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Kuhn CM, Koob GF, editors. Advances in the Neuroscience of Addiction. 2nd edition. Boca Raton (FL): CRC Press/Taylor & Francis; 2010.

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Advances in the Neuroscience of Addiction. 2nd edition.

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Chapter 1Advances in Animal Models of Relapse for Addiction Research

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1.1. INTRODUCTION AND SCOPE

1.1.1. The Neurobehavioral Basis of Drug Seeking and Relapse

Drug addiction is a chronically relapsing disorder characterized by compulsive drug-seeking and use (Leshner 1997; McLellan et al. 2000; O'Brien et al. 1998; O'Brien and McLellan 1996). Long-lasting vulnerability to relapse has been recognized as a phenomenon pivotal for the understanding and treatment of drug addiction. Elucidation of the neurobiological mechanisms underlying the chronically relapsing nature of addiction and identification of pharmacological treatment targets for relapse prevention has therefore emerged as the central issue of importance in addiction research. The clinical as well as experimental literature implicates three major factors precipitating craving and relapse. One of these is learned responses evoked by environmental stimuli that have become associated with the subjective actions of drugs of abuse by means of classical conditioning. Exposure to such stimuli can evoke drug desire and drug seeking, effects that have been implicated both in maintaining ongoing drug use and eliciting drug-seeking during abstinence (Everitt et al. 2001; Littleton 2000; O'Brien et al. 1998; See 2002; Van De Laar et al. 2004). Drug-related stimuli can also elicit automatic responses that lead to drug-seeking and relapse without recruiting conscious desire or distinct feelings of craving (Ingjaldsson et al. 2003; Miller and Gold 1994; Stormark et al. 1995; Tiffany and Carter 1998; Tiffany and Conklin 2000). Studies in animals have confirmed that environmental stimuli that have become associated with the reinforcing actions of drugs of abuse reliably elicit drug-seeking in animal models of relapse drug-seeking behavior (for review, see See 2002; Shaham and Miczek 2003; Shaham et al. 2003; Shalev et al. 2002). In particular, contextual stimuli predictive of cocaine (Ciccocioppo et al. 2004b, 2001b; Weiss et al. 2000, 2001), ethanol (Ciccocioppo et al. 2001a, 2003, 2002; Katner et al. 1999; Katner and Weiss 1999; Liu and Weiss 2002b), or heroin (Gracy et al. 2000) availability reliably elicit strong recovery of extinguished drug-seeking behavior. Indeed, drug seeking induced by these stimuli shows remarkable resistance to extinction (Weiss et al. 2001; Ciccocioppo et al. 2001a) and, in the case of cocaine, can still be observed after several months of abstinence (Ciccocioppo et al. 2001b; Weiss et al. 2001). Moreover, cocaine seeking induced by drug-related stimuli can progressively increase in strength (incubate) during long-term abstinence (Grimm et al. 2001). Overall, the persistence of the behavioral effects of drug-associated environmental cues resembles the persistence of conditioned cue reactivity and cueinduced craving in humans (e.g., Childress et al. 1993).

Stress is the second factor with an established role in relapse to drug and alcohol use in humans (e.g., Brown et al. 1995; Kreek and Koob 1998; Marlatt 1985; McKay et al. 1995; Sinha 2000, 2001; Sinha et al. 1999, 2000, 2006). The significance of stress in drug seeking and use is also well documented in the animal literature. Various stressors facilitate acquisition of drug self-administration or increased drug intake in rodents (Blanchard et al. 1987; Goeders and Guerin 1994; Haney et al. 1995; Higley et al. 1991; Mollenauer et al. 1993; Nash and Maickel 1988; Ramsey and Van Ree 1993). More importantly, with respect to the present discussion, stress consistently elicits reinstatement of ethanol seeking in drug-free animals, with footshock being the predominant model of stress (for review, see Le and Shaham 2002; Sarnyai et al. 2001; Shaham et al. 2000; Shalev et al. 2002).

