• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Curr Opin Pharmacol. Author manuscript; available in PMC Feb 1, 2010.
Published in final edited form as:
PMCID: PMC2741727
NIHMSID: NIHMS104319

Opiate and Cocaine Addiction: From Bench to Clinic and Back to the Bench

Summary

This review primarily focuses on our recent findings in bidirectional translational research on opiate and cocaine addictions. First, we present neurobiological and molecular studies on endogenous opioid systems (e.g., proopiomelanocortin, mu opioid receptor, dynorphin, and kappa opioid receptor), brain stress responsive systems (e.g., orexin, arginine vasopressin, V1b receptor, and corticotropin-releasing factor), hypothalamic-pituitary-adrenal axis and neurotransmitters (especially dopamine), in response to both chronic cocaine or opiate exposure and to drug withdrawal, using several newly developed animal models and molecular approaches. The second aspect is human molecular genetic association investigations including hypothesis-driven studies and genome-wide array studies, to define particular systems involved in vulnerability to develop specific addictions, and response to pharmacotherapy.

Introduction

In the field of drug addiction, like many others, for years there has been a focus of “bench-to-clinic,” that is translational, research. In our field, we have emphasized that there remains a continuing need to make careful observations in the clinic, as well as in real-world settings, and then to model findings of pattern, mode, and frequency, as well as specific types and routes of administration of drugs of abuse, for designing studies for research at “the bench” [1]. There, animal models, and molecular and cellular constructs are used, as appropriate, employing a variety of techniques of modern science, ranging from analytical and medicinal chemistry, and the newer techniques of molecular and cell biology and imaging, at the molecular up through the whole animal research, along with integrated neurobiological and behavioral studies. Our Laboratory of the Biology of Addictive Diseases focuses on what we began to refer to, in the late-1980s, as “bidirectional translational research.” It is enormously exciting to unravel the molecular and chemical mechanisms of the brain that underlie learning, memory, and behaviors. However, in our field, it is also very important, as promptly as possible, to translate those findings into the clinical setting for improvement of prevention and treatment of addictions. In this effort, an additional field is proving to be extremely helpful, that is, human molecular genetics.

In this brief concept paper, we will focus on two types of addiction: opiate addiction (to heroin, as well as to prescription opiates illicitly used) and cocaine addiction. We will present findings on the role of the endogenous opioid system, including the mu opioid receptor (MOP-r) system, which is involved in reward, the hypothalamic-pituitary-adrenal (HPA) stress-responsive system, and the countermodulatory kappa opioid receptor (KOP-r) system, as well as related classical neurotransmitter systems and other neuropeptides, in the pathophysiology of the addictive diseases. We also will cover some highlights of topics from recent work of human molecular genetics of these addictions, including hypothesis-driven studies and genome-wide array studies.

Although we have very effective treatments, when properly used, for opiate addiction, i.e., methadone maintenance, first developed by our laboratory in 1964 [2-3], and also buprenorphine maintenance, our laboratory and numerous others are still struggling to find a compound or several different compounds which may be demonstrated to be significantly effective in treatment of cocaine addiction, with willingness of clinical scientists and regulatory agencies to accept any specific medication documented to be helpful, on a long-term basis, to as low as 20% of those persons suffering from chronic cocaine addiction.

I. MOP-r, the HPA axis, and other stress responsive systems

Methadone (a selective MOP-r agonist, long-acting in humans) is widely used in treatment of short-acting opiate (primarily heroin) addiction [2, 3]. Methadone maintenance can decrease cocaine use in heroin-cocaine codependent patients [4, 5]. Consistent with our clinical and laboratory studies, other investigators have observed up-regulation of MOP-r binding in cocaine-dependent individuals, which is associated with cocaine craving [6]. In rats, after acute or chronic cocaine there is an increase in gene expression and MOP-r density in mesocorticolimbic regions [7, 8]. However, we have not found any increase in proopiomelanocortin (POMC) gene expression or one of its products, beta-endorphin, which is the longest of the endogenous opioid peptides, that normally acts at MOP-r.

