations into the effects of amphetamines on social behaviors. This information might help to identify at-risk individuals and in the future to develop treatments that take advantage of individualized genetic information. Keywords: Amphetamine, Methamphetamine, MDMA, Methylphenidate, Genetics, Mice, Inbred Strains, Selected Lines, QTL Mapping, Dopamine, Glutamate Illicit use of methamphetamine and methamphetamine-like drugs such as methylenedioxymethamphetamine (MDMA; “ecstasy”) has increased alarmingly in the past decade. Amphetamine was once therapeutically prescribed for the treatment of depression, asthma (due to its bronchial passage dilation properties), fatigue and weight problems, among other conditions ( Anglin et al., 2000). However, its abuse potential is now well established. The amphetamine derivative, methamphetamine, is the most commonly abused of the amphetamine-like drugs. It is easily manufactured and can be taken via several routes, including injection, orally, by nasal inhalation and even smoking. Although methamphetamine has some positive effects (e.g., increased alertness), they are far outweighed by the negative consequences of chronic use. These can include paranoia, memory loss (likely due to neural toxicity in more severe cases), malnutrition, and insomnia, as well as more serious medical complications like hypertension, neural damage, death from cardiac arrhythmia and hemorrhagic stroke. The mechanisms of action of the amphetamine-like drugs, including amphetamine, methamphetamine, methylphenidate, and MDMA have been reviewed in detail elsewhere ( Green et al., 2003; Rothman and Bauman, 2003; Sulzer et al., 2005). Amphetamines are substrates for the dopamine, norepinephrine, and serotonin transporters. Through actions at these transporters, amphetamines cause an increase in synaptic levels of the associated neurotransmitter and therefore act as indirect agonists. For example, as a substrate for the dopamine transporter (DAT), amphetamine is transported into the cytosol and disrupts the pH gradient of the synaptic vesicles, which inhibits vesicular dopamine accumulation ( Sulzer and Rayport, 1990; Sulzer et al., 1995). An accumulation of cytoplasmic dopamine then allows for its release from the cell by reverse transport via the DAT ( Kahlig et al., 2005). The differences among the amphetamines arise from their relative potencies at the different transporters. Amphetamine, methamphetamine, and methylphenidate have similar actions; they are more potent at inhibiting the dopamine and norepinephrine transporters compared to the serotonin transporter ( Eshleman et al., 1999; Han and Gu, 2006; Rothman and Bauman, 2003; Rothman et al., 2001). However, amphetamine and methamphetamine are more potent at inhibiting norepinephrine release than dopamine release. MDMA is different from the other amphetamines in that it is most potent at inhibiting the serotonin transporter ( Han and Gu, 2006), but has higher potency for inhibiting norepinephrine release than for inhibiting dopamine release ( Rothman et al., 2001). Mice are being used to define mechanisms of action of the amphetamines that are related to their abuse and toxicity (e.g., Itzhak and Ali, 2002). Genetic mouse models are being used to identify genes that may predict risk for the development of drug abuse and addiction. In particular, genetic mouse models have been used for estimating genetic correlations between drug-related traits ( Crabbe, 1999), for studying the roles of specific genes in drug-relevant behavioral and biological traits ( Crabbe et al., 2006; Cunningham and Phillips, 2003; Hall et al., 2004; Kieffer and Gaveriaux-Ruff, 2002; Laakso et al., 2002), and for addiction-related gene mapping ( Crabbe et al., 1999; Ferraro et al., 2005; Gill and Boyle, 2003; Janowsky et al., 2001; Palmer et al., 2005). The gene mapping work has the ultimate goal of gene identification and provision of genetic information relevant to complex human diseases, such as addiction ( Phillips et al., 2002a). This review covers the behavioral genetic literature examining amphetamine-like drug traits. The genetic models being used in amphetamine research are described as the existing data are reviewed. We have chosen not to include the cocaine-related literature in this review, but do mention specific cocaine-related studies for comparison to amphetamine effects. The information is organized by behavioral trait, starting with traits relevant to acute drug actions and progressing to more chronic drug effects, and then specific genetic information is discussed. We have not been completely inclusive, but have covered a large spectrum of the data, addressing the current state of the field with regard to genetic influences on the behavioral and physiological responses to amphetamine and amphetamine-like drugs. We note that there is a large behavioral genetic literature on responsiveness to amphetamines, but considerably less focused on genes that influence the development and acceleration of amphetamine use, withdrawal, relapse, and toxicity. In fact, the genetic influences on these different aspects of addiction liability and dependence are likely to be both unique and overlapping to some degree. Although the study of acute sensitivity traits will likely provide some insight into factors that influence the initiation of drug use, it would be beneficial to the field if more studies were aimed at defining genetic influences on traits thought to be more closely tied to the initial and plastic motivational responses to amphetamine-like drugs, excessive use of these drugs, and risk for drug dependence and relapse. For example, relatively few genetic studies have been aimed at amphetamine self-administration, using models that gauge the amount of effort an animal is willing to exert to obtain the drug, or place conditioning, which might provide information about genetic differences in sensitivity to drug-cue associations. Selective breeding procedures could be used to create lines that differ in rate or amount of amphetamine self-administered, followed by combined quantitative trait locus (QTL) and gene expression mapping to identify important genes (e.g., Palmer et al., 2005). More effort could be directed toward identifying mutants from N-ethyl-N-nitrosourea (ENU)-induced mutagenesis panels or transgenics that exhibit excessive intake or heightened risk for relapse. Existing reinstatement models and other developing models of drug relapse could be submitted to genetic analysis. Finally, genetic investigation into other important factors such as amphetamine-like drug influences on social behaviors that can be modeled in animals (e.g., Maldonado and Navarro, 2001), as well as prenatal developmental effects of amphetamines should be considered. All of this information might help to identify individuals at risk for both the development of amphetamine addiction and relapse, and could in the future lead to the development of treatments that take advantage of individualized genetic information. Acute Locomotor Stimulation One of the most widely investigated effects of amphetamines has been acute stimulation of locomotor behaviors. It has been suggested that acute drug stimulant effects in mice may model the euphoria experienced by humans, and may therefore be relevant at least to early drug use. It is difficult to determine the veracity of this claim. However, there are important functional connections between components of the motor system and the limbic system (brain areas shown to modulate the experience or prediction of reward), and motor behavior is required for the attainment of most rewards ( Mogenson et al., 1980). The focus on acute stimulant effects may be better supported by the idea that initial drug sensitivity influences continued drug use and thus, susceptibility to the development of drug abuse and addiction. This relationship has been strongly supported for alcohol ( Heath et al., 2001; Holdstock et al., 2000; Newlin and Thomson, 1999; Poikolainen, 2000; Schuckit and Smith 2000; 2001; King et al., 2002), and there are some intriguing results for psychostimulants as well. For example, the initial stimulant response to amphetamine predicted the likelihood of further drug use ( de Wit et al., 1986; Gabbay, 2003), and for cocaine, there was a significant positive relationship between subjects' ratings of positive cocaine effects, including euphoria, and lifetime cocaine use ( Davidson et al., 1993). However, whether these effects reflected genetically-determined differences in sensitivity that is predictive of future problem drug use is not known. Studies in humans that either validate or refute a genetic relationship between sensitivity to amphetamine-induced stimulation (or another sensitivity trait) and risk for amphetamine addiction would be a benefit to those trying to model relevant phenotypes in animals. Inbred strain studies The advantages and disadvantages of inbred strains have been described ( Crabbe, 1999; Crabbe et al., 1990; Wimer, 1992). One significant limitation is that differences in nuclear DNA may not be the source of inbred strain differences in phenotype, thus, careful interpretation is needed. Among the advantages are genetic homogeneity among the individuals of a given strain and genetic stability over time, so that data can be compared across laboratories for the same strains. Several studies have compared inbred mouse strains for their locomotor sensitivity to amphetamine-like drugs ( Anisman et al., 1975; Gould et al., 2001; Hamburger-Bar et al., 1986; Kitahama and Valatx, 1979; Moisset, 1977; Moisset and Welch, 1973; Orsini et al., 2004; Ralph et al., 2001; Remington and Anisman, 1976; Wenger, 1989; Zocchi et al., 1998). Some studies report large strain differences, which under controlled environmental conditions, could be due to genetic differences. Rat strains have also been found to be differentially sensitive to amphetamines ( Camp et al., 1994; Miserendino et al., 2003; Segal et al., 1975), and one study found that the strain distribution patterns for sensitivity to the locomotor stimulant effects of cocaine and d-amphetamine were not identical ( George et al., 1991). However, even for two of the most commonly used inbred mouse strains (or sometimes their sublines), C57BL/6 and DBA/2, the strain sensitivity order for amphetamine locomotor response has not been consistent ( Anisman et al., 1975; Cabib et al., 2000; Orsini et al., 2004; Phillips et al., 1994; Remington and Anisman, 1976; Wenger, 1989; Zocchi et al., 1998). Of course, it is likely that differences in the test details and other environmental circumstances have played a role in these apparent inconsistencies. There are some strain comparisons that have attempted to relate amphetamine (or methamphetamine) sensitivity differences to neurophysiological or neurochemical differences (e.g., Camp et al., 1994). For example, Zocchi et al. (1998) found that C57BL/6 mice showed a greater, dose-dependent locomotor stimulant response to an acute injection of d-amphetamine than DBA/2 mice, which corresponded with larger increases in dopamine levels in the nucleus accumbens after d-amphetamine treatment. Although these results provide fodder for further investigation, such studies lack the power to test the hypothesis that two variables share a genetic relationship (this is discussed in greater detail below) and would require follow-up with a suitable genetic model such as a larger panel of inbred strains. Study of the putative relationship identified by Zocchi et al. (1998) in a larger strain panel might indicate whether increased nucleus accumbens dopamine is necessary for increased amphetamine stimulation. Although recombinant inbred (RI) strains are now more commonly used for gene mapping purposes (see below), they are also useful for identifying genetic correlations and have been used to characterize genetic architecture for at least one amphetamine-related trait: locomotor response ( Oliverio et al., 1973). Not surprisingly, the authors concluded that this trait is influenced by multiple genes. One investigation used a panel of RI strains to identify genetic correlations (common genetic influence) for the effects of methamphetamine on locomotor activity, body temperature, stereotyped chewing and stereotyped climbing behavior. Twenty-five recombinant inbred strains derived from C57BL/6J and DBA/2J inbred strain progenitors (BXD RI) were included. The strongest association was for degree of locomotor stimulation and degree of hyperthermia induced by methamphetamine ( Grisel et al., 1997). It is possible that certain genes (and neurochemical mechanisms) influence both responses to methamphetamine, but also possible that high levels of locomotor behavior lead to increased body temperature. Another study used 26 of the BXD RI strains and found no evidence for a genetic correlation between the locomotor stimulant responses to phencyclidine and methamphetamine ( Alexander et al., 1996). Therefore, although both drugs can produce psychotic states in humans, and they share the involvement of dopamine in their behavioral effects ( Del Arco et al., 2007; Seeman et al., 2005; Zhang et al., 2001), the genetic mechanisms that determine sensitivity to these drugs may be disparate. Janowsky et al. (2001) made use of a large database of BXD RI strain means for multiple drug-related traits to identify genetic correlations with DAT density. They found that DAT density in the neostriatum was negatively genetically correlated with the acute locomotor stimulant responses to methamphetamine and cocaine, but not ethanol. Data for large strain panels tested for the motivational effects of amphetamines that might permit a direct evaluation of the genetic relationship between acute sensitivity and drug reinforcement have not been published. Selected lines Selective breeding results in changes in the frequencies of alleles that influence the trait of interest (see Falconer and Mackay, 1996). In theory, those that influence the trait will become fixed in the homozygous state that maximizes the trait, whereas those with no role in the trait will remain genetically segregating (if there was more than one allele in the population to begin with). The use of selected lines for studying the genetic and neurochemical underpinnings of the selected trait is intuitive. However, they are also often used to identify traits that share common genetic influence with the selection trait (i.e., genetically correlated traits). Although this may seem akin to testing two inbred strains, it is quite different because trait-relevant allele frequencies have been specifically manipulated by breeding, whereas gene frequency differences between a pair of inbred strains were not intentionally manipulated for a single trait. Thus, there is a higher probability that correlated trait differences in selected lines have as their source genetic differences associated with the original selection trait. This conclusion can be strengthened when similar findings are obtained in replicated selected lines (i.e., when two or more lines are selectively bred for the same trait from independent breeding populations; see Crabbe et al., 1990). The HMACT and LMACT lines were bred for high and low methamphetamine activation responses, respectively, after a 2 mg/kg dose of methamphetamine ( Kamens et al., 2005). The lines exhibited a 5-fold difference in methamphetamine activation response in the last generation of selection (generation 4). They were also found to differ in acute locomotor response to cocaine and ethanol (HMACT > LMACT in both cases), and the LMACT line consumed more methamphetamine, cocaine and ethanol than the HMACT line in two-bottle choice tests versus water ( Kamens et al., 2005; 2006). Thus, heightened sensitivity to the acute stimulant effects of methamphetamine appears to confer protection against high levels of methamphetamine, cocaine and ethanol self-administration. This result is opposite to that predicted from the human literature on alcohol that has suggested that greater sensitivity to the behavioral stimulant effects of alcohol is associated with a positive family history of alcoholism ( Newlin and Thomson, 1999) and with heightened levels of alcohol consumption ( Holdstock et al., 2000; King et al., 2002). However, it is possible that with methamphetamine, there is a biphasic relationship such that modest levels of stimulation are pleasant and extreme levels aversive. Examination of methamphetamine in the selected lines at various stages of the selection might have revealed a positive genetic association between stimulation and drinking at a stage of less extreme stimulation. The method used for the creation of these lines was mass selection (i.e., breeding the highest scoring animals to each other and the lowest scoring animals to each other, regardless of their relatedness except that sib mating is excluded). This selection method results in a rapid response, but with the cost of an increased rate of inbreeding, compared to some other methods (and thus, an increased probability of the chance fixation of selection trait-irrelevant alleles). However, when the number of selection generations is kept small (i.e., ≤ 5), excessive inbreeding can be avoided ( Belknap et al., 1997). Since only one set of HMACT and LMACT lines was created, it is reasonable to question whether the correlated trait differences were associated with selection trait relevant genes or with those differing in frequency between the lines due to random drift (inbreeding). Data from other sets of selected lines help to address this question. The FAST and SLOW selected lines were bred in replicate for 37 generations (i.e., there is a FAST-1 and FAST-2 line and a SLOW-1 and SLOW-2 line) for increased and decreased sensitivity to the locomotor stimulant effects of ethanol, respectively ( Crabbe et al., 1987; Phillips et al., 1991; 2002b; Shen et al., 1995). A within-family rotational breeding scheme was used for this long-term selection project to reduce inbreeding. In earlier selection generations, there was little evidence for a genetic correlation between locomotor sensitivity to d-amphetamine and ethanol ( Phillips et al., 1992). Later in selection, a difference in response to methamphetamine arose in one replicate set of the FAST and SLOW lines ( Bergstrom et al., 2003). We do not believe that these results are peculiar to methamphetamine, as the same pattern of results was found for d-amphetamine (Phillips, unpublished data). In an even later generation, a significant line difference in one replicate and a statistical trend toward a line difference in the other was found for methamphetamine response ( Bergstrom et al., 2003). These results provide strong evidence for some common genetic regulation of the locomotor stimulant responses to ethanol and methamphetamine. There has also been a study in humans showing that subjects who experienced more pronounced stimulant-like effects from ethanol reported greater stimulant effects from amphetamine (Holdstock and de Wit, 2001). However, the study design did not allow for determination of whether the relationship was due to common genetic influences or not. The late appearance of the differences in response to methamphetamine between FAST and SLOW mice, compared to the early divergence of the lines in response to ethanol, suggests that genes recruited later in the selection, and thus with a more minor impact on ethanol sensitivity are those which also influence the locomotor stimulant response to methamphetamine. This conclusion is consistent with the small magnitude of difference in stimulant response to ethanol found between the HMACT and LMACT selected lines ( Kamens et al., 2006). Similar results with respect to both line and replicate were found when FAST and SLOW mice were tested for stimulant response to cocaine ( Bergstrom et al., 2003; Phillips and Shen, 1996). Further, two lines of mice bred for their large locomotor stimulant response to cocaine exhibited a larger stimulant response to d-amphetamine, compared to two lines bred for low cocaine response ( Marley et al., 1998). Finally, Short Sleep mice bred for decreased sensitivity to the sedative-hypnotic effects of ethanol have been found to exhibit heightened sensitivity to the locomotor stimulant effects of (+)amphetamine, cocaine and ethanol, compared to Long Sleep mice, which were bred for increased sensitivity to the sedative-hypnotic effects of ethanol ( Hanania and Zahniser, 2002). Collectively, the results from multiple sets of selected lines suggest some shared genetic regulation of sensitivity to the locomotor stimulant effects of amphetamine, ethanol and cocaine. This is not surprising considering the evidence that all three drugs, given in doses that stimulate locomotion, increase dopamine signaling. However, as mentioned above, DAT density in the neostriatum appears to be a shared mechanism determining sensitivity to the locomotor stimulant effects of methamphetamine and cocaine, but not ethanol. High dose amphetamine treatment or repeated treatment can result in repetitive movements commonly referred to as stereotypy. In rodents, stereotypic behaviors may include head swaying or bobbing, repetitive forelimb movements, repetitive chewing, and self-mutilation ( Atkins et al., 2001; Grisel et al., 1997; Muller et al., 1982). In humans, methamphetamine-induced stereotypic behavior is sometimes referred to as “punding”. Punding may be defined as compulsively performing a useless task over and over again ( Schiorring, 1981). Examples are repetitively assembling and disassembling a multicomponent item, or repetitive stacking and unstacking of magazines. In addition to stereotypy, with excessive amphetamine use, schizophrenia-like symptoms may develop that are often indistinguishable from non-drug-induced schizophrenia. Dopaminergic alterations thought to underlie stereotypic behaviors also appear to be responsible for these schizophrenia-like symptoms. Certain psychological aspects of amphetamine-induced schizophrenia-like symptoms, such as delusions, cannot be modeled in animals; however, there have been a few investigations of genetic influences on amphetamine-induced stereotypy. Inbred strains Recently, a set of inbred strains has been characterized for vertical leaping behavior (sometimes called “popping,” “jumping,” or “hopping”) induced by high dose d-amphetamine (10 mg/kg; McKerchar et al., 2006). The authors suggest that pharmacologically induced leaping behavior