A third factor with a major role in relapse is neuroadaptive dysregulation induced by chronic drug use. Such disturbances are thought to underlie symptoms of anxiety, irritability, autonomic arousal, and exaggerated responsiveness to anxiogenic stimuli that emerge when drug use is discontinued (Kajdasz et al. 1999; Kampman et al. 2001; McDougle et al. 1994). Growing evidence suggests that neuroadaptive changes outlast physical withdrawal and detoxification (Kowatch et al. 1992). For example, detoxified cocaine addicts exhibit increased panic and anxiety (Goodwin et al. 2002; Razzouk et al. 2000; Rounsaville et al. 1991; Walfish et al. 1990; Ziedonis et al. 1994) that may result directly from prior cocaine use (Aronson and Craig 1986; Blanchard and Blanchard 1999). Anxiety and other symptoms, such as drug craving, sleep dysregulation, and somatic symptoms, predict poor outcome (Kasarabada et al. 1998). Such “protracted withdrawal” symptoms, originally described in opiate addicts (Martin and Jasinski 1969), also represent a common complication in patients recovering from cocaine and alcohol addiction (Angres and Benson 1985; Gawin and Kleber 1986; Kreek 1987; Meyer 1996; Satel et al. 1993) and introduce alleviation of discomfort and negative affect and, thus, negative reinforcement as a motivational basis for relapse.

This chapter reviews animal models of relapse with emphasis on recent applications to study and elucidate (a) the role of dependence history in susceptibility to relapse, (b) interactions among risk factors for relapse in eliciting drug-seeking behavior, and (c) procedures designed to study and differentiate the distinctly compulsive nature of drug-seeking as opposed to behavior motivated by natural rewards. This review will center on alcohol-seeking behavior as a model. However, the issues to be addressed apply to other drugs of abuse as well, and where applicable, the reader is referred to the appropriate literature.

1.1.2. Modeling Relapse in Animals

The most widely employed animal model of craving and relapse use is the extinction-reinstatement model. This model has perhaps been most extensively applied for investigations of the significance of environmental stimuli conditioned to the reinforcing actions of drugs of abuse in the relapse process, but is also widely employed to study the effects of stress and drug priming on the resumption of drug seeking. Here, we will focus predominantly on reinstatement in the context of conditioning studies.

The model, its range of applications, and its limitations have been reviewed extensively elsewhere (See 2005; Shaham et al. 2003; Shalev et al. 2002; Katz and Higgins 2003; Shaham and Miczek 2003; Weiss 2005). Briefly, several variants of the model exist. In the most commonly employed procedure, animals are trained to respond at an operandum (e.g., lever or nose-poke sensor), and completion of a given schedule requirement results in delivery of the drug. Each drug-reinforced response is paired with brief presentation of one or more environmental stimuli (e.g., a tone, cue light). In this variant of the model, both drug administration and presentation of these conditioned stimuli (CS) are contingent upon the animal's operant response. Use of a compound stimulus (i.e., concurrent presentation of two or more CS) typically produces more robust conditioned reinstatement than a single stimulus (See et al. 1999). Once reliable drug self-administration is acquired, drug-reinforced responding is extinguished by withholding both the drug and CS until a given extinction criterion is reached. Reinstatement tests then are conducted in which the degree of recovery of responding at the previously drug-paired operandum, now maintained by response-contingent presentation of the CS only, serves as a measure of craving or relapse. Extinction and reinstatement tests can be conducted according to a within-session, between-session, and within-between session sequence. In the within-session procedure, a single extinction session is conducted, followed immediately by the reinstatement test (Figure 1.1A). In the between-session protocol, extinction sessions are conducted daily, and reinstatement tests commence typically one day after the extinction criterion is reached (Figure 1.1C). This procedure “adds” a drug-free (i.e., abstinence) period to the mere extinction of drug-reinforced responding. In the between-within procedure, no extinction sessions are conducted after rats acquire drug-reinforced responding. Instead, an abstinence period is imposed, after which extinction and reinstatement sessions are conducted in a within-session manner (Figure LIB). In this application of the model, extinction responses (i.e., resistance to extinction) are often taken as a measure of craving and drug seeking, rather than reinstatement responses (Grimm et al. 2001; Lu et al. 2004). The great majority of contemporary applications of the extinction-reinstatement model employ the between-session or between-within-session procedure.