In collaboration with Leri and colleagues, we investigated the effect of methadone on cocaine conditioned place preference (CPP) in rats, a rodent model for cocaine wanting/liking behaviors. Since methadone has a short half-life in rodents (about 60-80 min) [3], methadone was delivered through osmotic pumps [9] to mimic steady-state methadone (SSM) maintenance in humans. We found that 1) rats with SSM prior to cocaine conditioning did not develop and/or express cocaine CPP; 2) rats with SSM after cocaine conditioning expressed neither spontaneous nor cocaine-evoked CPP; and 3) increased MOP-r mRNA levels in nucleus accumbens (NAc) core after cocaine conditioning was dose-dependently prevented by SSM. Together, our results suggest that SSM blocks cocaine wanting and drug-precipitated cocaine “liking,” possibly by preventing MOP-r alterations in NAc core and thus avoiding a relative endorphin deficiency [10••].

Using small interfering RNAs (siRNA) targeting MOP-r, specifically in the ventral tegmental area/sub-substantia nigra compacta, we recently found that mice with reduced expression of MOP-r showed attenuated heroin-enhanced locomotor activity and CPP expression [11•]. Our results demonstrate the utility of siRNA in integrated neurobiological studies of specific genes expressed in specific brain regions, an approach which may have potential therapeutic value in the future.

Studies from our laboratory and others have examined the effects of withdrawal from chronic opioid administration on MOP-r gene expression in animal brain. Administration of opiates using pellets, used in some studies, differs from heroin addicts who use an intermittent pattern of self-administration to achieve rewarding effects and expose to withdrawal in between-dose intervals [3]. Therefore, an administration paradigm of chronic intermittent escalating-dose heroin or morphine was developed in our laboratory. Using this paradigm, we found that acute morphine withdrawal (but not chronic exposure) resulted in increased MOP-r mRNA levels in NAc core, lateral hypothalamus (LHypo) and caudate-putamen [12], again further supporting the need for chronic MOP-r agonist or partial agonist treatment of opiate addiction.

Recent evidence suggests an important role for orexins/hypocretins in modulation of drug reward and addiction-like behaviors in rodents [13]. Preprodynorphin (pDYN) expresses in all the orexin neurons in LHypo. While acute cocaine withdrawal increased both LHypo orexin and pDYN mRNA levels [14], morphine withdrawal only increased orexin levels [12], suggesting that the orexin/dynorphin system is differentially involved in cocaine and opiate withdrawal (see section II). The orexin system may be a target for therapeutic interventions.

Recent human studies have demonstrated that severe or unavoidable psychological stressors elevate cocaine and alcohol craving and HPA activity, whereas modest activation of the HPA axis, for instance by MOP-r antagonist administration, may reduce craving, and the HPA responses in part predict subsequent drug relapse [15•, 16]. In rats, chronic cocaine and its withdrawal dynamically alter HPA activity and expression levels of stress responsive genes (Table 1) [17]. Stress-related anxiety and depression are major psychiatric consequences of chronic drug abuse, especially during withdrawal [18•]. Cocaine withdrawal increases arginine vasopressin (AVP) mRNA levels in rat medial amygdala [19]. Amygdalar AVP mRNA increases are further found during early heroin withdrawal and also after foot shock in the rat withdrawn from heroin for 2 weeks [20•]. There are three subtypes of AVP receptors: V1a, V1b, and V2. While V2 is located in the kidney and mediates the antidiuretic action, V1a and V1b are expressed in extended amygdala. Selective V1b antagonists dose-dependently attenuated foot-shock-induced reinstatement of heroin-seeking behavior, and blunted the HPA activation by stress [20•]. Our data suggest that the stress-responsive AVP/V1b system may provide new therapeutic targets for prevention of drug relapse.