may be a relevant model for studying schizophrenia. Whether or not to include vertical leaping among the stereotypic behaviors is not clear, but it does not appear to occur at lower acute doses of amphetamines ( Colpaert et al., 1975; Lal et al., 1975; 1976). Among the 5 inbred strains and one outbred stock examined, only the BALB/cJ strain exhibited vertical leaping behavior in response to d-amphetamine ( McKerchar et al., 2006). McKerchar et al. (2006) describe some similarities in strain sensitivities to vertical leaping induced by d-amphetamine, dizocilpine ( Deutsch et al., 1997) and naloxone-precipitated morphine withdrawal ( Kest et al., 2002), although they point out the difficulty in making meaningful comparisons due to differences in dosing regimens and methods for quantification. In the course of measuring leaping behavior across the 5 treatment days, behavioral sensitization was seen in bouts of low mobility (a measure of spatial confinement due to focused stereotypy). However, the pattern of increase across treatment days did not differ significantly among the genotypes ( McKerchar et al., 2006). Thus, genetic differences among these mouse genotypes did not influence magnitude of sensitization to the stereotypic effects of the drug. Selected lines The HMA and LMA lines were bred for high and low numbers of stereotyped chewing episodes, respectively, in response to 10 mg/kg methamphetamine ( Atkins et al., 2001). The dose of methamphetamine used for selection was adjusted after the second selection generation to avoid floor and ceiling effects. These lines were bred using mass selection for a total of 4 selection generations. At the end of selection, when tested for response to the original 10 mg/kg dose of methamphetamine, the lines exhibited a 7-fold difference in number of stereotyped chewing episodes. Locomotor stimulant responses to methamphetamine (measured as line crossings in the home cage) at doses up to 3.5 mg/kg were identical for the two lines. At doses of 7 mg/kg and higher, LMA mice exhibited more locomotor behavior, perhaps because the HMA line was experiencing more competing stereotypy behaviors at these doses. In fact, the LMA mice also exhibited higher stereotyped circling and climbing behaviors after methamphetamine treatment, compared to HMA mice. That sensitivity to more purely stimulating doses of methamphetamine was similar in these lines indicates that methamphetamine-induced activation and stereotypy do not share common genetic regulation. This is an important point in the formulation of hypotheses about the development of problem amphetamine use versus the maintenance of excessive amphetamine use. Genetic factors that influence each of the stages in a psychostimulant abuse syndrome may be non- , or only partially, overlapping. When administered repeatedly at daily or less frequent intervals, there is enhanced sensitivity to the motoric and stereotypic effects of amphetamines, a phenomenon referred to as behavioral sensitization. Many opinions have been expressed regarding the importance of sensitization to addiction. Bartlett et al. (1997) have hypothesized that the neuroadaptations underlying behavioral sensitization contribute to the paranoia and psychosis characteristic of psychostimulant abuse. Robinson and Berridge (1993) have proposed that repeated drug use renders certain neural systems sensitized to drugs and drug-associated stimuli, leading to a pathological focus on drug-associated stimuli, that then come to exert powerful control over behavior (such as drug seeking behavior). Koob and Le Moal (2006) have expressed the opinion that sensitization is not worthy of consideration in models of drug dependence. However, they do concede a possible role of sensitization in the early phase of drug use, perhaps because sensitization can be seen after a single previous drug exposure ( Robinson et al., 1982; Vanderschuren et al., 1999). Further, a role in relapse seems plausible given that psychostimulant sensitization is extremely long-lasting and is best seen with intermittent schedules of drug administration ( Kuribara, 1996; Robinson, 1984). Animal models that measure behavioral sensitization provide behavioral markers of neuroadaptation induced by repeated drug exposure. Although there have been many studies exploring the neurobiological mechanisms associated with psychostimulant sensitization, few studies have focused on genetic differences that may influence susceptibility to behavioral sensitization; nor has the field found a convincing way to demonstrate a causal relationship between sensitization seen behaviorally or neurochemically and a change in motivational response to a psychostimulant drug. Further, it is likely that the genetic influences on context-dependent (conditioned) and context-independent (pharmacological) sensitization are not entirely the same, and that each type may play a different role in the development of addiction and in relapse to drug use, following periods of abstention. These speculative comments can be validated (or refuted) only by direct investigation. Inbred strains Few studies have been performed examining strain differences in behavioral sensitization to amphetamines. In comparisons of C57BL/6J and DBA/2J strain mice, DBA/2J mice were more sensitive to the development of sensitization. This was true when methamphetamine was repeatedly administered ( Phillips et al., 1994) or when the sensitizing agent was repeated daily restraint stress ( Badiani et al., 1992). However, the opposite strain order has also been reported for repeated amphetamine-induced sensitization ( Cabib, 1993). Selected lines To our knowledge, selection for magnitude of sensitization has not been attempted for any drug. However, degree of sensitization to methamphetamine was assessed during each generation of selection for acute methamphetamine sensitivity in the HMACT and LMACT lines. No differences in magnitude of sensitization were found when the treatment and test dose was 2 mg/kg. However, when sensitization was examined in response to a lower dose of methamphetamine (1 mg/kg), the HMACT line exhibited more behavioral sensitization than the LMACT line ( Kamens et al., 2005). The authors speculated that the line difference was not observable at the higher dose of methamphetamine due to a ceiling effect. The lines were also examined for sensitization to a 10 mg/kg dose of cocaine, and did not differ. Unfortunately, no other doses of cocaine were used, and the lines are extinct. We are currently selectively breeding mice for high and low sensitization to methamphetamine and will be testing these lines for correlated psychostimulant- and possibly ethanol-related traits during the course of selection. Reward and Conditioned Effects Surprisingly few studies have examined genetic contributions to the rewarding effects of amphetamines using measures like self-administration or conditioned place preference. We believe that greater attention needs to be aimed in this direction. However, it is necessary to acknowledge that most mammalian genetic studies utilize mice because of the wealth of genetic information available for this species, and that data using the preferred route of psychostimulant self-administration, intravenous, is technically difficult to obtain in mice, although not impossible ( Yan et al., 2006). We have utilized an oral route of self-administration in our genetic studies ( Kamens et al., 2005), but we assume that there will be healthy skepticism regarding the veracity of the claim that this reflects differential reinforcement until we can demonstrate concordance of our results with more widely accepted measures, such as intravenous self-administration or conditioned place preference. Although place conditioning procedures appear to offer a less technically challenging method for the measurement of the rewarding effects of drugs, it can be difficult to demonstrate place preference, rather than place aversion, to amphetamine-like drugs in mice. This method offers a different dimension to the study of drug reinforcement, compared to self-administration, in that it focuses on the important role of cues that have been assigned biological significance by virtue of their association with reinforcing drug effects. Comparisons of C57BL/6J and DBA/2J mice suggest that the former strain develops a preference for locations formerly associated with amphetamine and the latter strain develops an aversion, but that these outcomes can be influenced by environmental factors ( Cabib et al., 2000; Orsini et al., 2004). Conditioned taste aversion methods offer another means for examining the motivational effects of drugs. Taste aversion induced by amphetamine treatment was similar for C57BL/6J and DBA/2J mice ( Orsini et al., 2004), but has not been used in models appropriate for genetic analysis. Some studies suggest that response to novelty can predict faster acquisition of amphetamine self-administration ( Piazza et al., 1989; 1990). However, in those studies, rats were separated into subgroups based on locomotor response in a novel environment. This design does not permit attribution of the locomotor differences to genetic differences. In an attempt to develop a genetic animal model that could be used to examine the notion that novelty-related behavior might be genetically associated with sensitivity to drug reward, Kliethermes et al. (2007) report the selective breeding of mice for divergent exploration of a hole board apparatus. When tested for differential sensitivity to d-amphetamine-induced place conditioning, no consistent line differences were found. Further, the lines did not differ in level of methamphetamine self-administration or in behavioral sensitization to methamphetamine. These results do not support a genetic relationship between novelty seeking reflected in the head dipping behavior and drug reward. However, as noted by the authors, if their selection trait had been based on a measure of explicit novelty seeking, the genetic correlation results may have been different. Brain alterations associated with chronic methamphetamine abuse have been documented in humans using imaging techniques ( McCann et al., 1998; Volkow et al., 2001; Wang et al., 2004). Neurotoxic effects on striatal dopamine systems are well-established from animal research ( Davidson et al., 2001; Schmidt et al., 1985), although the role of hyperthermia versus more direct drug effects, is not entirely clear ( Yuan et al., 2006). It has been suggested that reactive oxygen species play a critical role in the toxic effects of chronic methamphetamine use through methamphetamine-induced hyperthermia, changes in dopamine or glutamate transmission, and mitochondrial disruption ( Riddle et al., 2006). Some components of dopamine systems appear to recover from chronic methamphetamine effects, whereas others do not ( Segal et al., 2005). Although the behavioral consequences of treatment with neurotoxic doses of methamphetamine has received some attention (e.g., Itzhak and Ali, 2002), the research in this area is not extensive and has not focused on the question of genetic influences on susceptibility to neurotoxic effects. This is an area of importance because it may explain some of the variation among individuals in the magnitude of negative impact of excessive amphetamine use. There are several studies using single gene mutant mice to examine the neurotoxic effects of amphetamine-like drugs (e.g., Fumagalli et al., 1998; 1999; Itzhak et al., 2004; Perez et al., 2005; Numachi et al., 2007), but few have examined behavior, and thus this literature will not be discussed here. Genetic Findings from Mapping and Mutants Gene Mapping The use of QTL mapping for addiction-related traits in mice began about 15 years ago ( Gora-Maslak et al., 1991). For a primer on QTL theory and methods in different genotype structures, see Palmer and Phillips (2002). A quantitative trait, sometimes referred to as a complex trait, is one influenced by multiple genetic and environmental factors. Initial QTL mapping identifies chromosomal regions that harbor genes that contribute to variation in the trait of interest. Finer mapping may then ensue to narrow the region to one containing a small number of genes. Examination of existing sequence information or additional sequencing may be used to identify functional polymorphisms that may account for behavioral variation. Gene expression analyses may also be used to identify genes in the region that are differentially expressed depending upon magnitude of the behavioral trait. For additional information and issues regarding the search for quantitative genes, several papers are available at every level of complexity (e.g., Belknap et al., 2001; Nadeau and Frankel, 2000; Phillips et al., 2002a; Willis-Owen and Flint, 2007; Wu and Lin, 2006). Table 1 summarizes the existing QTL mapping data for amphetamine-related behavioral and thermal traits. The data are sparse, and many of the QTL are considered provisional. In other words, they are supported at a statistical level that will require additional confirmatory evidence. Some of the QTL are considered to be definitive, but the specific genes that are responsible for determining trait variation have not yet been identified. | Table 1Quantitative trait loci (QTL) mapped in mice for behavioral and thermal responses to amphetamine and methamphetamine |
Recombinant Inbred (RI) Strains The use of RI strains to identify traits that share common genetic influence (genetic correlation) was described above. In the past two decades, RI strains have also been used to identify trait-specific QTL, including QTL for amphetamine-related traits. As nicely reviewed by Belknap and Crabbe (1992), RI strains were originally developed for major gene mapping. However, technological advances have resulted in their use for the mapping of minor gene loci – regions harboring genes relevant to multigenically mediated traits. Some of the earliest mapping data for an amphetamine-related trait assessed in mice were obtained using hyperthermia data collected by Seale et al. (1985) for 10 of the BXD RI. These data were subjected to QTL mapping first by Gora-Maslak et al. (1991) and then again using a denser marker set ( Belknap and Crabbe, 1992). The most significant result for a gene influencing the hyperthermic response to a single dose of 20 mg/kg d-amphetamine was for a locus on mouse chromosome 1. We are not aware of any attempts to directly identify the influential gene responsible for what appeared to be a major single gene effect. However, in a more recent study ( Grisel et al., 1997), BXD RI mice were used for mapping the hyperthermic response to 3 doses of methamphetamine (4, 8 and 16 mg/kg). A region of interest was identified on chromosome 1; however, a major gene effect was not strongly indicated in this 27-strain study, as it was in the previous 10-strain study. One possible explanation for non-confirmation of a major gene effect is that the QTL is dose-specific. Another is that the original finding was a false positive. Finer mapping would be needed to examine the possibility that one or more genes influence this response in this region of chromosome 1. Associations with genes on other chromosomes were also indicated. Other amphetamine-related traits that have been subjected to gene mapping efforts using RI strains include methamphetamine-induced stereotyped climbing, repetitive chewing, and acute locomotor activation ( Grisel et al., 1997; Torkamanzehi et al., 2006). In all cases, provisional QTL have been identified, but additional work is needed for confirmation, finer mapping and gene identification. None of this work has yet progressed to the point where a quantitative trait gene (QTG) has been definitively identified based on collective evidence (see Belknap et al., 2001; Phillips et al., 2002a) from initial QTL mapping. Data for methamphetamine-induced place conditioning in a set of the BXD RIs were used for correlation with DAT binding ( Janowsky et al., 2001), however, the gene mapping results have not been published (CL Cunningham, personal communication). Selected lines QTL can also be mapped using selected lines. To our knowledge, the only selected lines that have been used to map an amphetamine-related trait are the HMACT and LMACT lines, bred for high and low sensitivity to the acute stimulant effects of methamphetamine. QTL analyses using DNA from mice of these lines provided evidence that there are genes that influence sensitivity to methamphetamine on chromosomes 5, 9, 11, 12, and 15 ( Palmer et al., 2005). In an attempt to align possible differences in gene expression with genes that reside within these QTL regions, nucleus accumbens tissue from the HMACT and LMACT lines was used in a microarray gene expression analysis. Because the mice were not methamphetamine-treated prior to brain biopsy, these differentially expressed genes represent innate genetic differences that might be expected to influence methamphetamine response. Of the genes found to be differentially expressed, some of them reside in the methamphetamine sensitivity QTL regions ( Palmer et al., 2005). One that resides on chromosome 15 and was differentially expressed is casein kinase 1 epsilon ( Csnk1e). This is a particularly interesting candidate gene for an influence on sensitivity to methamphetamine because the Csnk1e protein is known to increase the activity of DARPP-32 (dopamine- and adenosine 3',5'-monophosphate (cAMP)-regulated phosphoprotein of 32 kilodaltons). DARPP-32 is phosphorylated after psychostimulant administration through increasing extracellular dopamine levels, and is a likely player in the regulation of the locomotor response to psychostimulant drugs ( Greengard, 2001). A difference in Darpp-32 expression between the HMACT and LMACT lines was also found ( Palmer et al., 2005). This work was translated to an investigation of healthy human volunteers in which their subjective responses to placebo, 10 or 20 mg of d-amphetamine was examined and compared to polymorphisms in the CSNK1E region. The subjects' ratings of whether they felt a drug effect was significantly associated with one single-nucleotide polymorphism in that region ( Veenstra-VanderWeele et al., 2006). Thus, casein kinase 1 epsilon allelic variation is a strong candidate for predicting amphetamine responsiveness in the human and mouse. Single Gene Mutants Tables 2- 9 summarize the large number of amphetamine response studies that have been performed using mice carrying single gene mutations. In these tables, we have included the most accurate genetic background information that we could glean from the published literature, as this may affect interpretation. In some cases, these mutations are naturally occurring, some were targeted and created using homologous recombination (knockout mice; KO), and some are over- or under-expression transgenics. Methods for creation of single gene mutant mice by homologous recombination and some of the issues associated with the almost exclusive use of 129 strains as the source of embryonic stem (ES) cells were recently summarized in an update by Seong et al. (2004). Several additional readings on this topic are cited in that paper, and we have had personal experience with experimental results in mutant mice that appear to have been influenced by varying genetic backgrounds ( Phillips et al., 1999; Phillips and Belknap, 2002). Although we have made an attempt to be comprehensive, there is some probability that papers have been omitted, and of course new papers have been published since our search was completed. Further, our interpretation of the data may differ from that of the authors; we leave it up to the reader to form their own opinions. Selected information from each of the tables is discussed below, with the exception of Table 9, which summarizes information that did not fit well into the other tables. The reader interested in a similar review of research in single gene mutants for ethanol-related traits is referred to Crabbe et al. (2006). | Table 2Dopamine-related studies in single gene mutants for methamphetamines and amphetamines. |
| Table 9Other single gene mutant studies using Methamphetamines and amphetamines. |