FIGURE 1.1. Illustration of the temporal sequence of drug self-administration (SA), extinction (EXT), and reinstatement test (RST) sessions in three variants of the extinction-reinstatement model: the within-session (A), between-within (B), and between-session (C) procedure.

FIGURE 1.1

Illustration of the temporal sequence of drug self-administration (SA), extinction (EXT), and reinstatement test (RST) sessions in three variants of the extinction-reinstatement model: the within-session (A), between-within (B), and between-session (C) (more...)

A second variant of the extinction-reinstatement procedure is the contextual model. The procedures here are similar to those above, except that contextual stimuli present continuously throughout the drug self-administration are used for conditioning. That is, these stimuli are neither discretely paired with drug delivery nor contingent upon a response. Multiple contextual reinstatement procedures exist. One utilizes differential reinforcement of behavior in the presence of discriminative stimuli. In this procedure, during self-administration learning, responses at the operandum are reinforced by the drug only in the presence of this stimulus. In the absence of this stimulus (or the presence of an alternative stimulus), responses remain nonreinforced. Owing to their predictive nature for drug availability, discriminative stimuli “set the occasion” for engaging in responding at the drug-paired lever (i.e., lead to the initiation of responding). Additionally, by virtue of their presence during drug consumption, these stimuli also become associated with the rewarding effects of the drug and thus acquire incentive motivational valence. As a result, these stimuli are particularly powerful in eliciting drug seeking and reinstatement. Another frequently employed contextual model, based on procedures by Bouton and colleagues (Bouton and Bolles 1979; Bouton and Swartzentruber 1986), utilizes distinct environments that provide compound contextual cues (i.e., concurrent presence of olfactory, auditory, tactile, and visual cues) to produce renewal of extinguished reward seeking. Briefly, in this model, responding is reinforced by a given (drug) reinforcer in one context. Instrumental responding then is extinguished in a second context. Subjects subsequently tested in the second context show low drug seeking because the behavior has been extinguished in this context. In contrast, drug seeking shows reactivation or renewal (i.e., nonreinforced responding at the previously active operandum) in animals tested in the first (drug-paired) context.

1.1.3. Significance of Considering Dependence History in Animal Models of Relapse

In the case of alcohol addiction, ample evidence exists to show that alcohol-associated stimuli or events can evoke drug desire that may lead to the resumption of drinking in abstinent alcoholics (Cooney et al. 1987, 1997; Eriksen and Gotestam 1984; Kaplan et al. 1985; Laberg 1986; Monti et al. 1987, 1993).