Table 1
Effects of chronic “binge” pattern cocaine administration (3 × 15 mg/kg/day i.p. at hourly intervals) across 14 days (A) and across 10 days of withdrawal from 14 days of chronic “binge” cocaine (B) on plasma ACTH ...

II. KOP-r/pDYN system

The KOP-r system, and its endogenous peptide agonists (dynorphins), have been implicated in the acute and chronic modulation of neurobiological and behavioral effects of drugs of abuse, including opiates and psychostimulants, and alcohol. This modulation is largely thought to be due to the prominent localization of this neuropeptide system in the mesocorticolimbic and nigrostriatal dopaminergic pathways, major direct and downstream targets of drugs of abuse. Acutely administered drugs of abuse (e.g., opiates, alcohol and psychostimulants) cause elevations in extracellular fluid dopamine in the striatum (including NAc), and dopamine surges are thought to partially underlie initial rewarding effects [21]. KOP-r agonists (synthetic or endogenous) tend to have the opposite effect, as a counter-regulatory mechanism. Also, the KOP-r/pDYN system is reoccurently up-regulated in response to both acute and chronic drugs of abuse, possibly priming a state of heightened vulnerability to relapse [7].

Thus it has been hypothesized that ligands acting at KOP-r may be potential pharmacotherapeutic agents for specific stages in the treatment of addictive diseases [1]. Acutely, high efficacy KOP-r agonists have been shown to block the rewarding and psychostimulant effects of cocaine [22]. However, high efficacy KOP-r agonists are known to have psychotomimetic effects in humans [23], and it is unknown whether doses of these compounds that do not produce such undesirable effects would be chronically active in the blockade of cocaine-induced reward. The shortcomings potentially associated with the use of high efficacy KOP-r agonists may suggest that a KOP-r partial agonist may effectively modulate hypo- or hyper-activity in the KOP-r/pDYN system, in the absence of severe psychotomimetic effects. There are currently no well studied selective KOP-r partial agonists, however several clinically used compounds have partial KOP-r agonist effects in addition to their actions at other sites (typically MOP-r sites; e.g., nalbuphine, butorphanol, pentazocine). Notably, nalmefene (a clinically available MOP-r antagonist) has also been shown to be a KOP-r partial agonist in humans, and does not produce psychotomimetic effects, consistent with its low efficacy at KOP-r [24]. Thus nalmefene, or a congener with reduced secondary affinity at MOP-r, may represent a valuable pharmacotherapeutic approach in the management of psychostimulant addiction.

Consistent with an alternative hypothesis that activation of the KOP-r/pDYN system may enhance vulnerability to relapse, a selective KOP-r antagonist, JDTic, was able to block shock-induced (a stressor), but not cocaine-induced, reinstatement of cocaine self-administration in rodents [25]. Similar to other KOP-r antagonists, JDTic also produced antidepressant-like effects [25]. Since depressed mood states and stress may be important vulnerability factors in relapse to cocaine addiction, administration of a selective KOP-r antagonist may be a potential pharmacotherapeutic approach. Of note JDTic, like most other known selective KOP-r antagonists, is of very long duration in vivo (at least several days). The molecular underpinnings, and pharmacotherapeutic consequences, of these long-lasting effects of KOP-r antagonists are potential areas for investigation.

III. Human molecular genetic studies

1. Genome-wide case-control association studies

Three pooled DNA studies of polysubstance abuse were reported by the Uhl group. The first study [26] scanned 1,494 SNPs, in European Americans (EA) and African Americans (AA), provided 41 candidate chromosomal regions including one spanning the genes encoding brain-derived neurotrophic factor (BDNF) and alcohol dehydrogenase 3. A 10K scan [27] identified 38 risk variants including genes implicated in “cell adhesion” and alcohol dehydrogenase gene clusters. The third 639K study [28] identified 89 potential risk genes including genes implicated in cell adhesion.