Dopamine-related Genes: Amphetamine & Methamphetamine ( Table 2) The known actions of amphetamines and methamphetamine on dopaminergic systems have created interest in the role of dopamine-related genes in the responses to these drugs. The influence of gene knockout on several behavioral responses to these stimulant drugs has been examined. The preponderance of studies has concentrated on locomotor sensitivity and sensitization, however, reward-related and sensory gaiting traits, such as place conditioning, brain stimulation reward, and prepulse inhibition (PPI), have also been examined. Sensory gaiting deficits have been a focus due to their possible relevance to the deficits seen in psychostimulant addiction. Both pharmacological and gene manipulation approaches have been used to study the role of the dopamine system in behavioral responses to amphetamines, but results across approaches have not always agreed. For example, cocaine- and amphetamine-regulated transcript (CART) was identified as an mRNA transcript that is upregulated in the striatum following an injection of psychostimulants ( Douglass et al., 1995). Intra-ventral tegmental area administration of the CART peptide has been shown to dose-dependently increase locomotor activity and to induce conditioned place preference ( Kimmel et al., 2000). However, when basal locomotor activity was examined in CART KO and wildtype (WT) mice, no difference was found. Further, the two genotypes showed equal sensitivity to the low-dose (1 and 3 mg/kg) stimulant effects of amphetamine, but at a higher dose (6 mg/kg) the WT mice were less sensitive than the KO mice ( Couceyro et al., 2005); no differences in stimulant response to 1, 2, 4 or 8 mg/kg amphetamine were found in another study ( Moffett et al., 2006). Conversely, WT mice showed enhanced conditioned place preference to 0.3 mg/kg amphetamine compared to CART KO mice ( Couceyro et al., 2005), suggesting that the CART peptide may normally confer sensitivity to the rewarding effects of stimuli associated with amphetamine. However, in a population of human methamphetamine addicts and controls, no association was found between polymorphisms in the CART gene and the likelihood of methamphetamine dependence ( Morio et al., 2006), suggesting that naturally occurring CART gene polymorphisms may not be important to the clinical syndrome. The DAT and each of the dopamine D 1, D 1A, D 2, D 3, and D 4 receptors have been examined for their roles in amphetamine responses using KO mice. Some data support an association of number of repeat alleles of the DAT gene with risk for methamphetamine psychosis ( Ujike et al., 2003). Further, DAT density, quantified using positron emission tomography, was decreased in methamphetamine users compared to non-users ( Sekine et al., 2003). These data cannot differentiate between a pre-existing versus a methamphetamine-induced reduction in DAT levels. However, DAT KO mice displayed amphetamine conditioned place preference sooner and the preference lasted longer than in WT mice ( Budygin et al., 2004), suggesting that the absence of DAT throughout development enhanced conditioned reinforcement. In multiple studies examining the acute locomotor response to amphetamine of DAT KO and WT mice, the markedly elevated baseline locomotion of the KO mice likely impacted their ability to exhibit a locomotor stimulant response. In fact, WT mice exhibited the typical activation, whereas KO mice showed locomotor depression ( Gainetdinov et al., 1999, Giros et al., 1996, Spielewoy et al., 2001, Zhuang et al., 2001). The ability of stimulants to reduce the hyperactivity of DAT KO mice has suggested to some that these mice may serve as a model of attention deficit hyperactivity disorder (ADHD). Results for amphetamine-related responses in dopamine receptor KO mice have been somewhat more variable or subject to the idiosyncrasies of specific experimental designs; the reader is encouraged to examine Table 2. One trait that has been examined in several of these and other dopamine-related mutants is PPI of the startle reflex and disruption of the reflex by amphetamines. PPI of the startle reflex was developed as an animal behavioral model of sensorimotor gating deficits. This animal model is thought to be relevant to several mental illnesses for which sensorimotor gating is affected, including schizophrenia ( Braff et al., 1995). Chronic amphetamine use can lead to schizophrenia-like symptoms that appear to follow a time course related to duration of use, progressing from a non-psychotic to a prepsychotic state and ultimately to a severely psychotic state ( Ujike and Sato, 2004). Measurement of PPI in single gene mutant mice has been used to identify neurobiological mechanisms associated with disruptions in sensorimotor gating, although the concentration has been on acute amphetamine effects, rather than chronic. Thus, in dopamine D1, D3, and D4 receptor KO mice, disruption of PPI by amphetamine was intact, whereas amphetamine did not disrupt PPI in D2 receptor KO mice ( Ralph et al., 1999; Ralph-Williams et al., 2002). In mice with deletion of only the long isoform of the D2 receptor, disruption of PPI by amphetamine was intact ( Xu et al., 2002), suggesting that the short isoform alone could mediate this effect of amphetamine on PPI. An additional study suggests that the signaling pathway requiring DARPP-32 is also critical in mediating amphetamine-induced disruption of PPI ( Svenningsson et al., 2003). One modulator of this protein is dopaminergic neurotransmission. The body of work examining amphetamine reward-related traits in mice with dopamine-related genetic alterations is small. At the time of our literature review, we found only 5 studies examining conditioned rewarding effects, and none examining self-administration. There was one study showing a deficit in brain stimulation reward in D 2 receptor KO mice ( Elmer et al., 2005). Given the large literature supporting dopamine involvement in the neural circuitry thought to mediate amphetamine reward, more research in this area seems warranted. Glutamate-related Genes: Amphetamine & Methamphetamine ( Table 3) | Table 3Glutamate- and glycine-related single gene mutant studies using methamphetamines and amphetamines. |
Glutamatergic neurons in the prefrontal cortex provide excitatory input to dopamine neurons in the nucleus accumbens and ventral tegmental area, thought to be involved in drug reward. Glutamate systems have been shown to function in both synaptic plasticity and conditioned behaviors, and several lines of evidence suggest that they may also play an important role in drug-associated learning and addiction ( Jones and Bonci, 2005). Pharmacological studies have shown that glutamate receptor antagonists impair the development of place preference for amphetamine ( Jackson et al., 2000). In addition, NMDA-type glutamate receptor antagonists blocked the development of behavioral sensitization to amphetamine, while AMPA-type glutamate receptor antagonists impaired the maintenance of sensitization and decreased conditioned responding for amphetamine self-administration ( Jackson et al., 2000). Glutamate levels increased in response to amphetamine exposure ( Del Arco et al., 1999), and pretreatment with metabotropic glutamate receptor antagonists decreased the levels of extracellular dopamine released in response to methamphetamine ( Golembiowska et al., 2003). Results from gene targeting experiments have extended these results and confirmed that glutamate systems are relevant to amphetamine-related behaviors ( Table 3). However, with the exception of one study that examined amphetamine-induced conditioned place preference in GluRε1 (a.k.a. NR2A) KO mice, the focus has been largely on sensitivity and neuroadaptation. Deletion of GluRε1 caused a reduction of locomotor stimulation in response to acute methamphetamine, as well as a lower magnitude of sensitization to repeated methamphetamine exposure ( Miyamoto et al., 2004b). Mice carrying a hypomorphic allele of NR1 (the receptor subunit common to all NMDA-type heteromers) also exhibited decreased locomotion relative to WT mice in response to acute amphetamine, but interpretation of this result may be complicated by the increased stereotypy of this strain ( Miyamoto et al., 2004a). Further, a mutant with an NR1 NMDA receptor subunit with reduced function that was expressed only in dopamine D1 receptor-containing cells, did not exhibit an alteration in amphetamine response ( Heusner and Palmiter, 2005). Deletion of the metabotropic GluR1 receptor subunit caused an increase of behavioral responses to amphetamine at higher doses, such that the KO mice exhibited less normal locomotion and more stereotypy and seizures than the WT ( Mao et al., 2001). The locomotor response to amphetamines of GluR2 KO mice has not been reported, but this mutant was impaired in certain aspects of stimulus-reward learning, and failed to increase conditioned responding after methamphetamine administration ( Mead and Stephens, 2003). Homer proteins are important modulators of glutamate signaling and interact with both NMDA and AMPA receptors. Deletion of either Homer-1 or -2 caused a decrease in basal extracellular glutamate levels in the nucleus accumbens, whereas Homer-1 mutants also exhibited increased glutamate content in the prefrontal cortex ( Szumlinski et al., 2004). In addition, both of these mutants were more sensitive to the stimulatory effects of acute methamphetamine ( Szumlinski et al., 2005). Another important regulator of glutamatergic signaling is glycine, which must bind to the strychnine insensitive glycine modulatory site in the process of NMDA receptor activation. Deletion of the GlyT1 glycine transporter caused increased concentrations of glycine at the synapse, and thus an increased ratio of NMDA/AMPA signaling. Animals heterozygous for the GlyT1 deletion showed WT levels of stimulation in response to amphetamine administration, but did not display the normal disruption of PPI exhibited by WT animals ( Tsai et al., 2004). This suggests yet another target for consideration in the search for the precise substrates involved in the effects of amphetamines on PPI. Recent findings also support deficits in glutamate transmission in schizophrenia, a condition associated with deficits in sensorimotor gating ( Hahn et al., 2006). Noradrenergic-related genes: Amphetamine & Methamphetamine ( Table 4) | Table 4Noradrenergic-related studies of single gene mutant mice using methamphetamines and amphetamines. |
The locus coeruleus is a noradrenergic nucleus that projects to regions including the nucleus accumbens, ventral tegmental area, and prefrontal cortex. Psychostimulant administration has been associated with increased norepinephrine (NE) levels in the prefrontal cortex ( Florin et al., 1994). In addition, lesions of the locus coeruleus cause a reduction in amphetamine-induced hyperactivity ( Mohammed et al., 1986), indicating that noradrenergic signaling is involved in this behavioral response. Mice which are deficient in NE from birth (dopamine β-hydroxylase KO mice) are more sensitive to the locomotor effects of a single dose of amphetamine, but exhibit a reduction in sensitization to the drug over repeated doses ( Weinshenker et al., 2002). Mice lacking the norepinephrine transporter also have increased sensitivity to acute amphetamine ( Xu et al., 2000a). The adrenergic receptor gene family is diverse, and although these proteins were originally defined pharmacologically (for review see Calzada and DeArtinano, 2001), a detailed characterization of the functions of various receptor subtypes has been difficult due to a lack of highly selective antagonist compounds. α 1-adrenoceptors (AR) are coupled to G q and signal via phospholipase C and inositol triphosphate pathways ( Koshimizu et al., 2003). α 1-AR activity is considered important for motor activity, arousal, and exploratory behaviors ( Stone et al., 1999), and the α 1-AR antagonist prazosin reduces amphetamine-induced hyperactivity ( Blanc et al., 1994). In contrast, α 2-ARs couple to G i/G o ( Kurose et al., 1991), which inhibits production of cAMP by adenylyl cyclase, and inhibits NE release and firing of noradrenergic neurons ( Starke, 2001). KO mice deficient in specific AR subtypes have contributed to our understanding of the role that noradrenergic signaling plays in amphetamine-related behaviors. Consistent with an excitatory role for α 1-ARs, knockout of either α 1B-AR or α 1D-AR resulted in reduced locomotor stimulation in response to an acute dose of amphetamine ( Auclair et al., 2002; 2004; Drouin et al., 2002; Saldage et al., 2003). Further, α 1B-AR KO mice were impaired for behavioral sensitization to repeated amphetamine or methamphetamine administration, compared to their WT counterparts ( Auclair et al., 2004; Battaglia et al., 2003; Drouin et al., 2002). Mice lacking the α 2A-AR exhibited a phenotype similar to that of the NE-deficient dopamine β-hydroxylase KO mice. They showed an increase in acute stimulation and decreased development of behavioral sensitization to amphetamine ( Juhila et al., 2005). The role of α 2C-AR is less clear, since male, but not female, KO mice exhibited increased sensitivity to acute amphetamine, but this result is still consistent with an inhibitory role for α 2-ARs ( Sallinen et al., 1998). Future work using these subtype-specific KO strains will hopefully provide more information on the behavioral functions of this complex receptor family. Cell Support and Signaling Proteins: Amphetamine & Methamphetamine ( Table 5) | Table 5Cell support and signaling-related protein studies in single gene mutant mice using methamphetamines and amphetamines. |
Signaling cascades that contribute to addiction, and that protect or delay the development of addiction, have been nicely reviewed by Ron and Jurd (2005), with a specific focus on cocaine and ethanol. Some of the same molecular events are likely to be involved in amphetamine-mediated behaviors. A small number of studies with single gene mutants have involved cell signaling-related proteins. Details can be found in Table 5. Obvious candidates to examine for involvement in the effects of amphetamines are those that mediate coupling of dopamine receptors to adenylyl cyclase. The GTP-binding protein Gα olf subunit is the predominant form in the striatum that is involved in dopamine D1 and adenosine A 2A receptor signaling. Mice possessing a single copy of a null mutant allele for the gene that expresses Gα olf exhibited both reduced baseline and amphetamine-stimulated behavior, compared to WT controls ( Herve et al., 2001). In mice lacking G protein-coupled receptor kinase 6, which mediates desensitization of dopamine receptors, increased sensitivity to the locomotor stimulant effects of amphetamine was seen ( Gainetdinov et al., 2003). The enhanced coupling of D2-like dopamine receptors to striatal G proteins seen in these mice could have played a role in this increased stimulant response. Phosphodiesterase 1B KO mice also exhibited an enhanced locomotor response to methamphetamine ( Reed et al., 2002). This calcium/calmodulin-dependent phosphodiesterase is highly expressed in the striatum, as well as in other regions with high levels of dopaminergic innervation. Striatal slices from these mice were used to demonstrate increased sensitivity to dopamine D1 receptor activation, as indicated by increased levels of DARPP-32 and other transduction related molecules ( Reed et al., 2002). Thus, phosphodiesterase 1B appears to play a significant role in dopaminergic functioning, and its absence resulted in enhanced dopamine receptor signaling. Another signaling pathway relevant to the effects of amphetamine involves the dopamine D2 receptor and the Akt/glycogen synthase kinase 3 (GSK-3) signaling cascade. Mice heterozygous for a null mutation of the GSK-3β gene exhibited a blunted response to amphetamine. The set of studies reviewed in this paragraph support both dopamine D1 and D2 receptor signaling in locomotor stimulation to amphetamines. Some differences in locomotor response to amphetamine have also been seen in D1 and D2 receptor KO mice (see Table 2). Behavioral sensitization induced by repeated psychostimulant administration is thought to involve specific changes in dopaminergic pathways. The R11 β-protein kinase A (PKA) isoform is highly expressed in mouse stratium and serves a role in dopamine receptor signaling. R11β-PKA mutant mice did not differ in acute locomotor response to amphetamine; however, they exhibited a larger magnitude of behavioral sensitization ( Brandon et al., 1998). This suggests a role for this PKA isoform in behavioral neuroadaptation to amphetamine. Cell support and signaling proteins involved in neural development, neuroprotection, and survival have also been examined for their roles in amphetamine-related behaviors using null mutant mice. Mice heterozygous for a mutant brain derived neurotrophic factor (BDNF) allele exhibited increased sensitivity to the stimulant effects of amphetamine ( Dluzen et al., 2001; Pineda et al., 2005). These mice were also found to have increased striatal dopamine levels in the absence of amphetamine treatment; the effect of acute amphetamine on striatal dopamine concentrations was not examined in these mice ( Dluzen et al., 2001). When the BDNF KO was combined with the expression of the Huntington gene (htt), these mice showed an exacerbation of the insensitivity to amphetamine seen in the HTT transgenic. These data suggest that the decreased BDNF expression that has been observed in Huntington's disease patients may contribute to exacerbation of dopamine-related motor disturbances characteristic of this disease ( Pineda et al., 2005). Finally, glial derived neurotrophic factor overexpression transgenic mice exhibited enhanced sensitivity to amphetamine-induced locomotor stimulation ( Kholodilov et al., 2004). This may have been related to the increased number of ventral tegmental area neurons surviving into adulthood in these mice. In general, additional research is needed to define which of these signaling and cell support molecules might be involved in more complex amphetamine reward-related traits. In addition, extension of the information on the effects of these mutations on brain circuitry underlying amphetamine sensitivity, neuroadaptation and reward would be particularly useful as the research community attempts to move toward a more comprehensive approach to genetic investigations (e.g., examining combined genetic effects and interactions), from a one-gene-at-a-time approach. Steroids and Other Peptides: Amphetamine & Methamphetamine ( Table 6) | Table 6Methamphetamine and amphetamine studies in steroid- and peptide-related single gene mutants. |
Amphetamine-related research involving single gene knockout or overexpression mutants for a diverse set of steroid- and other peptide-related genes is summarized in Table 6. This research area has not been extensive, and whether significant expansion is warranted will depend upon the significance of the initial results, and whether evidence from other approaches suggests the involvement of specific peptides in amphetamine-related traits. The cholecystokinin receptor 2 (CCK 2) and one of its associated ligands have been studied. Ventral tegmental area dopamine cells have been shown to express cholecystokinin ( Hokfelt et al., 1980), and cholecystokinin enhances dopamine-induced locomotor activity ( Crawley, 1992). Pretreatment with the CCK 2 receptor antagonist, L-365,260, was shown to have no effect on amphetamine-induced locomotor stimulation in one study ( Vasar et al., 1991), but enhanced the magnitude of this amphetamine effect in another ( Alttoa and Harro, 2004). Results from studies using KO mice were dose-dependent and present somewhat complicated results with regard to interpretation. Mice lacking functional CCK 2 receptors were less stimulated by 3 mg/kg amphetamine compared to WT mice, but more stimulated by 6 mg/kg amphetamine; a 1 mg/kg dose did not induce stimulation in either genotype ( Koks et al., 2001; 2003; Runkorg et al., 2006). L-365,260 has been shown to alter the development of behavioral sensitization to amphetamine; low doses increased sensitization while higher doses attenuated amphetamine-induced locomotor sensitization ( Wunderlich et al., 2000). CCK 2 receptor KO mice showed an enhanced magnitude of amphetamine-induced locomotor sensitization compared to WT mice ( Runkorg et al., 2006). These results would seem to agree most closely with the results using lower doses of L-365,260. Perhaps the specificity of the antagonist for the CCK 2 receptor is reduced at higher doses. Previous research has shown that infusion of cholecystokinin into the ventral tegmental area, which would presumably activate CCK 2 receptors, can enhance amphetamine-induced conditioned place preference ( Pettit and Mueller, 1989). Consistent with these findings, WT mice show enhanced amphetamine conditioned place preference compared to mice lacking CCK 2 receptors ( Runkorg et al., 2006). Gastrin also binds to CCK 2 receptors with agonist properties, and this peptide has been implicated in some amphetamine-related behaviors. Mutant mice lacking gastrin were less affected by amphetamine-induced disruption of prepulse inhibition compared to WT mice ( van den Buuse et al., 2005b). | Table 7Single gene mutant studies using methylphenidate. |
ADHD, or attention deficit hyperactivity disorder, is a psychiatric disorder that is diagnosed when patients present with hyperactivity (particularly motor hyperactivity), attention deficits, and impulsive behavior that supersedes normal daily functioning ( Himelstein et al., 2000). For over 50 years, this disorder has been treated with amphetamines, including methylphenidate ( Swanson et al., 1998). These drugs improve attention and decrease motor hyperactivity. Since methylphenidate is widely prescribed for this disorder, much of the research performed to understand the genetic basis of the behaviors caused by this drug has focused on alleviating ADHD-like symptoms. Results from studies examining the behavioral response to methylphenidate in genetically engineered mice are summarized in Table 7. Methylphenidate acts as an indirect dopamine agonist, having effects on the DAT. A number of studies have examined the role of naturally occurring DAT variants in the clinical response to methylphenidate, but results from these studies are not entirely consistent. While some studies show no difference in response to methylphenidate among groups of individuals with different DAT polymorphisms ( Mick et al., 2006; van der Meulen et al., 2005; Zeni et al., 2007), other studies have shown an association between DAT polymorphism and the response to methylphenidate, but not always in the same direction ( Cheon et al., 2005; Kirley et al., 2003; Roman et al., 2002; Winsberg and Comings, 1999). The DAT KO mouse has been examined for a number of behaviors. Mice lacking the DAT exhibit greater baseline locomotion than WT mice. When the mice were treated with methylphenidate they displayed a paradoxical response; WT mice showed the predicted stimulation after methylphenidate treatment, whereas mice lacking the DAT showed locomotor depression ( Gainetdinov et al., 1999). A similar paradoxical effect was observed when these mice were tested for PPI. Mice lacking the DAT displayed a reduced baseline PPI compared to WT mice. Methylphenidate (60 mg/kg) enhanced PPI in the DAT KO mice, but reduced this response in WT mice ( Yamashita et al., 2006). These data are consistent with motor symptoms in ADHD individuals. Therefore, the DAT KO mouse appears to model the motor aspects of this disorder, as well as the attentional aspects, given their reduced baseline PPI. In contrast, when tested for methylphenidate-induced conditioned place preference, mice of the two genotypes were equally sensitive ( Sora et al., 1998). ADHD co-occurs with generalized thyroid hormone resistance; 50-70% of patients with this thyroid condition meet the criteria for ADHD ( Hauser et al., 1993). Generalized thyroid hormone resistance is caused by a mutation in the human thyroid receptor-β gene, and is characterized by elevated levels of thyroid hormones in serum ( Mixson et al., 1992, Takeda et al., 1992). Because of the association between generalized thyroid hormone resistance and ADHD in the literature, mice carrying alterations in the thyroid receptor-β gene have been studied as a possible model of ADHD. Male knock-in mice carrying a mutated thyroid receptor-β allele from a patient who was diagnosed with both generalized thyroid hormone resistance and ADHD were less impaired by methylphenidate on a vigilance task compared to heterozygous or WT mice. Female mice were equally sensitive to this effect, regardless of genotype ( Siesser et al., 2005). The same mutated allele was used to create a pituitary specific transgenic mouse. When this transgenic mouse was tested, there were no observable differences in baseline locomotor activity, but male WT mice were more stimulated by methylphenidate compared to transgenic mice. Female transgenic and WT mice were equally sensitive ( Siesser et al., 2006). These data provide support for the involvement of the thyroid receptor-β in methylphenidate behaviors. Further work will be needed to fully dissect this relationship. | Table 8Single gene mutant studies using MDMA (methylenedioxymethamphetamine), also known as ecstasy. |