The animal literature confirms a significant role for such conditioning factors in alcohol seeking and relapse. Studies using the extinction-reinstatement model show that stimuli discretely paired with alcohol delivery and alcohol-related contextual stimuli exert powerful and long-lasting control over ethanol-seeking behavior. Such stimuli reliably reinstate extinguished ethanol-seeking behavior as measured by the resumption of responding at a previously active ethanol-paired lever (Bachteler et al. 2005; Bienkowski et al. 1999; Ciccocioppo et al. 2001a, 2004a, 2003, 2002; Katner et al. 1999; Katner and Weiss 1999; Liu and Weiss 2002a, 2002b). The response-reinstating effects of ethanol-related contextual stimuli are surprisingly resistant to extinction in that the efficacy of these cues to elicit resumption of ethanol-seeking behavior does not diminish even when presented repeatedly under non-reinforced conditions (Figure 1.2A,B)—in contrast to behavior induced by stimuli conditioned to highly palatable natural reward (Figure 1.3). In this context, it should be noted that the data in Figures 1.2 and 1.3 document that the initial efficacy of reward-predictive contextual stimuli to elicit behavior directed at obtaining a given reward is similar regardless of whether the behavior is directed at obtaining hedonic gain associated with drug or alcohol reward versus nondrug reward. However, the pattern of differential resistance to extinction with repeated exposure suggests that the conditioned incentive effects of alcohol or drug-related stimuli do not resemble the effects of stimuli conditioned to even highly desirable conventional reinforcers. Specifically drug-related environmental stimuli exert longer-lasting control over behavior than stimuli conditioned to potent conventional reinforcers. This therefore suggests that learning and associative processes responsible for ethanol-related conditioning are distinct from those mediating associations between stimuli paired with the rewarding effects of conventional reinforcers and, presumably, these specific drug- or ethanol-related associative processes lead to compulsive-like drug seeking. Consistent with clinical findings, reinstatement induced by alcohol cues is sensitive to reversal by opioid antagonist administration (Bienkowski et al. 1999; Burattini et al. 2006; Ciccocioppo et al. 2003, 2002; Katner et al. 1999). In alcoholics, naltrexone attenuates cue-induced craving (Monti et al. 1999; Rohsenow et al. 2000) and reduces relapse rates (O'Brien et al. 1996; Volpicelli et al. 1992). Moreover, excellent correspondence exists between neural mapping studies in animals (Dayas et al. 2007; Zhao et al. 2006) and functional brain imaging studies in drinkers (e.g., Braus et al. 2001; George et al. 2001; Kareken et al. 2004; Myrick et al. 2004; Schneider et al. 2001) with respect to the neurocircuitry activated by alcohol cue manipulations that, in humans, result in self-reports of craving and, in animals, alcohol-seeking behavior. Conditioned reinstatement of ethanol seeking in animals, therefore, has good predictive validity as a model of craving and relapse linked to alcohol cue exposure.

FIGURE 1.2. (A) Persistence of the effects of a drug-related discriminative stimulus (S+) determined at 3-day intervals over a 39-day period for ethanol (EtOH) in Indiana Alcohol Preferring P rats (upper panel; modified from Ciccocioppo R, Angeletti S, Weiss F (2001a) Long-lasting resistance to extinction of response reinstatement induced by ethanol-related stimuli: role of genetic ethanol preference.

FIGURE 1.2

(A) Persistence of the effects of a drug-related discriminative stimulus (S+) determined at 3-day intervals over a 39-day period for ethanol (EtOH) in Indiana Alcohol Preferring P rats (upper panel; modified from Ciccocioppo R, Angeletti S, Weiss F (2001a) (more...)

FIGURE 1.3. Self-administration: responding reinforced by 10% (w/v) ethanol (EtOH) or sweetened condensed milk (SCM; representing original results (SCM1) and a replication (SCM2)) in the presence of a discriminative stimulus (S+) associated with the availability of EtOH or SCM.

FIGURE 1.3

Self-administration: responding reinforced by 10% (w/v) ethanol (EtOH) or sweetened condensed milk (SCM; representing original results (SCM1) and a replication (SCM2)) in the presence of a discriminative stimulus (S+) associated with the availability (more...)

The literature on alcohol cue effects in animal models of relapse complements the clinical literature on conditioned cue reactivity and craving in alcoholics and confirms that alcohol cue conditioning is a critical factor in the susceptibility to relapse. What must be kept in mind, however, is that animal studies are typically conducted in rats with a history of restricted daily access (30-60 min) to ethanol, during which typically only modest blood alcohol levels of 50–80 mg% are attained. Conditioned reinstatement induced by alcohol cues under these conditions is consistent with evidence that even light drinkers that are not dependent show conditioned cue reactivity and mild craving in response to alcohol cue exposure (Greeley et al. 1993; Streeter et al. 2002). However, cue-induced ethanol seeking in nondependent animals depends on conditioning of alcohol cues to the positive reinforcing effects of modest ethanol doses only, and is therefore limited with respect to modeling the learning history and motivational forces underlying conditioned cue reactivity and craving in alcoholics with long histories of heavy drinking and repeated withdrawal episodes.