A recent 10K scan from our laboratory [29•] was conducted in an EA population of former heroin addicts in methadone treatment. The most significant associations were obtained with two intergenic variants (rs965972 and rs1986513), and the intronic SNP rs1714984 (myocardin gene). An association was also shown for a genotype pattern (rs1714984, rs965972 and rs1867898). Evidence for association was also detected for SNPs located upstream/downstream (11-75 kb) of the hypothesis-driven genes encoding MOP-r, metabotropic receptors mGluR6 and mGluR8, nuclear receptor NR4A2 as well as cryptochrome 1 (photolyase-like).

2. Hypothesis-driven gene association studies

Hypothesis-driven gene association studies have reported association of heroin addiction with variants in various genes (Table 2). These genes are encoding the MOP-r, KOP-r, delta-opioid receptor (DOP-r), dopamine receptors D2 and D4, serotonin receptor 1B, serotonin transporter, gamma-aminobutryic acid (GABA) receptor gamma 2, catechol-O-methyltransferase (COMT, involved in metabolism of estrogen and dopamine), period circadian protein 3, proenkephalin, POMC, tryptophan hydroxylase 2, BDNF and melanocortin receptor type 2 (ACTH receptor). In a recent hypothesis-driven multi-gene study [30••], we scanned 1350 variants in 130 candidate genes in an EA population of 412 former severe heroin addicts in methadone treatment, and 184 healthy controls. The nine variants that showed the most significant associations were in non-coding regions of the genes encoding the MOP-r, KOP-r and DOP-r, serotonin receptor 3B, galanin (involved in regulation of food intake, behavioral and neurochemical effects of opiates and high stress response), and casein kinase 1epsilon (participates in important signaling pathways including the phosphorylation of the circadian rhythm protein, period).

Table 2
Genes associated with heroin and/or cocaine addiction by hypothesis-driven single or multiple gene association studies

Several studies reported association of cocaine addiction (with or without alcohol comorbidity) with genetic variants (Table 2). These include the genes encoding DOP-r, pDYN, COMT, dopamine transporter 1, dopamine receptor D2, cannabinoid receptor 1, tachykinin receptor 3 (involved in activation of phospholipase C by binding of substance P, associated with the regulation of anxiety, depression and stress), Homer1 (a dendritic protein that has a role in signal transduction and regulates group 1 mGluR function), and nicotinic cholinergic receptor subunits alpha 3 and 5. Also, associations were reported for mixed addictions (cocaine and/or heroin) with variants in the genes encoding the MOP-r, multiple ADH genes, proenkephalin, POMC, cholinergic muscarinic 2 receptor, cannabinoid receptor 1 and dopamine receptor D2 (Table 2).

3. P-glycoprotein gene (ABCB1, MDR1) variants and methadone dose requirements

The inter-individual variability in methadone dose effectiveness may be determined in part by genetic factors. Since methadone is a substrate of P-glycoprotein, we assessed the association between ABCB1 SNPs and methadone dose requirements in 98 methadone-maintained heroin addicts from Israel [31•]. A significant difference in genotype frequencies was found between the “higher” (>150 mg/day) and “lower” (≤150 mg/day) dose groups for the synonymous SNP 1236C>T (rs1128503) and for a 3-locus genotype pattern TT-TT-TT (rs1045642, rs2032582 and rs1128503).

4 A functional PDYN haplotype is associated with cocaine/alcohol dependence

In a recent study [32•] we tested for association of PDYN polymorphisms with vulnerability to develop cocaine and/or cocaine/alcohol dependence, in EA and AA subjects. An association was found with three linked 3′ UTR SNPs, independently and as a haplotype, in EA. We showed differential allelic expression for SNP rs910079 in caudate and nucleus accumbens of human postmortem brains. There were also lower levels of total PDYN expression of postmortem brains in subjects having the risk haplotype.

Each of these genes, enumerated above, may turn out to be interesting targets for further studies in animal modeling and might, in the future, yield targets for specific compounds for challenge studies in humans and possibly therapeutic agents [33].