Most of the studies on MDMA using KO models have focused on the serotonin and dopamine systems, consistent with the known mechanism of action of MDMA. The serotonin system has been implicated in MDMA-induced locomotor activity. In rats, pretreatment with serotonin uptake inhibitors attenuated MDMA-induced locomotion ( Callaway et al., 1990). Similarly, in humans, pretreatment with the uptake inhibitor, fluoxetine, attenuated many of the subjective effects of MDMA including: elation, positive mood, arousal, and feeling high and stimulated ( Tancer and Johanson, 2007). These data are consistent with results from KO mice lacking the serotonin transporter gene. Mice lacking this gene were less stimulated by MDMA than were WT mice ( Bengel et al., 1998). The serotonin 1B subtype receptor in particular has been implicated in a number of MDMA-induced behaviors. This receptor can function as both an autoreceptor on serotonin neurons and as a postsynaptic receptor. The lack of specific agonists and antagonists for this receptor make the null mutant the best approach for examining its role. Compared to serotonin 1B KO mice, WT mice were more stimulated by MDMA, however mice of these genotypes did not differ in sensitivity to the depressant effects of MDMA on rearing behavior or nose pokes ( Scearce-Levie et al., 1999a, b). In contrast, the mutant mice were more sensitive to the stereotypic effect of MDMA compared to WT mice ( Scearce-Levie et al., 1999a). The serotonin 1B receptor has also been shown to be involved in the effect of MDMA on PPI. There were no baseline differences in magnitude of startle or PPI; however, mice lacking serotonin 1B receptors were less sensitive to the depressant effect of MDMA on startle magnitude compared to WT mice, and they exhibited greater sensitivity to the increase in PPI associated with MDMA treatment ( Dulawa et al., 2000). These data were interpreted as indicating that serotonin-induced activation of serotonin 1B receptors disrupts PPI. Pharmacological studies have implicated dopamine receptors in MDMA-induced locomotor stimulation. Haloperidol (a dopamine receptor antagonist that has high affinity for D 1, D 2, D 3, and D 4 receptors), eticlopride (a D 2 antagonist), and SCH-23390 (a D 1 antagonist), have all be shown to attenuate MDMA-induced locomotor stimulation ( Ball et al., 2003; Bubar et al., 2004; Kehne et al., 1996). In some, but not all, cases, data from mice carrying null mutations of one of the dopamine receptors have provided similar results. Consistent with the results of pharmacology studies, mice lacking D 2 or D 3 receptors were less sensitive to MDMA-induced stimulation compared to WT mice; some of these results were sex-specific. However, mice lacking the D 1A receptor were more stimulated by MDMA, a result that is opposite to the pharmacological antagonist result ( Risbrough et al., 2006). Inbred strain studies and selective breeding projects have confirmed that genetic variation influences relative sensitivity and neuroadaptation to amphetamine-like drugs, as reflected by behavioral trait measurements. Further, genetic correlations identified in selected lines have suggested some common genetic influences for different amphetamine effects and for some effects of amphetamine compared to those of other abused drugs. These data suggest that common neurobiological mechanisms can also be identified. Comparison of inbred strain behavioral and neurobiological variation is one approach that can provide convincing evidence for a particular mechanism, when very large inbred strain panels are used; the more common two to four strain comparisons will not provide a rigorous test of such relationships. Large strain panels have not often been used in psychostimulant drug research, although the work of Janowsky et al. (2001) which examined DAT density in a panel of recombinant inbred strains and correlated this with multiple behavioral traits serves as one example. As genome-wide sequence information for multiple inbred strains has increased, more direct genotype-phenotype, in silico mapping approaches (e.g., Grupe et al., 2001) are becoming feasible. Direct gene and gene expression co-mapping in selected lines (e.g., Palmer et al., 2005) also represents a more direct path to gene finding for complex, drug-related traits. As is apparent from the multiple tables in this review, many investigators have used mice with single gene manipulations to get at mechanisms associated with the behavioral effects of amphetamine-like drugs. Some of the mechanisms which had been previously identified using other techniques, such as pharmacological antagonism, were confirmed by analyses involving single gene mutant mice. However, some data arising from the use of such mice have suggested new targets for investigation as well. For example, not discussed above, but included in Table 9, are the results from investigations of the role of the trace amine 1 receptor (TA1) in amphetamine sensitivity ( Wolinsky et al., 2007). Trace amines can be synthesized from amines more abundant amines, such as phenylalanine or tyrisone, and are found in low concentrations in the brain. They have been suggested to play a role in some neuropsychiatric disorders, and amphetamines are potent agonists at TA1 receptors ( Bunzow et al., 2001; Wolinsky et al., 2007). TA1 KO mice showed altered sensitivity to the effects of amphetamine on locomotor behavior. Because this receptor is found in high concentrations in the amygdala and other limbic regions that are part of the drug reward circuitry (Borowsky et al., 2001; Bonzow et al., 2001), it is an exciting target for additional study into its influence on amphetamine-related traits. There are relatively few cases where a single gene mutant has been examined for the same behavioral response to more than one amphetamine-like drug. One case where this has occurred is with the serotonin 1B receptor mutant. Mice lacking this gene are more sensitive to the locomotor stimulant effects of methylphenidate ( Scearce-Levie et al., 1999a) and amphetamine ( Scearce-Levie et al., 1999a; Bronsert et al., 2001) than WT mice, but are less sensitive than WT mice to the stimulant effects of MDMA ( Scearce-Levie et al., 1999a, b). This is interesting because MDMA is more potent at inhibiting the serotonin transporter than the other amphetamines. DAT knockout mice have also been tested for their acute stimulant response to these three drugs. In general WT mice are stimulated by an acute injection of methylphenidate, MDMA, and amphetamine while KO mice are depressed by an acute injection of these drugs ( Gainetdinov et al., 1999; Powell et al., 2004; Spielewoy et al., 2001; Zhuang et al., 2001; but see Giros et al., 1996). Therefore, for this trait, the consequence of DAT KO had similar consequences across the three drugs. Finally, mu opioid receptor KO and WT mice have been tested for susceptibility to conditioned place preference induced by amphetamine (Marquez et al., 2007) and MDMA ( Robledo et al., 2004). Sensitivity of the WT and KO mice was equivalent for both drugs. An approach that examines the role of a particular gene for systematically measured traits, using equipotent drug doses, may provide important insights about differences in actions of these structurally related drugs for specific phenotypes. It has been pointed out many times that one advantage of the single gene mutation approach is specificity that may not exist with pharmacological antagonism. However, as we have argued previously, complete deletion of a major receptor or other critical protein could require massive developmental compensation for viability ( Crabbe et al., 2006). Thus, results may not be the same for an animal that has never possessed a given protein as for one in which the protein function is blocked or attenuated in adulthood. Development of conditional knockout and rescue methods offer the promise of better interpretability, but has not yet found wide usage ( Choi et al., 2002; Gaveriaux-Ruff and Kieffer, 2007). On the other hand, identification and study of the specific compensations occurring as a result of gene deletion can provide insight into the potential for functional redundancy in the developing nervous system. Some investigators have included heterozygous KO mice in their investigations. Sometimes this is for the practical reason that mice that are homozygous for a particular mutant allele are not viable. However, even when the homozygous KO is fully viable, this practice could serve to assuage concerns related to developmental compensations. An effect of a mutant allele may be seen in a heterozygous KO mouse in the absence of the more extreme developmental compensations that may occur in the homozygous KO. Further, it has been argued that because human disorders are more likely to be associated with genetic alterations resulting in reduced function, rather than complete loss of function, heterozygous mutants may be more relevant for study ( Kalueff et al., 2007). The combined information gained from studying all three genotypes could add important insights into the influence of the mutant allele on the trait in question. Gene mapping and expression analyses are beginning to identify specific genomic regions where genetic variation influences amphetamine-related responses. The ultimate goal of this research is to identify the specific genes that are involved and then determine their precise role in a given behavior. Due to the complexity of drug-related traits and their likely multigenic determination, this is a difficult, but not intractable, goal. However, gene mapping and expression analyses ask a somewhat different question than analyses with mutant animals. With the exception of overexpression transgenics and rare knockdown mutants, single gene mutants are engineered to possess a complete gene deletion. Thus, no functional protein is produced (however, see discussion of the use of heterozygote knockouts above). Gene mapping and expression analyses take advantage of existing polymorphisms which may represent differences in sequence that predict conformational changes in the protein. Thus, in at least some cases, more than one version of a protein may exist in a given population, with differing functional characteristics. Some sequence differences may result in altered gene expression. This relative difference in function or expression is likely to be markedly different than absent function and may be more representative of population-based genetic variation. However, there are also naturally occurring disease-related gene deletions that can be validly modeled in deletion mutants. QTL analysis can be validly defined as a non-hypothesis driven fishing expedition, unless one is satisfied with the general hypothesis that there are genes in specific regions of the genome that influence the behavioral trait under study. However, with the technological developments that have been seen in the past two decades, making genome-wide analysis more efficient and less costly, this approach can now be seen as a reasonable tool for hypothesis generation. Further, there are now many internet resources that allow more sophisticated genetic hypothesis generation. Trait x genotype correlations may point to specific genes that should be examined for drug-related responses. Utilization of this information provides a more thoughtful approach to identifying genes for examination than restricting research to the obvious candidates based on pharmacology and circuitry. However, we should not lose sight of environmental factors, which may act additively with genetic effects or interact with specific genes, in the determination of complex addiction-related traits. Even a simple factor like rearing from birth in all-male, all-female, or mixed-sex litters has been shown to influence an amphetamine response ( Cirulli et al., 1997). Further, the direction of effect of a stressor on the balance of dopamine systems can be influenced by past individual experiences ( Cabib et al., 2002). One might suspect that these factors would additionally interact with genetic differences in the determination of drug responses. In fact, Cabib et al. (2000) showed that strain differences in place conditioning and locomotor response to amphetamine were strongly affected by a forced period of food shortage. More work is needed that examines gene x environment interactions important in amphetamine addiction. In conclusion, at this time there is a large literature on responsiveness to amphetamines in single gene mutant mice, and considerably less information from more direct genetic approaches such as gene mapping, gene expression, or viral-mediated gene transfer. QTL mapping has identified genetic regions of interest and even some promising candidate genes. However, as we have argued previously, proof of a quantitative trait gene will require the careful assembly of evidence from multiple sources ( Belknap et al., 2001). To date, the largest body of literature on the genetics associated with amphetamine-related behavioral effects has focused on locomotor responses. There is a smattering of reports examining conditioned place preference, but no literature as yet examining the genetics of other reward-related traits such as self-administration, nor is there a literature on aversive effects other than stereotypy. There is also a need for genetic investigations into susceptibility to relapse/reinstatement. Yan et al. (2006) have shown that such investigations are not intractable in mice. We did not search the literature for studies examining differential genetic sensitivity to amphetamine-induced neurotoxicity that did not also measure behavior, but this would be another important area to pursue. In general, there is a great deal of work to be done in the quest for genes that influence the development and acceleration of amphetamine use, dependence, withdrawal, relapse, and toxicity. This chapter was written with the support of the Department of Veterans Affairs (TJP), P50 DA018165 (TJP), and F31 AA015822 (HMK). The authors would like to thank Dr. John Crabbe for his useful comments on an earlier version of this review. - Abeliovich A, Schmitz Y, Farinas I, Choi-Lundberg D, Ho WH, Castillo PE, Shinsky N, Verdugo JM, Armanini M, Ryan A, Hynes M, Phillips H, Sulzer D, Rosenthal A. Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron. 2000;25:239–252. [PubMed]
- Alexander RC, Wright R, Freed W. Quantitative trait loci contributing to phencyclidine-induced and amphetamine-induced locomotor behavior in inbred mice. Neuropsychopharmacology. 1996;15:484–490. [PubMed]
- Alttoa A, Harro J. Effect of CCK1 and CCK2 receptor blockade on amphetamine-stimulated exploratory behavior and sensitization to amphetamine. Eur Neuropsychopharmacol. 2004;14:324–331. [PubMed]
- Anglin MD, Burke C, Perrochet B, Stamper E, Dawud-Noursi S. History of the methamphetamine problem. J Psychoactive Drugs. 2000;32:137–141. [PubMed]
- Anisman H, Wahlsten D, Kokkinidis L. Effects of d-amphetamine and scopolamine on activity before and after shock in three mouse strains. Pharmacol Biochem Behav. 1975;3:819–824. [PubMed]
- Atkins AL, Helms ML, O'Toole LA, Belknap JK. Stereotypic behaviors in mice selectively bred for high and low methamphetamine-induced stereotypic chewing. Psychopharmacology (Berl). 2001;157:96–104. [PubMed]
- Auclair A, Cotecchia S, Glowinski J, Tassin JP. D-amphetamine fails to increase extracellular dopamine levels in mice lacking alpha 1b-adrenergic receptors: relationship between functional and nonfunctional dopamine release. J Neurosci. 2002;22:9150–9154. [PubMed]
- Auclair A, Drouin C, Cotecchia S, Glowinski J, Tassin JP. 5-HT2A and alpha1b-adrenergic receptors entirely mediate dopamine release, locomotor response and behavioural sensitization to opiates and psychostimulants. Eur J Neurosci. 2004;20:3073–3084. [PubMed]
- Backman C, You ZB, Perlmann T, Hoffer BJ. Elevated locomotor activity without altered striatal dopamine contents in Nurr1 heterozygous mice after acute exposure to methamphetamine. Behav Brain Res. 2003;143:95–100. [PubMed]
- Badiani A, Cabib S, Puglisi-Allegra S. Chronic stress induces strain-dependent sensitization to the behavioral effects of amphetamine in the mouse. Pharmacol Biochem Behav. 1992;43:53–60. [PubMed]
- Ball KT, Budreau D, Rebec GV. Acute effects of 3,4-methylenedioxymethamphetamine on striatal single-unit activity and behavior in freely moving rats: differential involvement of dopamine D(1) and D(2) receptors. Brain Res. 2003;994:203–215. [PubMed]
- Bartlett E, Hallin A, Chapman B, Angrist B. Selective sensitization to the psychosis-inducing effects of cocaine: a possible marker for addiction relapse vulnerability? Neuropsychopharmacology. 1997;16:77–82. [PubMed]
- Bastia E, Xu YH, Scibelli AC, Day YJ, Linden J, Chen JF, Schwarzschild MA. A crucial role for forebrain adenosine A(2A) receptors in amphetamine sensitization. Neuropsychopharmacology. 2005;30:891–900. [PubMed]
- Battaglia G, Fornai F, Busceti CL, Lembo G, Nicoletti F, De Blasi A. Alpha-1B adrenergic receptor knockout mice are protected against methamphetamine toxicity. J Neurochem. 2003;86:413–421. [PubMed]
- Beaulieu JM, Sotnikova TD, Marion S, Lefkowitz RJ, Gainetdinov RR, Caron MG. An Akt/β-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell. 2005;122:261–273. [PubMed]
- Beaulieu JM, Sotnikova TD, Yao WD, Kockeritz L, Woodgett JR, Gainetdinov RR, Caron MG. Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade. Proc Natl Acad Sci U S A. 2004;101:5099–5104. [PubMed]
- Belknap JK, Crabbe JC. Chromosome mapping of gene loci affecting morphine and amphetamine responses in BXD recombinant inbred mice. Ann N Y Acad Sci. 1992;654:311–323. [PubMed]
- Belknap JK, Hitzemann R, Crabbe JC, Phillips TJ, Buck KJ, Williams RW. QTL analysis and genomewide mutagenesis in mice: complementary genetic approaches to the dissection of complex traits. Behav Genet. 2001;31:5–15. [PubMed]
- Belknap JK, Richards SP, O'Toole LA, Helms ML, Phillips TJ. Short-term selective breeding as a tool for QTL mapping: ethanol preference drinking in mice. Behav Genet. 1997;27:55–66. [PubMed]
- Bengel D, Murphy DL, Andrews AM, Wichems CH, Feltner D, Heils A, Mossner R, Westphal H, Lesch KP. Altered brain serotonin homeostasis and locomotor insensitivity to 3, 4-methylenedioxymethamphetamine (“Ecstasy”) in serotonin transporter-deficient mice. Mol Pharmacol. 1998;53:649–655. [PubMed]
- Bergstrom HC, Palmer AA, Wood RD, Burkhart-Kasch S, McKinnon CS, Phillips TJ. Reverse selection for differential response to the locomotor stimulant effects of ethanol provides evidence for pleiotropic genetic influence on locomotor response to other drugs of abuse. Alcohol Clin Exp Res. 2003;27:1535–1547. [PubMed]
- Biala G, Betancur C, Mansuy IM, Giros B. The reinforcing effects of chronic D-amphetamine and morphine are impaired in a line of memory-deficient mice overexpressing calcineurin. Eur J Neurosci. 2005;21:3089–3096. [PubMed]
- Blanc G, Trovero F, Vezina P, Herve D, Godeheu AM, Glowinski J, Tassin JP. Blockade of prefronto-cortical alpha 1-adrenergic receptors prevents locomotor hyperactivity induced by subcortical D-amphetamine injection. Eur J Neurosci. 1994;6:293–298. [PubMed]
- Borgkvist A, Puelles E, Carta M, Acampora D, Ang SL, Wurst W, Goiny M, Fisone G, Simeone A, Usiello A. Altered dopaminergic innervation and amphetamine response in adult Otx2 conditional mutant mice. Mol Cell Neurosci. 2006;31:293–302. [PubMed]
- Braff DL, Swerdlow NR, Geyer MA. Gating and habituation deficits in the schizophrenia disorders. Clin Neurosci. 1995;3:131–139. [PubMed]
- Brandon EP, Logue SF, Adams MR, Qi M, Sullivan SP, Matsumoto AM, Dorsa DM, Wehner JM, McKnight GS, Idzerda RL. Defective motor behavior and neural gene expression in RIIbeta-protein kinase A mutant mice. J Neurosci. 1998;18:3639–3649. [PubMed]
- Bronsert MR, Mead AN, Hen R, Rocha BA. Amphetamine-induced locomotor activation in 5-HT(1B) knockout mice: effects of injection route on acute and sensitized responses. Behav Pharmacol. 2001;12:549–555. [PubMed]
- Brun P, Begou M, Andrieux A, Mouly-Badina L, Clerget M, Schweitzer A, Scarna H, Renaud B, Job D, Suaud-Chagny MF. Dopaminergic transmission in STOP null mice. J Neurochem. 2005;94:63–73. [PubMed]
- Bubar MJ, Pack KM, Frankel PS, Cunningham KA. Effects of dopamine D1- or D2-like receptor antagonists on the hypermotive and discriminative stimulus effects of (+)-MDMA. Psychopharmacology (Berl). 2004;173:326–336. [PubMed]
- Budygin EA, Brodie MS, Sotnikova TD, Mateo Y, John CE, Cyr M, Gainetdinov RR, Jones SR. Dissociation of rewarding and dopamine transporter-mediated properties of amphetamine. Proc Natl Acad Sci U S A. 2004;101:7781–7786. [PubMed]
- Bunzow JR, Sonders MS, Arttamangkul S, Harrison LM, Zhang G, Quigley DI, Darland T, Suchland KL, Pasumamula S, Kennedy JL, Olson SB, Magenis RE, Amara SG, Grandy DK. Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor. Mol Pharmacol. 2001;60:1181–1188. [PubMed]
- Cabib S. Strain-dependent behavioural sensitization to amphetamine: role of environmental influences. Behav Pharmacol. 1993;4:367–374. [PubMed]
- Cabib S, Orsini C, Le Moal M, Piazza PV. Abolition and reversal of strain differences in behavioral responses to drugs of abuse after a brief experience. Science. 2000;289:463–465. [PubMed]
- Cabib S, Ventura R, Puglisi-Allegra S. Opposite imbalances between mesocortical and mesoaccumbens dopamine responses to stress by the same genotype depending on living conditions. Behav Brain Res. 2002;129:179–185. [PubMed]
- Callaway CW, Wing LL, Geyer MA. Serotonin release contributes to the locomotor stimulant effects of 3,4-methylenedioxymethamphetamine in rats. J Pharmacol Exp Ther. 1990;254:456–464. [PubMed]
- Calzada BC, De Artinano AA. Alpha-adrenoceptor subtypes. Pharm Res. 2001;44:195–208.