Cessation of ethanol intake after chronic use leads to symptoms of negative affect including, among others, anxiety, mood disturbances, and exaggerated responsiveness to stress. Data from animal models have confirmed that major consequences of acute withdrawal from chronic ethanol exposure are increased sensitivity to anxiogenic stimuli as measured in the elevated plus maze, acoustic startle, and social interaction tests (Breese et al. 2004; Knapp et al. 2004; Overstreet et al. 2004; Rassnick et al. 1993) as well as in reward deficits (Schulteis et al. 1995). These findings suggest that symptoms of negative affect that result from ethanol withdrawal motivate the maintenance and resumption of ethanol intake. Consistent with this hypothesis, pharmacological manipulations that reverse stresslike and anxiogenic consequences of ethanol withdrawal (Macey et al. 1996; Valdez et al. 2002) also reverse withdrawal-associated increases in ethanol self-administration (Roberts et al. 1996; Valdez et al. 2002,2003). Clinical studies support the hypothesis that negative affect symptoms during abstinence maintain drinking and promote relapse through negative reinforcement mechanisms (e.g., Cooney et al. 1997; Hershon 1977; Sinha et al. 2000). Most importantly, in alcoholics the severity of craving induced by alcohol cues is highly correlated with the history and severity of dependence (Greeley et al. 1993; Laberg 1986; Streeter et al. 2002). A likely explanation for these findings is that consumption of ethanol during withdrawal allows for new learning to occur (i.e., the reversal or avoidance of withdrawal distress by resumption of ethanol use), thereby modifying an individual's ethanol reinforcement history to include learning about negative reinforcement as an important aspect of ethanol's actions. As a result, ethanol becomes a qualitatively different and more potent reinforcer. Clearly, environmental stimuli can become associated with both the positive and negative aspects of ethanol's reinforcing actions. However, the significance of a history of negative reinforcement by ethanol for craving and relapse associated with ethanol cue exposure has not been extensively studied in animal models.

With these considerations in mind, efforts are beginning to be made to examine and model the significance of a history of dependence in the relapse process. The following sections will examine the application and potential of the extinction-reinstatement model to elucidate the role of dependence history in susceptibility to relapse as well as interactions among relapse risk facts in producing craving and relapse, drawing from studies in alcohol reinforcement and addiction literature.

1.2. MODELING THE INCENTIVE EFFECTS OF DRUG CUES IN DEPENDENT SUBJECTS

Given the motivational significance of a dependence history discussed above, a hypothesis testable in animal models is that self-administration of ethanol during withdrawal increases the incentive salience of ethanol-related environmental stimuli. Specifically, two questions can be asked: (1) does learning about escape from the aversive effects of withdrawal by active ethanol self-administration alter alcohol-seeking induced by stimuli that had previously been associated only with the positive reinforcing effects of ethanol, and (2) to what extent do stimuli that are associated specifically with ethanol self-administration during withdrawal (i.e., negative reinforcement) promote reinstatement of ethanol-seeking behavior?

1.2.1. Significance of History of Negative Reinforcement in Reinstatement

In a study addressing the first question, ethanol reinforced responses in nondependent rats were response-contingently paired with a discrete light cue. Rats then were either made dependent by ethanol vapor intoxication or remained nondependent. During the last 3 days of dependence induction, rats were removed daily from the ethanol vapor chambers and allowed to operantly self-administer ethanol for 12 h, followed by reex-posure to ethanol vapor for 12 h. The rats then were fully withdrawn from ethanol, and ethanol-reinforced operant responding was extinguished in daily sessions over a 3-week period. Animals then were tested for reinstatement by response-contingent presentation of the ethanol cue that had been conditioned to the positive reinforcing effects of ethanol during self-administration training. As shown in Figure 1.4 (EXT vs. EtOH CS), ethanol-dependent rats that had been given the opportunity to self-administer ethanol during withdrawal showed significantly greater conditioned reinstatement than nondependent rats that had been given the same amount of exposure to the cue than the dependent animals (Liu and Weiss 2002a), indicating that learning about negative ethanol reinforcement during withdrawal enhances drug-seeking by cues previously associated only with positive reinforcement by ethanol. One should note that, procedurally, these findings also exemplify differences in the robustness of conditioning associated with a simple versus compound CS. Ethanol reinforcement in this study had been conditioned to a simple CS (light cue) only, rather than a compound stimulus (See et al. 1999). As alluded to above, the former class of stimuli are typically less effective in reinstating extinguished drug-seeking behavior than compound stimuli. Thus, in contrast to studies employing compound stimuli or contextual conditioning procedures, only subthreshold effects on reinstatement were obtained with the simple CS in nondependent rats.