IV. Conclusion

The bidirectional translational approach continues to yield both discovery of new potential targets, as well as confirm or refute hypothesis-driven sites of action, downstream events, and the various dynamic changes which occur during the development and persistence of, as well as relapse to and addiction to a specific drug of abuse. This type of bench-to-bedside and back again is undoubtedly critical for future advances in our field.

Acknowledgments

We thank Mr. Kitt Lavoie and Ms. Susan Russo for help in preparation of this manuscript. Funding support was received from the National Institutes of Health-National Institute on Drug Abuse Research Center P60-DA05130 (Kreek), National Institutes of Health-National Institute on Mental Health MH-79880 (Kreek), National Center for Research Resources UL1RR024143 (Coller), and the New York State Office of Alcoholism and Substance Abuse Services C003189 (Kreek).

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

1. Kreek MJ, LaForge KS, Butelman E. Pharmacotherapy of addictions. Nat Rev Drug Discov. 2002;1:710–726. [PubMed]
2. Dole VP, Nyswander ME, Kreek MJ. Narcotic blockade. Arch Intern Med. 1966;118:304–309. [PubMed]
3. Kreek MJ. Medical safety and side effects of methadone in tolerant individuals. JAMA. 1973;223:665–667. [PubMed]
4. Borg L, Broe DM, Ho A, Kreek MJ. Cocaine abuse sharply reduced in an effective methadone maintenance program. J Addict Dis. 1999;18:63–75. [PubMed]
5. Peles E, Kreek MJ, Kellogg S, Adelson M. High methadone dose significantly reduces cocaine use in methadone maintenance treatment (MMT) patients. J Addict Dis. 2006;25:43–50. [PubMed]
6. Gorelick DA, Kim YK, Bencherif B, Boyd SJ, Nelson R, Copersino M, Endres CJ, Dannals RF, Frost JJ. Imaging brain mu-opioid receptors in abstinent cocaine users: time course and relation to cocaine craving. Biol Psychiatry. 2005;57:1573–1582. [PubMed]
7. Unterwald EM, Rubenfeld JM, Kreek MJ. Repeated cocaine administration upregulates kappa and mu, but not delta, opioid receptors. Neuroreport. 1994;5:1613–1616. [PubMed]
8. Yuferov V, Zhou Y, Spangler R, Maggos CE, Ho A, Kreek MJ. Acute “binge” cocaine increases mu-opioid receptor mRNA levels in areas of the rat mesolimbic mesocortical dopamine system. Brain Res Bull. 1999;48:109–112. [PubMed]
9. Zhou Y, Spangler R, LaForge KS, Maggos CE, Ho A, Kreek MJ. Steady-state methadone in rats does not change mRNA levels of corticotropin-releasing factor, its pituitary receptor or proopiomelanocortin. Eur J Pharmacol. 1996;315:31–35. [PubMed]
••10. Leri F, Zhou Y, Goddard B, Cummins E, Kreek MJ. Effects of high dose methadone maintenance on cocaine place conditioning, cocaine self-administration, and mu-opioid receptor mRNA expression in the rat brain. Neuropsychopharmacology. 2006;31:1462–1474. [PubMed]Using both quantitative assays of gene expression and conditioned place preference behavioral model, the authors demonstrate that high-dose steady-state methadone (through osmotic pumps) to mimic methadone maintenance in humans, blocks cocaine-wanting and seeking behaviors, possibly by preventing the MOP-r mRNA increase in rat nucleus accumbens core.
•11. Zhang Y, Landthaler M, Schlussman SD, Yuferov V, Ho A, Tuschl T, Kreek MJ. Mu opioid receptor knockdown in the substantia nigra/ventral tegmental area by synthetic small interfering RNA blocks the rewarding and locomotor effects of heroin. Neuroscience. 2008 in press. [PMC free article] [PubMed]This study demonstrates that knockdown of MOP-r in mouse substantia nigra/ventral tegmental area by siRNA specifically targeting MOP-r, attenuated heroin CPP expression. Our results demonstrate the utility of siRNA in integrated neurobiological studies of specific genes and approach which may have potential therapeutic value for the future.