- Camp DM, Browman KE, Robinson TE. The effects of methamphetamine and cocaine on motor behavior and extracellular dopamine in the ventral striatum of Lewis versus Fischer 344 rats. Brain Res. 1994;668:180–193. [PubMed]
- Chen JF, Beilstein M, Xu YH, Turner TJ, Moratalla R, Standaert DG, Aloyo VJ, Fink JS, Schwarzschild MA. Selective attenuation of psychostimulant-induced behavioral responses in mice lacking A(2A) adenosine receptors. Neuroscience. 2000;97:195–204. [PubMed]
- Chen JF, Fredduzzi S, Bastia E, Yu L, Moratalla R, Ongini E, Schwarzschild MA. Adenosine A2A receptors in neuroadaptation to repeated dopaminergic stimulation: implications for the treatment of dyskinesias in Parkinson's disease. Neurology. 2003a;61:S74–81. [PubMed]
- Chen JF, Moratalla R, Impagnatiello F, Grandy DK, Cuellar B, Rubinstein M, Beilstein MA, Hackett E, Fink JS, Low MJ, Ongini E, Schwarzschild MA. The role of the D(2) dopamine receptor (D(2)R) in A(2A) adenosine receptor (A(2A)R)-mediated behavioral and cellular responses as revealed by A(2A) and D(2) receptor knockout mice. Proc Natl Acad Sci U S A. 2001;98:1970–1975. [PubMed]
- Chen JF, Moratalla R, Yu L, Martin AB, Xu K, Bastia E, Hackett E, Alberti I, Schwarzschild MA. Inactivation of adenosine A2A receptors selectively attenuates amphetamine-induced behavioral sensitization. Neuropsychopharmacology. 2003b;28:1086–1095. [PubMed]
- Chen PC, Lao CL, Chen JC. Dual alteration of limbic dopamine D1 receptor-mediated signalling and the Akt/GSK3 pathway in dopamine D3 receptor mutants during the development of methamphetamine sensitization. J Neurochem. 2007;100:225–241. [PubMed]
- Cheon KA, Ryu YH, Kim JW, Cho DY. The homozygosity for 10-repeat allele at dopamine transporter gene and dopamine transporter density in Korean children with attention deficit hyperactivity disorder: relating to treatment response to methylphenidate. Eur Neuropsychopharmacol. 2005;15:95–101. [PubMed]
- Choi DS, Wang D, Dadgar J, Chang WS, Messing RO. Conditional rescue of protein kinase C epsilon regulates ethanol preference and hypnotic sensitivity in adult mice. J Neurosci. 2002;22:9905–9911. [PubMed]
- Cirulli F, Adriani W, Laviola G. Sexual segregation in infant mice: behavioural and neuroendocrine responses to d-amphetamine administration. Psychopharmacology (Berl). 1997;134:140–152. [PubMed]
- Coitinho AS, Dietrich MO, Hoffmann A, Dall'Igna OP, Souza DO, Martins VR, Brentani RR, Izquierdo I, Lara DR. Decreased hyperlocomotion induced by MK-801, but not amphetamine and caffeine in mice lacking cellular prion protein (PrP(C)). Brain Res Mol Brain Res. 2002;107:190–194. [PubMed]
- Colpaert FC, Wauquier A, Niemegeers C, Lal H. Reversal by a central antiacetylcholine drug of pimozide-induced inhibition of mouse-jumping in amphetamine-dopa treated mice. J Pharm Pharmacol. 1975;27:536–537. [PubMed]
- Cossu G, Ledent C, Fattore L, Imperato A, Bohme GA, Parmentier M, Fratta W. Cannabinoid CB1 receptor knockout mice fail to self-administer morphine but not other drugs of abuse. Behav Brain Res. 2001;118:61–65. [PubMed]
- Couceyro PR, Evans C, McKinzie A, Mitchell D, Dube M, Hagshenas L, White FJ, Douglass J, Richards WG, Bannon AW. Cocaine- and amphetamine-regulated transcript (CART) peptides modulate the locomotor and motivational properties of psychostimulants. J Pharmacol Exp Ther. 2005;315:1091–1100. [PubMed]
- Crabbe JC. Animal models in neurobehavioral genetics: Methods for estimating genetic correlation. In: Mormède P, Jones BC, editors. Neurobehavioral Genetics: Methods and Applications. CRC Press; Boca Raton, FL: 1999. pp. 121–138.
- Crabbe JC, Phillips TJ, Buck KJ, Cunningham CL, Belknap JK. Identifying genes for alcohol and drug sensitivity: recent progress and future directions. Trends Neurosci. 1999;22:173–179. [PubMed]
- Crabbe JC, Phillips TJ, Harris RA, Arends MA, Koob GF. Alcohol-related genes: contributions from studies with genetically engineered mice. Addict Biol. 2006;11:195–269. [PubMed]
- Crabbe JC, Phillips TJ, Kosobud A, Belknap JK. Estimation of genetic correlation: interpretation of experiments using selectively bred and inbred animals. Alcohol Clin Exp Res. 1990;14:141–151. [PubMed]
- Crabbe JC, Young ER, Deutsch CM, Tam BR, Kosobud A. Mice genetically selected for differences in open-field activity after ethanol. Pharmacol Biochem Behav. 1987;27:577–581. [PubMed]
- Crawford CA, Drago J, Watson JB, Levine MS. Effects of repeated amphetamine treatment on the locomotor activity of the dopamine D1A-deficient mouse. Neuroreport. 1997;8:2523–2527. [PubMed]
- Crawley JN. Subtype-selective cholecystokinin receptor antagonists block cholecystokinin modulation of dopamine-mediated behaviors in the rat mesolimbic pathway. J Neurosci. 1992;12:3380–3391. [PubMed]
- Cunningham CL, Phillips TJ. Genetic basis of ethanol reward. In: Maldonado R, editor. Molecular Biology of Drug Addiction. Humana Press, Inc; Totowa, NJ: 2003. pp. 263–294.
- Cyr M, Morissette M, Barden N, Beaulieu S, Rochford J, Di Paolo T. Dopaminergic activity in transgenic mice underexpressing glucocorticoid receptors: effect of antidepressants. Neuroscience. 2001;102:151–158. [PubMed]
- Dai H, Okuda T, Sakurai E, Kuramasu A, Kato M, Jia F, Xu AJ, Iinuma K, Sato I, Yanai K. Blockage of histamine H1 receptor attenuates social isolation-induced disruption of prepulse inhibition: a study in H1 receptor gene knockout mice. Psychopharmacology (Berl). 2005;183:285–293. [PubMed]
- Davidson C, Gow AJ, Lee TH, Ellinwood EH. Methamphetamine neurotoxicity: necrotic and apoptotic mechanisms and relevance to human abuse and treatment. Brain Res Brain Res Rev. 2001;36:1–22. [PubMed]
- Davidson ES, Finch JF, Schenk S. Variability in subjective responses to cocaine: initial experiences of college students. Addict Behav. 1993;18:445–453. [PubMed]
- de Wit H, Uhlenhuth EH, Johanson CE. Individual differences in the reinforcing and subjective effects of amphetamine and diazepam. Drug Alcohol Depend. 1986;16:341–360. [PubMed]
- Del Arco A, Gonzalez-Mora JL, Armas VR, Mora F. Amphetamine increases the extracellular concentration of glutamate in striatum of the awake rat: involvement of high affinity transporter mechanisms. Neuropharmacology. 1999;38:943–954. [PubMed]
- Del Arco A, Mora F, Mohammed AH, Fuxe K. Stimulation of D2 receptors in the prefrontal cortex reduces PCP-induced hyperactivity, acetylcholine release and dopamine metabolism in the nucleus accumbens. J Neural Transm. 2007;114:185–193. [PubMed]
- Deutsch SI, Rosse RB, Paul SM, Riggs RL, Mastropaolo J. Inbred mouse strains differ in sensitivity to “popping” behavior elicited by MK-801. Pharmacol Biochem Behav. 1997;57:315–317. [PubMed]
- Dluzen DE, Gao X, Story GM, Anderson LI, Kucera J, Walro JM. Evaluation of nigrostriatal dopaminergic function in adult +/+ and +/− BDNF mutant mice. Exp Neurol. 2001;170:121–128. [PubMed]
- Douglass J, McKinzie AA, Couceyro P. PCR differential display identifies a rat brain mRNA that is transcriptionally regulated by cocaine and amphetamine. J Neurosci. 1995;15:2471–2481. [PubMed]
- Dracheva S, Xu M, Kelley KA, Haroutunian V, Holstein GR, Haun S, Silverstein JH, Sealfon SC. Paradoxical locomotor behavior of dopamine D1 receptor transgenic mice. Exp Neurol. 1999;157:169–179. [PubMed]
- Draski LJ, Nash DJ, Gerhardt GA. CNS monoamine levels and motoric behaviors in the hotfoot ataxic mutant. Brain Res. 1994;645:69–77. [PubMed]
- Drouin C, Darracq L, Trovero F, Blanc G, Glowinski J, Cotecchia S, Tassin JP. Alpha1b-adrenergic receptors control locomotor and rewarding effects of psychostimulants and opiates. J Neurosci. 2002;22:2873–2884. [PubMed]
- Dulawa SC, Scearce-Levie KA, Hen R, Geyer MA. Serotonin releasers increase prepulse inhibition in serotonin 1B knockout mice. Psychopharmacology (Berl). 2000;149:306–312. [PubMed]
- Eells JB, Lipska BK, Yeung SK, Misler JA, Nikodem VM. Nurr1-null heterozygous mice have reduced mesolimbic and mesocortical dopamine levels and increased stress-induced locomotor activity. Behav Brain Res. 2002;136:267–275. [PubMed]
- Eilam R, Peter Y, Elson A, Rotman G, Shiloh Y, Groner Y, Segal M. Selective loss of dopaminergic nigro-striatal neurons in brains of Atm-deficient mice. Proc Natl Acad Sci U S A. 1998;95:12653–12656. [PubMed]
- Elmer GI, Pieper JO, Levy J, Rubinstein M, Low MJ, Grandy DK, Wise RA. Brain stimulation and morphine reward deficits in dopamine D2 receptor-deficient mice. Psychopharmaoclogy. 2005;182:33–44.
- Eshleman AJ, Carmolli M, Cumbay M, Martens CR, Neve KA, Janowsky A. Characteristics of drug interactions with recombinant biogenic amine transporters expressed in the same cell type. J Pharmacol Exp Ther. 1999;289:877–885. [PubMed]
- Falconer DS, Mackay TFC. Introduction to Quantitative Genetics. Prentice Hall; Essex, England: 1996.