FIGURE 1.4. (A) Illustration of the sequence of experimental stages for the data in Figure 1.

FIGURE 1.4

(A) Illustration of the sequence of experimental stages for the data in Figure 1.4B. (B) Responses at a previously active and inactive lever in ethanol nondependent and dependent rats trained to operantly self-administer ethanol, with presentation of (more...)

1.2.2. Significance of Stimuli Conditioned to Negative Reinforcement in Reinstatement

Data also exist pertinent to the second question, namely, whether stimuli conditioned specifically to the withdrawal-ameliorating actions of ethanol acquire motivational significance in terms of eliciting alcohol-seeking behavior. Here, the same conditioning and reinstatement procedures as above were used, except that a second and distinctly different CS was introduced, paired specifically and only with ethanol-reinforced responses during the 12-h self-administration sessions conducted over the 3-day withdrawal phase. The effects of this stimulus on reinstatement then were tested during acute ethanol withdrawal and 3 weeks following termination of ethanol vapor exposure. Both the CS that had been paired with the positive reinforcing actions of ethanol prior to induction of dependence only and the stimulus that had been paired with negative reinforcement during withdrawal only produced substantial reinstatement during acute withdrawal (Figure 1.5A). Robust reinstatement was still obtained in rats tested following 3 weeks of abstinence (Figure 1.5B,C). These observations reveal that stimuli conditioned specifically to amelioration of withdrawal are of substantial motivational significance and elicit or contribute to ethanol-seeking behavior in their own right.

FIGURE 1.5. (A) Cue-induced response reinstatement during acute ethanol withdrawal.

FIGURE 1.5

(A) Cue-induced response reinstatement during acute ethanol withdrawal. The left panels show responses at the active and inactive lever during the extinction phase preceding reexposure of the animals to ethanol vapor and the subsequent reinstatement test. (more...)

With respect to animal model development, an important point to be taken from findings such as these is that an induction of alcohol dependence alone, without providing an opportunity for negative reinforcement by ethanol to occur, is not sufficient to document and study the significance of ethanol cues associated with a history of dependence. This point is exemplified by an earlier study that compared reinstatement produced by a contextual ethanol cue in nondependent rats to the effects of the same cue in rats with a history of dependence that consisted of either single or multiple ethanol vapor intoxication and withdrawal (Ciccocioppo et al. 2003). In this study, ethanol was initially self-administered in 30-min sessions, and the availability of ethanol was conditioned to the presence of a discriminative stimulus (SD). The rats then were subjected to single or multiple ethanol vapor intoxication, followed by 7 days of full withdrawal from ethanol. Responding at the lever previously producing ethanol during the self-administration of the experiment then was extinguished, and rats were tested for reinstatement in the presence of the ethanol-associated SD only. Contrary to expectations, the effects of this ethanol cue on the number of reinstatement responses did not differ as a function of either a single or repeated withdrawal history from that in nondependent rats. Examination of the contingencies that were in effect in this study reveals that two conditions had not been met that would be required for a valid test of the hypothesis that a history of negative reinforcement by ethanol modifies or enhances the motivating effects of alcohol-related environmental stimuli. First, the ethanol SD used to test for conditioned reinstatement had been paired with ethanol availability only while rats were in the nondependent state and, therefore, was associated only with the acute, positive reinforcing effects of ethanol. Second, although in rats subjected to multiple withdrawal cycles, reexposure to ethanol vapor did provide an opportunity for associations to develop between ethanol vapor and alleviation of withdrawal, these animals had been subjected to ethanol withdrawal without being given the opportunity to associate an active behavioral response (i.e., oral ethanol self-administration) with reversal of the aversive consequences of withdrawal.