- Ferraro TN, Golden GT, Smith GG, Martin JF, Schwebel CL, Doyle GA, Buono RJ, Berrettini WH. Confirmation of a major QTL influencing oral morphine intake in C57 and DBA mice using reciprocal congenic strains. Neuropsychopharmacology. 2005;30:742–746. [PubMed]
- Fetsko LA, Xu R, Wang Y. Alterations in D1/D2 synergism may account for enhanced stereotypy and reduced climbing in mice lacking dopamine D2L receptor. Brain Res. 2003;967:191–200. [PubMed]
- Fleming SM, Salcedo J, Hutson CB, Rockenstein E, Masliah E, Levine MS, Chesselet MF. Behavioral effects of dopaminergic agonists in transgenic mice overexpressing human wildtype alpha-synuclein. Neuroscience. 2006;142:1245–1253. [PubMed]
- Flores C, Manitt C, Rodaros D, Thompson KM, Rajabi H, Luk KC, Tritsch NX, Sadikot AF, Stewart J, Kennedy TE. Netrin receptor deficient mice exhibit functional reorganization of dopaminergic systems and do not sensitize to amphetamine. Mol Psychiatry. 2005;10:606–612. [PubMed]
- Florin SM, Kuczenski R, Segal DS. Regional extracellular norepinephrine responses to amphetamine and cocaine and effects of clonidine pretreatment. Brain Res. 1994;654:53–62. [PubMed]
- Fumagalli F, Gainetdinov RR, Valenzano KJ, Caron MG. Role of dopamine transporter in methamphetamine-induced neurotoxicity: evidence from mice lacking the transporter. J Neurosci. 1998;18:4861–4869. [PubMed]
- Fumagalli F, Gainetdinov RR, Wang YM, Valenzano KJ, Miller GW, Caron MG. Increased methamphetamine neurotoxicity in heterozygous vesicular monoamine transporter 2 knock-out mice. J Neurosci. 1999;19:2424–2431. [PubMed]
- Gabbay FH. Variations in affect following amphetamine and placebo: markers of stimulant drug preference. Exp Clin Psychopharmacol. 2003;11:91–101. [PubMed]
- Gainetdinov RR, Bohn LM, Sotnikova TD, Cyr M, Laakso A, Macrae AD, Torres GE, Kim KM, Lefkowitz RJ, Caron MG, Premont RT. Dopaminergic supersensitivity in G protein-coupled receptor kinase 6-deficient mice. Neuron. 2003;38:291–303. [PubMed]
- Gainetdinov RR, Wetsel WC, Jones SR, Levin ED, Jaber M, Caron MG. Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity. Science. 1999;283:397–401. [PubMed]
- Gaveriaux-Ruff C, Kieffer BL. Conditional gene targeting in the mouse nervous system: Insights into brain function and diseases. Pharmacol Ther. 2007;113:619–634. [PubMed]
- George FR, Porrino LJ, Ritz MC, Goldberg SR. Inbred rat strain comparisons indicate different sites of action for cocaine and amphetamine locomotor stimulant effects. Psychopharmacology (Berl). 1991;104:457–462. [PubMed]
- Gerber DJ, Sotnikova TD, Gainetdinov RR, Huang SY, Caron MG, Tonegawa S. Hyperactivity, elevated dopaminergic transmission, and response to amphetamine in M1 muscarinic acetylcholine receptor-deficient mice. Proc Natl Acad Sci U S A. 2001;98:15312–15317. [PubMed]
- Gill KJ, Boyle AE. Confirmation of quantitative trait loci for cocaine-induced activation in the AcB/BcA series of recombinant congenic strains. Pharmacogenetics. 2003;13:329–338. [PubMed]
- Giros B, Jaber M, Jones SR, Wightman RM, Caron MG. Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature. 1996;379:606–612. [PubMed]
- Glickstein SB, Schmauss C. Effect of methamphetamine on cognition and repetitive motor behavior of mice deficient for dopamine D2 and D3 receptors. Ann N Y Acad Sci. 2004a;1025:110–118. [PubMed]
- Glickstein SB, Schmauss C. Focused motor stereotypies do not require enhanced activation of neurons in striosomes. J Comp Neurol. 2004b;469:227–238. [PubMed]
- Golembiowska K, Konieczny J, Wolfarth S, Ossowska K. Neuroprotective action of MPEP, a selective mGluR5 antagonist, in methamphetamine-induced dopaminergic neurotoxicity is associated with a decrease in dopamine outflow and inhibition of hyperthermia in rats. Neuropharmacology. 2003;45:484–492. [PubMed]
- Gora-Maslak G, McClearn GE, Crabbe JC, Phillips TJ, Belknap JK, Plomin R. Use of recombinant inbred strains to identify quantitative trait loci in psychopharmacology. Psychopharmacology (Berl). 1991;104:413–424. [PubMed]
- Gould TJ, Keith RA, Bhat RV. Differential sensitivity to lithium's reversal of amphetamine-induced open-field activity in two inbred strains of mice. Behav Brain Res. 2001;118:95–105. [PubMed]
- Green AR, Mechan AO, Elliott JM, O'Shea E, Colado MI. The pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”). Pharmacol Rev. 2003;55:463–508. [PubMed]
- Greengard P. The neurobiology of slow synaptic transmission. Science. 2001;294:1024–1030. [PubMed]
- Grisel JE, Belknap JK, O'Toole LA, Helms ML, Wenger CD, Crabbe JC. Quantitative trait loci affecting methamphetamine responses in BXD recombinant inbred mouse strains. J Neurosci. 1997;17:745–754. [PubMed]
- Grupe A, Germer S, Usuka J, Aud D, Belknap JK, Klein RF, Ahluwalia MK, Higuchi R, Peltz G. In silico mapping of complex disease-related traits in mice. Science. 2001;292:1915–1918. [PubMed]
- Hahn CG, Wang HY, Cho DS, Talbot K, Gur RE, Berrettini WH, Bakshi K, Kamins J, Borgmann-Winter KE, Siegel SJ, Gallop RJ, Arnold SE. Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nat Med. 2006;12:824–828. [PubMed]
- Hall FS, Sora I, Drgonova J, Li XF, Goeb M, Uhl GR. Molecular mechanisms underlying the rewarding effects of cocaine. Ann N Y Acad Sci. 2004;1025:47–56. [PubMed]
- Hamburger-Bar R, Robert M, Newman M, Belmaker RH. Interstrain correlation between behavioural effects of lithium and effects on cortical cyclic AMP. Pharmacol Biochem Behav. 1986;24:9–13. [PubMed]
- Han DD, Gu HH. Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs. BMC Pharmacol. 2006;6:6. [PubMed]
- Hanania T, Zahniser NR. Locomotor activity induced by noncompetitive NMDA receptor antagonists versus dopamine transporter inhibitors: opposite strain differences in inbred long-sleep and short-sleep mice. Alcohol Clin Exp Res. 2002;26:431–440. [PubMed]
- Hauser P, Zametkin AJ, Martinez P, Vitiello B, Matochik JA, Mixson AJ, Weintraub BD. Attention deficit-hyperactivity disorder in people with generalized resistance to thyroid hormone. N Engl J Med. 1993;328:997–1001. [PubMed]
- Heath AC, Whitfield JB, Madden PA, Bucholz KK, Dinwiddie SH, Slutske WS, Bierut LJ, Statham DB, Martin NG. Towards a molecular epidemiology of alcohol dependence: analysing the interplay of genetic and environmental risk factors. Br J Psychiatry Suppl. 2001;40:s33–40. [PubMed]
- Herve D, Le Moine C, Corvol JC, Belluscio L, Ledent C, Fienberg AA, Jaber M, Studler JM, Girault JA. Galpha(olf) levels are regulated by receptor usage and control dopamine and adenosine action in the striatum. J Neurosci. 2001;21:4390–4399. [PubMed]
- Hess EJ, Collins KA, Wilson MC. Mouse model of hyperkinesis implicates SNAP-25 in behavioral regulation. J Neurosci. 1996;16:3104–3111. [PubMed]
- Heusner CL, Palmiter RD. Expression of mutant NMDA receptors in dopamine D1 receptor-containing cells prevents cocaine sensitization and decreases cocaine preference. J Neurosci. 2005;25:6651–6657. [PubMed]
- Himelstein J, Newcorn JH, Halperin JM. The neurobiology of attention-deficit hyperactivity disorder. Front Biosci. 2000;5:D461–478. [PubMed]
- Hokfelt T, Rehfeld JF, Skirboll L, Ivemark B, Goldstein M, Markey K. Evidence for coexistence of dopamine and CCK in meso-limbic neurones. Nature. 1980;285:476–478. [PubMed]
- Holdstock L, King AC, de Wit H. Subjective and objective responses to ethanol in moderate/heavy and light social drinkers. Alcohol Clin Exp Res. 2000;24:789–794. [PubMed]
- Houchi H, Babovic D, Pierrefiche O, Ledent C, Daoust M, Naassila M. CB1 receptor knockout mice display reduced ethanol-induced conditioned place preference and increased striatal dopamine D2 receptors. Neuropsychopharmacology. 2005;30:339–349. [PubMed]
- Huotari M, Garcia-Horsman JA, Karayiorgou M, Gogos JA, Mannisto PT. D-amphetamine responses in catechol-O-methyltransferase (COMT) disrupted mice. Psychopharmacology (Berl). 2004;172:1–10. [PubMed]
- Ihalainen JA, Tanila H, Scheinin M, Riekkinen P., Jr. alpha(2C)-Adrenoceptors modulate the effect of methylphenidate on response rate and discrimination accuracy in an operant test. Brain Res Bull. 2001;54:553–557. [PubMed]
- Ishiguro H, Liu QR, Gong JP, Hall FS, Ujike H, Morales M, Sakurai T, Grumet M, Uhl GR. NrCAM in addiction vulnerability: positional cloning, drug-regulation, haplotype-specific expression, and altered drug reward in knockout mice. Neuropsychopharmacology. 2006;31:572–584. [PubMed]
- Itier JM, Ibanez P, Mena MA, Abbas N, Cohen-Salmon C, Bohme GA, Laville M, Pratt J, Corti O, Pradier L, Ret G, Joubert C, Periquet M, Araujo F, Negroni J, Casarejos MJ, Canals S, Solano R, Serrano A, Gallego E, Sanchez M, Denefle P, Benavides J, Tremp G, Rooney TA, Brice A, Garcia de Yebenes J. Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse. Hum Mol Genet. 2003;12:2277–2291. [PubMed]
- Itzhak Y, Ali SF. Behavioral consequences of methamphetamine-induced neurotoxicity in mice: relevance to the psychopathology of methamphetamine addiction. Ann N Y Acad Sci. 2002;965:127–135. [PubMed]
- Itzhak Y, Anderson KL, Ali SF. Differential response of nNOS knockout mice to MDMA (“ecstasy”)- and methamphetamine-induced psychomotor sensitization and neurotoxicity. Ann N Y Acad Sci. 2004;1025:119–128. [PubMed]
- Itzhak Y, Gandia C, Huang PL, Ali SF. Resistance of neuronal nitric oxide synthase-deficient mice to methamphetamine-induced dopaminergic neurotoxicity. J Pharmacol Exp Ther. 1998;284:1040–1047. [PubMed]
- Itzhak Y, Martin JL, Ali SF. Comparison between the role of the neuronal and inducible nitric oxide synthase in methamphetamine-induced neurotoxicity and sensitization. Ann N Y Acad Sci. 2000;914:104–111. [PubMed]
- Iwabuchi K, Kubota Y, Ito C, Watanabe T, Watanabe T, Yanai K. Methamphetamine and brain histamine: a study using histamine-related gene knockout mice. Ann N Y Acad Sci. 2004;1025:129–134. [PubMed]
- Jackson A, Mead AN, Stephens DN. Behavioural effects of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate-receptor antagonists and their relevance to substance abuse. Pharmacol Ther. 2000;88:59–76. [PubMed]
- Janowsky A, Mah C, Johnson RA, Cunningham CL, Phillips TJ, Crabbe JC, Eshleman AJ, Belknap JK. Mapping genes that regulate density of dopamine transporters and correlated behaviors in recombinant inbred mice. J Pharmacol Exp Ther. 2001;298:634–643. [PubMed]
- Jinnah HA, Gage FH, Friedmann T. Amphetamine-induced behavioral phenotype in a hypoxanthine-guanine phosphoribosyltransferase-deficient mouse model of Lesch-Nyhan syndrome. Behav Neurosci. 1991;105:1004–1012. [PubMed]
- Jinnah HA, Langlais PJ, Friedmann T. Functional analysis of brain dopamine systems in a genetic mouse model of Lesch-Nyhan syndrome. J Pharmacol Exp Ther. 1992;263:596–607. [PubMed]
- Jones S, Bonci A. Synaptic plasticity and drug addiction. Curr Opin Pharmacol. 2005;5:20–25. [PubMed]
- Juhila J, Honkanen A, Sallinen J, Haapalinna A, Korpi ER, Scheinin M. alpha(2A)-Adrenoceptors regulate d-amphetamine-induced hyperactivity and behavioural sensitization in mice. Eur J Pharmacol. 2005;517:74–83. [PubMed]
- Kahlig KM, Binda F, Khoshbouei H, Blakely RD, McMahon DG, Javitch JA, Galli A. Amphetamine induces dopamine efflux through a dopamine transporter channel. Proc Natl Acad Sci U S A. 2005;102:3495–3500. [PubMed]
- Kalueff AV, Ren-Patterson RF, Murphy DL. The developing use of heterozygous mutant mouse models in brain monoamine transporter research. Trends Pharmacol Sci. 2007;28:122–127. [PubMed]
- Kamens HM, Burkhart-Kasch S, McKinnon CS, Li N, Reed C, Phillips TJ. Sensitivity to psychostimulants in mice bred for high and low stimulation to methamphetamine. Genes Brain Behav. 2005;4:110–125. [PubMed]
- Kamens HM, Burkhart-Kasch S, McKinnon CS, Li N, Reed C, Phillips TJ. Ethanol-related traits in mice selectively bred for differential sensitivity to methamphetamine-induced activation. Behav Neurosci. 2006;120:1356–1366. [PubMed]
- Karler R, Finnegan KT, Calder LD. Blockade of behavioral sensitization to cocaine and amphetamine by inhibitors of protein synthesis. Brain Res. 1993;603:19–24. [PubMed]
- Karper PE, De la Rosa H, Newman ER, Krall CM, Nazarian A, McDougall SA, Crawford CA. Role of D1-like receptors in amphetamine-induced behavioral sensitization: a study using D1A receptor knockout mice. Psychopharmacology (Berl). 2002;159:407–414. [PubMed]
- Kehne JH, Ketteler HJ, McCloskey TC, Sullivan CK, Dudley MW, Schmidt CJ. Effects of the selective 5-HT2A receptor antagonist MDL 100,907 on MDMA-induced locomotor stimulation in rats. Neuropsychopharmacology. 1996;15:116–124. [PubMed]
- Kest B, Palmese CA, Hopkins E, Adler M, Juni A, Mogil JS. Naloxone-precipitated withdrawal jumping in 11 inbred mouse strains: evidence for common genetic mechanisms in acute and chronic morphine physical dependence. Neuroscience. 2002;115:463–469. [PubMed]
- Kholodilov N, Yarygina O, Oo TF, Zhang H, Sulzer D, Dauer W, Burke RE. Regulation of the development of mesencephalic dopaminergic systems by the selective expression of glial cell line-derived neurotrophic factor in their targets. J Neurosci. 2004;24:3136–3146. [PubMed]
- Kieffer BL, Gaveriaux-Ruff C. Exploring the opioid system by gene knockout. Prog Neurobiol. 2002;66:285–306. [PubMed]
- Kim RH, Smith PD, Aleyasin H, Hayley S, Mount MP, Pownall S, Wakeham A, YouTen AJ, Kalia SK, Horne P, Westaway D, Lozano AM, Anisman H, Park DS, Mak TW. Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress. Proc Natl Acad Sci U S A. 2005;102:5215–5220. [PubMed]
- Kimmel HL, Gong W, Vechia SD, Hunter RG, Kuhar MJ. Intra-ventral tegmental area injection of rat cocaine and amphetamine-regulated transcript peptide 55-102 induces locomotor activity and promotes conditioned place preference. J Pharmacol Exp Ther. 2000;294:784–792. [PubMed]
- King AC, Houle T, de Wit H, Holdstock L, Schuster A. Biphasic alcohol response differs in heavy versus light drinkers. Alcohol Clin Exp Res. 2002;26:827–835. [PubMed]
- Kirley A, Lowe N, Hawi Z, Mullins C, Daly G, Waldman I, McCarron M, O'Donnell D, Fitzgerald M, Gill M. Association of the 480 bp DAT1 allele with methylphenidate response in a sample of Irish children with ADHD. Am J Med Genet B Neuropsychiatr Genet. 2003;121:50–54. [PubMed]
- Kitahama K, Valatx JL. Strain differences in amphetamine sensitivity in mice. I. A diallel analysis of open field activity. Psychopharmacology (Berl). 1979;66:189–194. [PubMed]
- Kliethermes CL, Kamens HM, Crabbe JC. Drug reward and intake in lines of mice selectively bred for divergent exploration of a hole board apparatus. Genes Brain Behav. 2007;6:608–618. [PubMed]
- Koks S, Abramov U, Veraksits A, Bourin M, Matsui T, Vasar E. CCK2 receptor-deficient mice have increased sensitivity of dopamine D2 receptors. Neuropeptides. 2003;37:25–29. [PubMed]
- Koks S, Volke V, Veraksits A, Runkorg K, Sillat T, Abramov U, Bourin M, Huotari M, Mannisto PT, Matsui T, Vasar E. Cholecystokinin2 receptor-deficient mice display altered function of brain dopaminergic system. Psychopharmacology (Berl). 2001;158:198–204. [PubMed]
- Koob GF, Le Moal M. Neurobiology of Addiction. Academic Press; San Diego, CA: 2006.
- Koshimizu TA, Tanoue A, Hirasawa A, Yamauchi J, Tsujimoto G. Recent advances in alpha1-adrenoceptor pharmacology. Pharmacol Ther. 2003;98:235–244. [PubMed]
- Kruzich PJ, Suchland KL, Grandy DK. Dopamine D4 receptor-deficient mice, congenic on the C57BL/6J background, are hypersensitive to amphetamine. Synapse. 2004;53:131–139. [PubMed]
- Kubota Y, Ito C, Sakurai E, Sakurai E, Watanabe T, Ohtsu H. Increased methamphetamine-induced locomotor activity and behavioral sensitization in histamine-deficient mice. J Neurochem. 2002;83:837–845. [PubMed]
- Kuo DY, Inui A, Cheng JT. Effect of amphetamine repeated treatment on the feeding behavior in neuropeptide Y-overexpressing mice. Neurosci Lett. 2002;329:359–361. [PubMed]
- Kuribara H. Effects of interdose interval on ambulatory sensitization to methamphetamine, cocaine and morphine in mice. Eur J Pharmacol. 1996;316:1–5. [PubMed]
- Kurose H, Regan JW, Caron MG, Lefkowitz RJ. Functional interactions of recombinant alpha 2 adrenergic receptor subtypes and G proteins in reconstituted phospholipid vesicles. Biochemistry. 1991;30:3335–3341. [PubMed]
- Kuteeva E, Hokfelt T, Ogren SO. Behavioural characterisation of transgenic mice overexpressing galanin under the PDGF-B promoter. Neuropeptides. 2005a;39:299–304. [PubMed]
- Kuteeva E, Hokfelt T, Ogren SO. Behavioural characterisation of young adult transgenic mice overexpressing galanin under the PDGF-B promoter. Regul Pept. 2005b;125:67–78. [PubMed]
- Laakso A, Mohn AR, Gainetdinov RR, Caron MG. Experimental genetic approaches to addiction. Neuron. 2002;36:213–228. [PubMed]
- Labarca C, Schwarz J, Deshpande P, Schwarz S, Nowak MW, Fonck C, Nashmi R, Kofuji P, Dang H, Shi W, Fidan M, Khakh BS, Chen Z, Bowers BJ, Boulter J, Wehner JM, Lester HA. Point mutant mice with hypersensitive alpha 4 nicotinic receptors show dopaminergic deficits and increased anxiety. Proc Natl Acad Sci U S A. 2001;98:2786–2791. [PubMed]
- Lahdesmaki J, Sallinen J, MacDonald E, Scheinin M. Alpha2A-adrenoceptors are important modulators of the effects of D-amphetamine on startle reactivity and brain monoamines. Neuropsychopharmacology. 2004;29:1282–1293. [PubMed]
- Lal H, Colpaert FC, Laduron P. Narcotic withdrawal like mouse jumping produced by amphetamine and L-DOPA. Eur J Pharmacol. 1975;30:113–116. [PubMed]
- Lal H, Marky M, Fielding S. Effect of neuroleptic drugs on mouse jumping induced by L-DOPA in amphetamine treated mice. Neuropharmacology. 1976;15:669–671. [PubMed]
- Maldonado E, Navarro JF. MDMA (“ecstasy”) exhibits an anxiogenic-like activity in social encounters between male mice. Pharmacol Res. 2001;44:27–31. [PubMed]
- Mao L, Conquet F, Wang JQ. Augmented motor activity and reduced striatal preprodynorphin mRNA induction in response to acute amphetamine administration in metabotropic glutamate receptor 1 knockout mice. Neuroscience. 2001;106:303–312. [PubMed]
- Marazziti D, Golini E, Mandillo S, Magrelli A, Witke W, Matteoni R, Tocchini-Valentini GP. Altered dopamine signaling and MPTP resistance in mice lacking the Parkinson's disease-associated GPR37/parkin-associated endothelin-like receptor. Proc Natl Acad Sci U S A. 2004;101:10189–10194. [PubMed]
- Marley RJ, Arros DM, Henricks KK, Marley ME, Miner LL. Sensitivity to cocaine and amphetamine among mice selectively bred for differential cocaine sensitivity. Psychopharmacology (Berl). 1998;140:42–51. [PubMed]
- McCann UD, Wong DF, Yokoi F, Villemagne V, Dannals RF, Ricaurte GA. Reduced striatal dopamine transporter density in abstinent methamphetamine and methcathinone users: evidence from positron emission tomography studies with [11C]WIN-35,428. J Neurosci. 1998;18:8417–8422. [PubMed]
- McDougall SA, Reichel CM, Cyr MC, Karper PE, Nazarian A, Crawford CA. Importance of D(1) receptors for associative components of amphetamine-induced behavioral sensitization and conditioned activity: a study using D(1) receptor knockout mice. Psychopharmacology (Berl). 2005;183:20–30. [PubMed]
- McKerchar TL, Zarcone TJ, Fowler SC. Use of a force-plate actometer for detecting and quantifying vertical leaping induced by amphetamine in BALB/cJ mice, but not in C57BL/6J, DBA/2J, 129X1/SvJ, C3H/HeJ, and CD-1 mice. J Neurosci Methods. 2006;153:48–54. [PubMed]
- McNamara RK, Logue A, Stanford K, Xu M, Zhang J, Richtand NM. Dose-response analysis of locomotor activity and stereotypy in dopamine D3 receptor mutant mice following acute amphetamine. Synapse. 2006;60:399–405. [PubMed]
- Mead AN, Stephens DN. Involvement of AMPA receptor GluR2 subunits in stimulus-reward learning: evidence from glutamate receptor gria2 knock-out mice. J Neurosci. 2003;23:9500–9507. [PubMed]
- Mick E, Biederman J, Spencer T, Faraone SV, Sklar P. Absence of association with DAT1 polymorphism and response to methylphenidate in a sample of adults with ADHD. Am J Med Genet B Neuropsychiatr Genet. 2006;141:890–894. [PubMed]
- Miserendino MJ, Haile CN, Kosten TA. Strain differences in response to escapable and inescapable novel environments and their ability to predict amphetamine-induced locomotor activity. Psychopharmacology (Berl). 2003;167:281–290. [PubMed]
- Mixson AJ, Parrilla R, Ransom SC, Wiggs EA, McClaskey JH, Hauser P, Weintraub BD. Correlations of language abnormalities with localization of mutations in the beta-thyroid hormone receptor in 13 kindreds with generalized resistance to thyroid hormone: identification of four new mutations. J Clin Endocrinol Metab. 1992;75:1039–1045. [PubMed]
- Miyamoto S, Snouwaert JN, Koller BH, Moy SS, Lieberman JA, Duncan GE. Amphetamine-induced Fos is reduced in limbic cortical regions but not in the caudate or accumbens in a genetic model of NMDA receptor hypofunction. Neuropsychopharmacology. 2004a;29:2180–2188. [PubMed]
- Miyamoto Y, Yamada K, Nagai T, Mori H, Mishina M, Furukawa H, Noda Y, Nabeshima T. Behavioural adaptations to addictive drugs in mice lacking the NMDA receptor epsilon1 subunit. Eur J Neurosci. 2004b;19:151–158. [PubMed]
- Moffett M, Stanek L, Harley J, Rogge G, Asnicar M, Hsiung H, Kuhar M. Studies of cocaine- and amphetamine-regulated transcript (CART) knockout mice. Peptides. 2006;27:2037–2045. [PubMed]
- Mogenson GJ, Jones DL, Yim CY. From motivation to action: functional interface between the limbic system and the motor system. Prog Neurobiol. 1980;14:69–97. [PubMed]
- Mohammed AK, Danysz W, Ogren SO, Archer T. Central noradrenaline depletion attenuates amphetamine-induced locomotor behavior. Neurosci Lett. 1986;64:139–144. [PubMed]
- Moisset B. Genetic analysis of the behavioral response to d-amphetamine in mice. Psychopharmacology (Berl). 1977;53:269–276. [PubMed]
- Moisset B, Welch BL. Effects of d-amphetamine upon open field behaviour in two inbred strains of mice. Experientia. 1973;29:625–626. [PubMed]
- Mori A, Okuyama K, Horie M, Taniguchi Y, Wadatsu T, Nishino N, Shimada Y, Miyazawa N, Takeda S, Niimi M, Kyushiki H, Kondo M, Mitsumoto Y. Alteration of methamphetamine-induced striatal dopamine release in mint-1 knockout mice. Neurosci Res. 2002;43:251–257. [PubMed]
- Morio A, Ujike H, Nomura A, Tanaka Y, Morita Y, Otani K, Kishimoto M, Harano M, Inada T, Komiyama T, Yamada M, Sekine Y, Iwata N, Iyo M, Sora I, Ozaki N, Kuroda S. No association between CART (cocaine- and amphetamine-regulated transcript) gene and methamphetamine dependence. Ann N Y Acad Sci. 2006;1074:411–417. [PubMed]
- Mueller K, Saboda S, Palmour R, Nyhan WL. Self-injurious behavior produced in rats by daily caffeine and continuous amphetamine. Pharmacol Biochem Behav. 1982;17:613–617. [PubMed]
- Nabeshima T, Itoh A, Kobayashi K, Morita S, Mizuguchi T, Sawada H, Nitta A, Hasegawa T, Hayashi K, Nagatsu T. Effects of subacute administration of methamphetamine and nicotine on locomotor activity in transgenic mice expressing the human tyrosine hydroxylase gene. J Neural Transm Gen Sect. 1994;97:41–49. [PubMed]
- Nadeau JH, Frankel WN. The roads from phenotypic variation to gene discovery: mutagenesis versus QTLs. Nat Genet. 2000;25:381–384. [PubMed]
- Nagai T, Noda Y, Ishikawa K, Miyamoto Y, Yoshimura M, Ito M, Takayanagi M, Takuma K, Yamada K, Nabeshima T. The role of tissue plasminogen activator in methamphetamine-related reward and sensitization. J Neurochem. 2005;92:660–667. [PubMed]
- Nakajima A, Yamada K, Nagai T, Uchiyama T, Miyamoto Y, Mamiya T, He J, Nitta A, Mizuno M, Tran MH, Seto A, Yoshimura M, Kitaichi K, Hasegawa T, Saito K, Yamada Y, Seishima M, Sekikawa K, Kim HC, Nabeshima T. Role of tumor necrosis factor-alpha in methamphetamine-induced drug dependence and neurotoxicity. J Neurosci. 2004;24:2212–2225. [PubMed]
- Newlin DB, Thomson JB. Chronic tolerance and sensitization to alcohol in sons of alcoholics: II. Replication and reanalysis. Exp Clin Psychopharmacol. 1999;7:234–243. [PubMed]
- Nishii K, Matsushita N, Sawada H, Sano H, Noda Y, Mamiya T, Nabeshima T, Nagatsu I, Hata T, Kiuchi K, Yoshizato H, Nakashima K, Nagatsu T, Kobayashi K. Motor and learning dysfunction during postnatal development in mice defective in dopamine neuronal transmission. J Neurosci Res. 1998;54:450–464. [PubMed]
- Numachi Y, Ohara A, Yamashita M, Fukushima S, Kobayashi H, Hata H, Watanabe H, Hall FS, Lesch KP, Murphy DL, Uhl GR, Sora I. Methamphetamine-induced hyperthermia and lethal toxicity: Role of the dopamine and serotonin transporters. Eur J Pharmacol. 2007 doi:10.1016/j.ejphar.2007.06.022.
- Okabe C, Takeshima H, Murphy NP. Methamphetamine sensitization in nociceptin receptor knockout mice: locomotor and c-fos expression. Eur J Pharmacol. 2005;507:57–67. [PubMed]
- Oliverio A, Eleftheriou BE, Bailey DW. Exploratory activity: genetic analysis of its modification by scopolamine and amphetamine. Physiol Behav. 1973;10:893–899. [PubMed]
- Orb S, Wieacker J, Labarca C, Fonck C, Lester HA, Schwarz J. Knockin mice with Leu9′Ser alpha4-nicotinic receptors: substantia nigra dopaminergic neurons are hypersensitive to agonist and lost postnatally. Physiol Genomics. 2004;18:299–307. [PubMed]
- Orsini C, Buchini F, Piazza PV, Puglisi-Allegra S, Cabib S. Susceptibility to amphetamine-induced place preference is predicted by locomotor response to novelty and amphetamine in the mouse. Psychopharmacology (Berl). 2004;172:264–270. [PubMed]
- Palmer AA, Phillips TJ. Quantitative trait locus (QTL) mapping in mice. In: Yuan L, Lovinger DM, editors. Methods in Alcohol-Related Neuroscience Research. CRC Press; Boca Raton, FL: 2000. pp. 1–30.
- Palmer AA, Verbitsky M, Suresh R, Kamens HM, Reed CL, Li N, Burkhart-Kasch S, McKinnon CS, Belknap JK, Gilliam TC, Phillips TJ. Gene expression differences in mice divergently selected for methamphetamine sensitivity. Mamm Genome. 2005;16:291–305. [PubMed]
- Pettit HO, Mueller K. Infusions of cholecystokinin octapeptide into the ventral tegmental area potentiate amphetamine conditioned place preferences. Psychopharmacology (Berl). 1989;99:423–426. [PubMed]
- Phillips TJ, Belknap JK. Complex-trait genetics: emergence of multivariate strategies. Nat Rev Neurosci. 2002;3:478–485. [PubMed]
- Phillips TJ, Belknap JK, Hitzemann RJ, Buck KJ, Cunningham CL, Crabbe JC. Harnessing the mouse to unravel the genetics of human disease. Genes Brain Behav. 2002a;1:14–26. [PubMed]
- Phillips TJ, Burkhart-Kasch S, Gwiazdon CC, Crabbe JC. Locomotor responses of FAST and SLOW mice to several alcohols and drugs of abuse. Ann N Y Acad Sci. 1992;654:499–501. [PubMed]
- Phillips TJ, Burkhart-Kasch S, Terdal ES, Crabbe JC. Response to selection for ethanol-induced locomotor activation: genetic analyses and selection response characterization. Psychopharmacology (Berl). 1991;103:557–566. [PubMed]
- Phillips TJ, Dickinson S, Burkhart-Kasch S. Behavioral sensitization to drug stimulant effects in C57BL/6J and DBA/2J inbred mice. Behav Neurosci. 1994;108:789–803. [PubMed]
- Phillips TJ, Hen R, Crabbe JC. Complications associated with genetic background effects in research using knockout mice. Psychopharmacology (Berl). 1999;147:5–7. [PubMed]
- Phillips TJ, Shen EH. Neurochemical bases of locomotion and ethanol stimulant effects. Int Rev Neurobiol. 1996;39:243–282. [PubMed]
- Phillips TJ, Shen EH, McKinnon CS, Burkhart-Kasch S, Lessov CN, Palmer AA. Forward, relaxed, and reverse selection for reduced and enhanced sensitivity to ethanol's locomotor stimulant effects in mice. Alcohol Clin Exp Res. 2002b;26:593–602. [PubMed]
- Piazza PV, Deminiere JM, Le Moal M, Simon H. Factors that predict individual vulnerability to amphetamine self-administration. Science. 1989;245:1511–1513. [PubMed]
- Piazza PV, Deminiere JM, Maccari S, Mormede P, Le Moal M, Simon H. Individual reactivity to novelty predicts probability of amphetamine self-administration. Behav Pharmacol. 1990;1:339–345. [PubMed]
- Pillai-Nair N, Panicker AK, Rodriguiz RM, Gilmore KL, Demyanenko GP, Huang JZ, Wetsel WC, Maness PF. Neural cell adhesion molecule-secreting transgenic mice display abnormalities in GABAergic interneurons and alterations in behavior. J Neurosci. 2005;25:4659–4671. [PubMed]
- Pineda JR, Canals JM, Bosch M, Adell A, Mengod G, Artigas F, Ernfors P, Alberch J. Brain-derived neurotrophic factor modulates dopaminergic deficits in a transgenic mouse model of Huntington's disease. J Neurochem. 2005;93:1057–1068. [PubMed]
- Poikolainen K. Risk factors for alcohol dependence: a case-control study. Alcohol Alcohol. 2000;35:190–196. [PubMed]
- Powell SB, Lehmann-Masten VD, Paulus MP, Gainetdinov RR, Caron MG, Geyer MA. MDMA “ecstasy” alters hyperactive and perseverative behaviors in dopamine transporter knockout mice. Psychopharmacology (Berl). 2004;173:310–317. [PubMed]
- Ralph-Williams RJ, Lehmann-Masten V, Otero-Corchon V, Low MJ, Geyer MA. Differential effects of direct and indirect dopamine agonists on prepulse inhibition: a study in D1 and D2 receptor knock-out mice. J Neurosci. 2002;22:9604–9611. [PubMed]
- Ralph RJ, Paulus MP, Geyer MA. Strain-specific effects of amphetamine on prepulse inhibition and patterns of locomotor behavior in mice. J Pharmacol Exp Ther. 2001;298:148–155. [PubMed]
- Ralph RJ, Varty GB, Kelly MA, Wang YM, Caron MG, Rubinstein M, Grandy DK, Low MJ, Geyer MA. The dopamine D2, but not D3 or D4, receptor subtype is essential for the disruption of prepulse inhibition produced by amphetamine in mice. J Neurosci. 1999;19:4627–4633. [PubMed]
- Reed TM, Repaske DR, Snyder GL, Greengard P, Vorhees CV. Phosphodiesterase 1B knock-out mice exhibit exaggerated locomotor hyperactivity and DARPP-32 phosphorylation in response to dopamine agonists and display impaired spatial learning. J Neurosci. 2002;22:5188–5197. [PubMed]
- Remington G, Anisman H. Genetic and ontogenetic variations in locomotor activity following treatment with scopolamine or d-amphetamine. Dev Psychobiol. 1976;9:579–585. [PubMed]
- Resnick A, Homanics GE, Jung BJ, Peris J. Increased acute cocaine sensitivity and decreased cocaine sensitization in GABA(A) receptor beta3 subunit knockout mice. J Neurochem. 1999;73:1539–1548. [PubMed]
- Reynolds DS, O'Meara GF, Newman RJ, Bromidge FA, Atack JR, Whiting PJ, Rosahl TW, Dawson GR. GABA(A) alpha 1 subunit knock-out mice do not show a hyperlocomotor response following amphetamine or cocaine treatment. Neuropharmacology. 2003;44:190–198. [PubMed]
- Richfield EK, Thiruchelvam MJ, Cory-Slechta DA, Wuertzer C, Gainetdinov RR, Caron MG, Di Monte DA, Federoff HJ. Behavioral and neurochemical effects of wild-type and mutated human alpha-synuclein in transgenic mice. Exp Neurol. 2002;175:35–48. [PubMed]
- Riddle EL, Fleckenstein AE, Hanson GR. Mechanisms of methamphetamine-induced dopaminergic neurotoxicity. Aaps J. 2006;8:E413–418. [PubMed]
- Risbrough VB, Masten VL, Caldwell S, Paulus MP, Low MJ, Geyer MA. Differential contributions of dopamine D1, D2, and D3 receptors to MDMA-induced effects on locomotor behavior patterns in mice. Neuropsychopharmacology. 2006;31:2349–2358. [PubMed]
- Robinson TE. Behavioral sensitization: characterization of enduring changes in rotational behavior produced by intermittent injections of amphetamine in male and female rats. Psychopharmacology (Berl). 1984;84:466–475. [PubMed]
- Robinson TE, Becker JB, Presty SK. Long-term facilitation of amphetamine-induced rotational behavior and striatal dopamine release produced by a single exposure to amphetamine: sex differences. Brain Res. 1982;253:231–241. [PubMed]
- Robinson TE, Berridge KC. The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev. 1993;18:247–291. [PubMed]
- Robledo P, Mendizabal V, Ortuno J, de la Torre R, Kieffer BL, Maldonado R. The rewarding properties of MDMA are preserved in mice lacking mu-opioid receptors. Eur J Neurosci. 2004;20:853–858. [PubMed]
- Roman T, Szobot C, Martins S, Biederman J, Rohde LA, Hutz MH. Dopamine transporter gene and response to methylphenidate in attention-deficit/hyperactivity disorder. Pharmacogenetics. 2002;12:497–499. [PubMed]
- Ron D, Jurd R. The “ups and downs” of signaling cascades in addiction. Sci STKE. 2005;2005:re14. [PubMed]
- Rothman RB, Baumann MH. Monoamine transporters and psychostimulant drugs. Eur J Pharmacol. 2003;479:23–40. [PubMed]
- Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS. Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. Synapse. 2001;39:32–41. [PubMed]
- Rubinstein M, Phillips TJ, Bunzow JR, Falzone TL, Dziewczapolski G, Zhang G, Fang Y, Larson JL, McDougall JA, Chester JA, Saez C, Pugsley TA, Gershanik O, Low MJ, Grandy DK. Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine. Cell. 1997;90:991–1001. [PubMed]
- Runkorg K, Varv S, Matsui T, Koks S, Vasar E. Differences in behavioural effects of amphetamine and dopamine-related gene expression in wild-type and homozygous CCK(2) receptor deficient mice. Neurosci Lett. 2006;406:17–22. [PubMed]