1.3. MODELING INTERACTIONS AMONG RISK FACTORS FOR RELAPSE

Abstinent drug addicts likely are frequently exposed to multiple external risk factors, while at the same time suffering various degrees of anxiety or mood-dysregulation resulting from neuroadaptive changes. Consideration of the concurrent operation of multiple risk factors will be of importance in animal model development, both to gain a better understanding of the relapse process per se and to improve the likelihood of identifying effective treatment targets. For example, whereas both craving and stress have been implicated as critical risk factors for relapse, the predictive relationship between subjective reports of stress or craving and subsequent actual relapse remains controversial (Drummond 2001; Katz and Higgins 2003; Sinha 2001; Tiffany et al. 2000). However, risk factors for relapse are typically studied in isolation, that is, conditions that exclude consideration of the impact of multiple external risk factors. Indeed, it seems likely that the probability of relapse varies as a function of the number and intensity of risk factors operative at a given time, with relapse occurring when the sum of these motivating forces reaches a critical threshold. Several recent studies have begun to address this issue in reinstatement models.

1.3.1. Interactive Effects of Drug Cues and Stress

Stress has an established role in alcohol abuse in humans and is a major determinant of relapse (Brown et al. 1995; Marlatt 1985; McKay et al. 1995; Sinha 2000, 2001; Sinha et al. 2003; Wallace 1989). The significance of stress in drug-seeking behavior is well documented also in the animal literature. Physical, social, and emotional stress can facilitate acquisition or increase self-administration of ethanol in rodents and nonhuman primates (Blanchard et al. 1987; Higley et al. 1991; Mollenauer et al. 1993; Nash and Maickel 1988).

Importantly with respect to the present discussion, stress consistently elicits reinstatement of ethanol-seeking in drug-free animals, with footshock being the predominant model of stress (see Le and Shaham 2002 for review). Interactive effects of stress and drug-related cues on drug seeking were modeled in an original series of studies by testing for the concurrent effects of footshock stress and an ethanol-associated CS on reinstatement (Liu and Weiss 2002a,2003). Rats were trained to self-administer ethanol, and reinforced responses were paired with brief presentation of a simple CS. After withdrawal, ethanol-reinforced responding was extinguished, and the reinstatement of alcohol-seeking behavior was studied under three conditions: (1) during response-contingent presentation of the CS alone, (2) after exposure to 10 min of intermittent footshock stress alone, and (3) during response-contingent presentation of the CS following exposure to footshock stress. Under these conditions the ethanol CS and footshock, when presented alone, produced only threshold effects on alcohol-seeking behavior. However, the ethanol CS elicited strong responding in animals that had been subjected to footshock stress before the session (Figure 1.6; EtOH CS and Stress). Thus, interactive effects between stress and drug-related cues exacerbating drug-seeking can readily be demonstrated in animal models. Indeed, the existence of such interactive effects has recently been confirmed with another drug of abuse and in the context of a different stress manipulation.

FIGURE 1.6. Responses at a previously active and inactive lever in nondependent rats trained to operantly self-administer ethanol.

FIGURE 1.6

Responses at a previously active and inactive lever in nondependent rats trained to operantly self-administer ethanol. SA: Ethanol-reinforced responses at the end of self-administration training. EXT: Responses during the final three extinction sessions. (more...)

Yohimbine—a noradrenergic α2receptor antagonist with anxiogenic action—that has found increasing application as an alternative stressor in animal models of drug seeking (Feltenstein and See 2006; Marinelli et al. 2007) and reward seeking (Ghitza et al. 2006; Nair et al. 2006) potentiated conditioned reinstatement of cocaine seeking (Feltenstein and See 2006).

1.3.2. Interactive Effects of History of Dependence, Drug Cues, and Stress

The above findings document the existence of interactive effects between two factors implicated in craving and relapse: stress and drug-related cues. In view of the significance of a history of dependence in relapse risk, the question arises as to whether an impact of such a drug history on other “triggers” for drug seeking can be documented and studied in animal models. To examine this possibility, a group of animals in the study described above was made dependent via an ethanol vapor procedure following acquisition of operant ethanol self-administration. During the last 2 days of dependence induction, the rats were removed from the vapor chambers each day for 12 h, but allowed to self-administer ethanol paired with response-contingent presentation of an ethanol CS. Rats then were withdrawn from ethanol and subjected to reinstatement tests 3 weeks after termination of the ethanol vapor exposure. In these previously dependent rats, response-contingent presentation of the ethanol CS after footshock substantially enhanced the interactive effects of these stimuli compared to nondependent rats and, in fact, produced synergistic effects on ethanol-seeking (Figures 1.7A,B).

FIGURE 1.7. (A) Responses at a previously active and inactive lever in nondependent and postdependent rats.

FIGURE 1.7

(A) Responses at a previously active and inactive lever in nondependent and postdependent rats. SA: Ethanol-reinforced responses at the end of self-administration training. EXT: Responses during the final three extinction sessions. Reinstatement: Responses (more...)

The significance of a dependence history with respect to its role in the effects of alcohol cues and stress is illustrated further by the finding that previously ethanol-dependent rats show enhanced reinstatement induced not only by footshock stress but also by a CS conditioned to footshock stress. But importantly, again, both significant individual and interactive effects of conditioned stress and ethanol cues were observed only in rats with a history of ethanol dependence but not in nondependent rats (Figure 1.5A,B).

FIGURE 1.8. (A) Responses in ethanol-nondependent rats after exposure to conditioned stress (Stress CS) during response-contingent presentation of an ethanol-associated conditioned stimulus (EtOH CS) and during response-contingent availability of the EtOH CS preceded by exposure to the Stress CS (Stress CS + EtOH CS).

FIGURE 1.8

(A) Responses in ethanol-nondependent rats after exposure to conditioned stress (Stress CS) during response-contingent presentation of an ethanol-associated conditioned stimulus (EtOH CS) and during response-contingent availability of the EtOH CS preceded (more...)

1.4. CONCLUDING REMARKS

Persistent vulnerability to relapse represents a formidable challenge for the successful treatment of drug addiction. Understanding of the neurobiological basis of relapse and identification of treatment targets for relapse prevention are issues of particularly high priority in addiction research. Valid and increasingly sophisticated animal models of relapse have become available over the past decade and have been instrumental in expanding our understanding of the neurocircuitry and neural signaling mechanisms that mediate conditioned drug-seeking behavior and contribute to the long-lasting nature of susceptibility to relapse. An important consideration for behavioral strategies in addiction research will be to continue to develop methods that effectively model the diverse aspects of the addiction cycle. The data presented in this chapter document that a history of drug dependence and the experience of negative reinforcement, in addition to the positive-reinforcing, hedonic aspects of the drug experience, convey an additional dimension to the motivating actions of substances of abuse that requires understanding and consideration in medication development. Similarly, the finding that synergistic interactions exist between the response-reinstating effects of drug-associated cues and stress contributes to a better understanding of the relapse process per se by suggesting that the probability of relapse is likely to vary as a function of the number and intensity of risk factors operative at a given time. As well, this finding illustrates that effective pharmacotherapeutic prevention of relapse may require agents that provide concurrent protective effects against multiple risk factors. Using these models, valuable information about agents with such a pharmacological profile are being generated (e.g., Aujla et al. 2007; Baptista et al. 2004; Zhao et al. 2006), information that ultimately will contribute to the development of effective treatment drugs for relapse prevention.

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