- Sadalge A, Coughlin L, Fu H, Wang B, Valladares O, Valentino R, Blendy JA. alpha 1d Adrenoceptor signaling is required for stimulus induced locomotor activity. Mol Psychiatry. 2003;8:664–672. [PubMed]
- Sallinen J, Haapalinna A, Viitamaa T, Kobilka BK, Scheinin M. D-amphetamine and L-5-hydroxytryptophan-induced behaviours in mice with genetically-altered expression of the alpha2C-adrenergic receptor subtype. Neuroscience. 1998;86:959–965. [PubMed]
- Scearce-Levie K, Chen JP, Gardner E, Hen R. 5-HT receptor knockout mice: pharmacological tools or models of psychiatric disorders. Ann N Y Acad Sci. 1999a;868:701–715. [PubMed]
- Scearce-Levie K, Viswanathan SS, Hen R. Locomotor response to MDMA is attenuated in knockout mice lacking the 5-HT1B receptor. Psychopharmacology (Berl). 1999b;141:154–161. [PubMed]
- Schiorring E. Psychopathology induced by “speed drugs” Pharmacol Biochem Behav. 1981;14(Suppl 1):109–122. [PubMed]
- Schmidt CJ, Ritter JK, Sonsalla PK, Hanson GR, Gibb JW. Role of dopamine in the neurotoxic effects of methamphetamine. J Pharmacol Exp Ther. 1985;233:539–544. [PubMed]
- Schuckit MA, Smith TL. The relationships of a family history of alcohol dependence, a low level of response to alcohol and six domains of life functioning to the development of alcohol use disorders. J Stud Alcohol. 2000;61:827–835. [PubMed]
- Schuckit MA, Smith TL. The clinical course of alcohol dependence associated with a low level of response to alcohol. Addiction. 2001;96:903–910. [PubMed]
- Seale TW, Carney JM, Johnson P, Rennert OM. Inheritance of amphetamine-induced thermoregulatory responses in inbred mice. Pharmacol Biochem Behav. 1985;23:373–377. [PubMed]
- Seeman P, Ko F, Tallerico T. Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics. Mol Psychiatry. 2005;10:877–883. [PubMed]
- Segal DS, Geyer MA, Weiner BE. Strain differences during intraventricular infusion of norepinephrine: possible role of receptor sensitivity. Science. 1975;189:301–303. [PubMed]
- Segal DS, Kuczenski R, O'Neil ML, Melega WP, Cho AK. Prolonged exposure of rats to intravenous methamphetamine: behavioral and neurochemical characterization. Psychopharmacology (Berl). 2005;180:501–512. [PubMed]
- Sekine Y, Minabe Y, Ouchi Y, Takei N, Iyo M, Nakamura K, Suzuki K, Tsukada H, Okada H, Yoshikawa E, Futatsubashi M, Mori N. Association of dopamine transporter loss in the orbitofrontal and dorsolateral prefrontal cortices with methamphetamine-related psychiatric symptoms. Am J Psychiatry. 2003;160:1699–1701. [PubMed]
- Seong E, Saunders TL, Stewart CL, Burmeister M. To knockout in 129 or in C57BL/6: that is the question. Trends Genet. 2004;20:59–62. [PubMed]
- Shaldubina A, Buccafusca R, Johanson RA, Agam G, Belmaker RH, Berry GT, Bersudsky Y. Behavioural phenotyping of sodium-myo-inositol cotransporter heterozygous knockout mice with reduced brain inositol. Genes Brain Behav. 2007;6:253–259. [PubMed]
- Shen EH, Harland RD, Crabbe JC, Phillips TJ. Bidirectional selective breeding for ethanol effects on locomotor activity: characterization of FAST and SLOW mice through selection generation 35. Alcohol Clin Exp Res. 1995;19:1234–1245. [PubMed]
- Shin DM, Korada S, Raballo R, Shashikant CS, Simeone A, Taylor JR, Vaccarino F. Loss of glutamatergic pyramidal neurons in frontal and temporal cortex resulting from attenuation of FGFR1 signaling is associated with spontaneous hyperactivity in mice. J Neurosci. 2004;24:2247–2258. [PubMed]
- Sieber BA, Kuzmin A, Canals JM, Danielsson A, Paratcha G, Arenas E, Alberch J, Ogren SO, Ibanez CF. Disruption of EphA/ephrin-a signaling in the nigrostriatal system reduces dopaminergic innervation and dissociates behavioral responses to amphetamine and cocaine. Mol Cell Neurosci. 2004;26:418–428. [PubMed]
- Siesser WB, Cheng SY, McDonald MP. Hyperactivity, impaired learning on a vigilance task, and a differential response to methylphenidate in the TRbetaPV knock-in mouse. Psychopharmacology (Berl). 2005;181:653–663. [PubMed]
- Siesser WB, Zhao J, Miller LR, Cheng SY, McDonald MP. Transgenic mice expressing a human mutant beta1 thyroid receptor are hyperactive, impulsive, and inattentive. Genes Brain Behav. 2006;5:282–297. [PubMed]
- Siuciak JA, McCarthy SA, Chapin DS, Fujiwara RA, James LC, Williams RD, Stock JL, McNeish JD, Strick CA, Menniti FS, Schmidt CJ. Genetic deletion of the striatum-enriched phosphodiesterase PDE10A: Evidence for altered striatal function. Neuropharmacology. 2006;51:374–385. [PubMed]
- Skelton MR, Ponniah S, Wang DZ, Doetschman T, Vorhees CV, Pallen CJ. Protein tyrosine phosphatase alpha (PTP alpha) knockout mice show deficits in Morris water maze learning, decreased locomotor activity, and decreases in anxiety. Brain Res. 2003;984:1–10. [PubMed]
- Smith DG, Tzavara ET, Shaw J, Luecke S, Wade M, Davis R, Salhoff C, Nomikos GG, Gehlert DR. Mesolimbic dopamine super-sensitivity in melanin-concentrating hormone-1 receptor-deficient mice. J Neurosci. 2005;25:914–922. [PubMed]
- Soderpalm B, Ericson M, Bohlooly M, Engel JA, Tornell J. Bovine growth hormone transgenic mice display alterations in locomotor activity and brain monoamine neurochemistry. Endocrinology. 1999;140:5619–5625. [PubMed]
- Sora I, Wichems C, Takahashi N, Li XF, Zeng Z, Revay R, Lesch KP, Murphy DL, Uhl GR. Cocaine reward models: conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice. Proc Natl Acad Sci U S A. 1998;95:7699–7704. [PubMed]
- Spielewoy C, Biala G, Roubert C, Hamon M, Betancur C, Giros B. Hypolocomotor effects of acute and daily d-amphetamine in mice lacking the dopamine transporter. Psychopharmacology (Berl). 2001;159:2–9. [PubMed]
- Starke K. Presynaptic autoreceptors in the third decade: focus on alpha2-adrenoceptors. J Neurochem. 2001;78:685–693. [PubMed]
- Steckler T, Holsboer F. Conditioned activity to amphetamine in transgenic mice expressing an antisense RNA against the glucocorticoid receptor. Behav Neurosci. 2001;115:207–219. [PubMed]
- Stone EA, Zhang Y, Rosengarten H, Yeretsian J, Quartermain D. Brain alpha 1-adrenergic neurotransmission is necessary for behavioral activation to environmental change in mice. Neuroscience. 1999;94:1245–1252. [PubMed]
- Sulzer D, Chen TK, Lau YY, Kristensen H, Rayport S, Ewing A. Amphetamine redistributes dopamine from synaptic vesicles to the cytosol and promotes reverse transport. J Neurosci. 1995;15:4102–4108. [PubMed]
- Sulzer D, Rayport S. Amphetamine and other psychostimulants reduce pH gradients in midbrain dopaminergic neurons and chromaffin granules: a mechanism of action. Neuron. 1990;5:797–808. [PubMed]
- Sulzer D, Sonders MS, Poulsen NW, Galli A. Mechanisms of neurotransmitter release by amphetamines: a review. Prog Neurobiol. 2005;75:406–433. [PubMed]
- Svenningsson P, Tzavara ET, Carruthers R, Rachleff I, Wattler S, Nehls M, McKinzie DL, Fienberg AA, Nomikos GG, Greengard P. Diverse psychotomimetics act through a common signaling pathway. Science. 2003;302:1412–1415. [PubMed]
- Swanson JM, Sergeant JA, Taylor E, Sonuga-Barke EJ, Jensen PS, Cantwell DP. Attention-deficit hyperactivity disorder and hyperkinetic disorder. Lancet. 1998;351:429–433. [PubMed]
- Szumlinski KK, Dehoff MH, Kang SH, Frys KA, Lominac KD, Klugmann M, Rohrer J, Griffin W, 3rd, Toda S, Champtiaux NP, Berry T, Tu JC, Shealy SE, During MJ, Middaugh LD, Worley PF, Kalivas PW. Homer proteins regulate sensitivity to cocaine. Neuron. 2004;43:401–413. [PubMed]
- Szumlinski KK, Lominac KD, Kleschen MJ, Oleson EB, Dehoff MH, Schwarz MK, Seeburg PH, Worley PF, Kalivas PW. Behavioral and neurochemical phenotyping of Homer1 mutant mice: possible relevance to schizophrenia. Genes Brain Behav. 2005;4:273–288. [PubMed]
- Takahashi N, Miner LL, Sora I, Ujike H, Revay RS, Kostic V, Jackson-Lewis V, Przedborski S, Uhl GR. VMAT2 knockout mice: heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity. Proc Natl Acad Sci U S A. 1997;94:9938–9943. [PubMed]
- Takeda K, Weiss RE, Refetoff S. Rapid localization of mutations in the thyroid hormone receptor-beta gene by denaturing gradient gel electrophoresis in 18 families with thyroid hormone resistance. J Clin Endocrinol Metab. 1992;74:712–719. [PubMed]
- Tanaka K, Shintani N, Hashimoto H, Kawagishi N, Ago Y, Matsuda T, Hashimoto R, Kunugi H, Yamamoto A, Kawaguchi C, Shimada T, Baba A. Psychostimulant-induced attenuation of hyperactivity and prepulse inhibition deficits in Adcyap1-deficient mice. J Neurosci. 2006;26:5091–5097. [PubMed]
- Tancer M, Johanson CE. The effects of fluoxetine on the subjective and physiological effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans. Psychopharmacology (Berl). 2007;189:565–573. [PubMed]
- Tappe A, Kuner R. Regulation of motor performance and striatal function by synaptic scaffolding proteins of the Homer1 family. Proc Natl Acad Sci U S A. 2006;103:774–779. [PubMed]
- Torkamanzehi A, Boksa P, Ayoubi M, Fortier ME, Ng Ying Kin NM, Skamene E, Rouleau G, Joober R. Identification of informative strains and provisional QTL mapping of amphetamine (AMPH)-induced locomotion in recombinant congenic strains (RCS) of mice. Behav Genet. 2006;36:903–913. [PubMed]
- Toyota H, Dugovic C, Koehl M, Laposky AD, Weber C, Ngo K, Wu Y, Lee DH, Yanai K, Sakurai E, Watanabe T, Liu C, Chen J, Barbier AJ, Turek FW, Fung-Leung WP, Lovenberg TW. Behavioral characterization of mice lacking histamine H(3) receptors. Mol Pharmacol. 2002;62:389–397. [PubMed]
- Tsai G, Ralph-Williams RJ, Martina M, Bergeron R, Berger-Sweeney J, Dunham KS, Jiang Z, Caine SB, Coyle JT. Gene knockout of glycine transporter 1: characterization of the behavioral phenotype. Proc Natl Acad Sci U S A. 2004;101:8485–8490. [PubMed]
- Ujike H, Harano M, Inada T, Yamada M, Komiyama T, Sekine Y, Sora I, Iyo M, Katsu T, Nomura A, Nakata K, Ozaki N. Nine- or fewer repeat alleles in VNTR polymorphism of the dopamine transporter gene is a strong risk factor for prolonged methamphetamine psychosis. Pharmacogenomics J. 2003;3:242–247. [PubMed]
- Ujike H, Sato M. Clinical features of sensitization to methamphetamine observed in patients with methamphetamine dependence and psychosis. Ann N Y Acad Sci. 2004;1025:279–287. [PubMed]
- Umemori H, Ogura H, Tozawa N, Mikoshiba K, Nishizumi H, Yamamoto T. Impairment of N-methyl-D-aspartate receptor-controlled motor activity in LYN-deficient mice. Neuroscience. 2003;118:709–713. [PubMed]
- van den Buuse M, Martin S, Brosda J, Leck KJ, Matthaei KI, Hendry I. Enhanced effect of dopaminergic stimulation on prepulse inhibition in mice deficient in the alpha subunit of G(z). Psychopharmacology (Berl). 2005a;183:358–367. [PubMed]
- van den Buuse M, Simpson ER, Jones ME. Prepulse inhibition of acoustic startle in aromatase knock-out mice: effects of age and gender. Genes Brain Behav. 2003;2:93–102. [PubMed]
- van den Buuse M, van Driel IR, Samuelson LC, Pijnappel M, Martin S. Reduced effects of amphetamine on prepulse inhibition of startle in gastrin-deficient mice. Neurosci Lett. 2005b;373:237–242. [PubMed]
- van der Meulen EM, Bakker SC, Pauls DL, Oteman N, Kruitwagen CL, Pearson PL, Sinke RJ, Buitelaar JK. High sibling correlation on methylphenidate response but no association with DAT1-10R homozygosity in Dutch sibpairs with ADHD. J Child Psychol Psychiatry. 2005;46:1074–1080. [PubMed]
- Vanderschuren LJ, Schmidt ED, De Vries TJ, Van Moorsel CA, Tilders FJ, Schoffelmeer AN. A single exposure to amphetamine is sufficient to induce long-term behavioral, neuroendocrine, and neurochemical sensitization in rats. J Neurosci. 1999;19:9579–9586. [PubMed]
- Vasar E, Harro J, Lang A, Pold A, Soosaar A. Differential involvement of CCK-A and CCK-B receptors in the regulation of locomotor activity in the mouse. Psychopharmacology (Berl). 1991;105:393–399. [PubMed]
- Veenstra-VanderWeele J, Qaadir A, Palmer AA, Cook EH, Jr., de Wit H. Association between the casein kinase 1 epsilon gene region and subjective response to D-amphetamine. Neuropsychopharmacology. 2006;31:1056–1063. [PubMed]
- Ventura R, Pascucci T, Catania MV, Musumeci SA, Puglisi-Allegra S. Object recognition impairment in Fmr1 knockout mice is reversed by amphetamine: involvement of dopamine in the medial prefrontal cortex. Behav Pharmacol. 2004;15:433–442. [PubMed]
- Volkow ND, Chang L, Wang GJ, Fowler JS, Ding YS, Sedler M, Logan J, Franceschi D, Gatley J, Hitzemann R, Gifford A, Wong C, Pappas N. Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex. Am J Psychiatry. 2001;158:2015–2021. [PubMed]
- Wang GJ, Volkow ND, Chang L, Miller E, Sedler M, Hitzemann R, Zhu W, Logan J, Ma Y, Fowler JS. Partial recovery of brain metabolism in methamphetamine abusers after protracted abstinence. Am J Psychiatry. 2004;161:242–248. [PubMed]
- Wang JH, Short J, Ledent C, Lawrence AJ, van den Buuse M. Reduced startle habituation and prepulse inhibition in mice lacking the adenosine A2A receptor. Behav Brain Res. 2003;143:201–207. [PubMed]
- Wang YM, Gainetdinov RR, Fumagalli F, Xu F, Jones SR, Bock CB, Miller GW, Wightman RM, Caron MG. Knockout of the vesicular monoamine transporter 2 gene results in neonatal death and supersensitivity to cocaine and amphetamine. Neuron. 1997;19:1285–1296. [PubMed]
- Weinshenker D, Miller NS, Blizinsky K, Laughlin ML, Palmiter RD. Mice with chronic norepinephrine deficiency resemble amphetamine-sensitized animals. Proc Natl Acad Sci U S A. 2002;99:13873–13877. [PubMed]
- Wenger GR. The role of control activity levels in the reported strain differences to the behavioral effects of drugs in mice. Pharmacol Biochem Behav. 1989;32:241–247. [PubMed]
- Willis-Owen SA, Flint J. Identifying the genetic determinants of emotionality in humans; insights from rodents. Neurosci Biobehav Rev. 2007;31:115–124. [PubMed]
- Wimer RE. Some uses of inbred strains. In: Goldowitz D, Wahlsten D, Wimer RE, editors. Techniques for the Genetic Analysis of Brain and Behavior: Focus on the Mouse. Elsevier; Amsterdam: 1992. pp. 57–66.
- Winsberg BG, Comings DE. Association of the dopamine transporter gene (DAT1) with poor methylphenidate response. J Am Acad Child Adolesc Psychiatry. 1999;38:1474–1477. [PubMed]
- Wolinsky TD, Swanson CJ, Smith KE, Zhong H, Borowsky B, Seeman P, Branchek T, Gerald CP. The Trace Amine 1 receptor knockout mouse: an animal model with relevance to schizophrenia. Genes Brain Behav. 2007;6:628–639. [PubMed]
- Wu R, Lin M. Functional mapping - how to map and study the genetic architecture of dynamic complex traits. Nat Rev Genet. 2006;7:229–237. [PubMed]
- Wunderlich GR, DeSousa NJ, Vaccarino FJ. Cholecystokinin modulates both the development and the expression of behavioral sensitization to amphetamine in the rat. Psychopharmacology (Berl). 2000;151:283–290. [PubMed]
- Xu F, Gainetdinov RR, Wetsel WC, Jones SR, Bohn LM, Miller GW, Wang YM, Caron MG. Mice lacking the norepinephrine transporter are supersensitive to psychostimulants. Nat Neurosci. 2000a;3:465–471. [PubMed]
- Xu M, Guo Y, Vorhees CV, Zhang J. Behavioral responses to cocaine and amphetamine administration in mice lacking the dopamine D1 receptor. Brain Res. 2000b;852:198–207. [PubMed]
- Xu M, Koeltzow TE, Santiago GT, Moratalla R, Cooper DC, Hu XT, White NM, Graybiel AM, White FJ, Tonegawa S. Dopamine D3 receptor mutant mice exhibit increased behavioral sensitivity to concurrent stimulation of D1 and D2 receptors. Neuron. 1997;19:837–848. [PubMed]
- Xu R, Hranilovic D, Fetsko LA, Bucan M, Wang Y. Dopamine D2S and D2L receptors may differentially contribute to the actions of antipsychotic and psychotic agents in mice. Mol Psychiatry. 2002;7:1075–1082. [PubMed]
- Yamashita M, Fukushima S, Shen HW, Hall FS, Uhl GR, Numachi Y, Kobayashi H, Sora I. Norepinephrine transporter blockade can normalize the prepulse inhibition deficits found in dopamine transporter knockout mice. Neuropsychopharmacology. 2006;31:2132–2139. [PubMed]
- Yan Y, Nitta A, Mizoguchi H, Yamada K, Nabeshima T. Relapse of methamphetamine-seeking behavior in C57BL/6J mice demonstrated by a reinstatement procedure involving intravenous self-administration. Behav Brain Res. 2006;168:137–143. [PubMed]
- Yee BK, Keist R, von Boehmer L, Studer R, Benke D, Hagenbuch N, Dong Y, Malenka RC, Fritschy JM, Bluethmann H, Feldon J, Mohler H, Rudolph U. A schizophrenia-related sensorimotor deficit links alpha 3-containing GABAA receptors to a dopamine hyperfunction. Proc Natl Acad Sci U S A. 2005;102:17154–17159. [PubMed]
- Yuan J, Hatzidimitriou G, Suthar P, Mueller M, McCann U, Ricaurte G. Relationship between temperature, dopaminergic neurotoxicity, and plasma drug concentrations in methamphetamine-treated squirrel monkeys. J Pharmacol Exp Ther. 2006;316:1210–1218. [PubMed]
- Zeni CP, Guimaraes AP, Polanczyk GV, Genro JP, Roman T, Hutz MH, Rohde LA. No significant association between response to methylphenidate and genes of the dopaminergic and serotonergic systems in a sample of Brazilian children with attention-deficit/hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet. 2007;144:391–394. [PubMed]
- Zhang Y, Loonam TM, Noailles PA, Angulo JA. Comparison of cocaine- and methamphetamine-evoked dopamine and glutamate overflow in somatodendritic and terminal field regions of the rat brain during acute, chronic, and early withdrawal conditions. Ann N Y Acad Sci. 2001;937:93–120. [PubMed]
- Zhuang X, Oosting RS, Jones SR, Gainetdinov RR, Miller GW, Caron MG, Hen R. Hyperactivity and impaired response habituation in hyperdopaminergic mice. Proc Natl Acad Sci U S A. 2001;98:1982–1987. [PubMed]
- Zocchi A, Orsini C, Cabib S, Puglisi-Allegra S. Parallel strain-dependent effect of amphetamine on locomotor activity and dopamine release in the nucleus accumbens: an in vivo study in mice. Neuroscience. 1998;82:521–528. [PubMed]
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related Genes: Amphetamine & Methamphetamine (Table 2)