12. Zhou Y, Bendor J, Hofmann L, Randesi M, Ho A, Kreek MJ. Mu opioid receptor and orexin/hypocretin mRNA levels in the lateral hypothalamus and striatum are enhanced by morphine withdrawal. J Endocrinol. 2006;191:137–145. [PubMed]
13. Harris GC, Wimmer M, Aston-Jones G. A role for lateral hypothalamic orexin neurons in reward seeking. Nature. 2005;437:556–559. [PubMed]
14. Zhou Y, Cui CL, Schlussman SD, Choi J, Ho A, Han JS, Kreek MJ. Effect of cocaine place conditioning, chronic escalating-dose binge pattern cocaine and its acute withdrawal on orexin/hypocretin and preprodynorphin gene expressions in lateral hypothalamus of Fischer 344 and Sprague-Dawley rats. Neuroscience. 2008;153:1225–1234. [PMC free article] [PubMed]
•15. Sinha R, Garcia M, Paliwal P, Kreek MJ, Rounsaville BJ. Stress-induced cocaine craving and hypothalamic-pituitary-adrenal responses are predictive of cocaine relapse outcomes. Arch Gen Psychiatry. 2006;63:324–331. [PubMed]The first human study to show that psychological stressors elevate cocaine craving and HPA activity, and stress-induced HPA responses predict amounts of subsequent cocaine abuse.
16. O'Malley SS, Krishnan-Sarin S, Farren C, Sinha R, Kreek MJ. Naltrexone decreases craving and alcohol self-administration in alcohol dependent subjects and activates the hypothalamo-pituitary-adrenocortical axis. Psychopharmacology (Berl) 2004;160:19–29. [PubMed]
17. Zhou Y, Spangler R, LaForge KS, Maggos CE, Ho A, Kreek MJ. Corticotropin-releasing factor and type 1 corticotropin-releasing factor receptor messenger RNAs in rat brain and pituitary during “binge”-pattern cocaine administration and chronic withdrawal. J Pharmacol Exp Ther. 1996;279:351–358. [PubMed]
•18. Koob GF, Kreek MJ. Stress, dysregulation of drug reward pathways, and the transition to drug dependence. Am J Psychiatry. 2007;164:1149–1159. [PMC free article] [PubMed]One of the most rigorous of the recent reviews provides a neuroadaptive perspective regarding the role of the HPA hormonal system and brain stress system (particularly in the extended amygdala) in drug addiction with a focus on the changes that occur during the transition from limited access to drugs to long-term compulsive use of drugs.
19. Zhou Y, Bendor J, Yuferov V, Schlussman SD, Ho A, Kreek MJ. Amygdalar vasopressin mRNA increases in acute cocaine withdrawal: evidence for opioid receptor modulation. Neuroscience. 2005;134:1391–1397. [PubMed]
•20. Zhou Y, Leri F, Cummins E, Hoeschele M, Kreek MJ. Involvement of arginine vasopressin and V1b receptor in heroin withdrawal and heroin seeking precipitated by stress and by heroin. Neuropsychopharmacology. 2008;33:226–236. [PubMed]The first paper to show that arginine vasopressin mRNA levels are increased selectively in rat amygdala during early withdrawal from heroin, and selective V1b receptor antagonists block the reinstatement of heroin-seeking behavior and HPA activation induced by stress.
21. Di Chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci U S A. 1988;85:5274–5278. [PMC free article] [PubMed]
22. Zhang Y, Butelman ER, Schlussman SD, Ho A, Kreek MJ. Effects of the endogenous kappa opioid agonist dynorphin A(1-17) on cocaine-evoked increases in striatal dopamine levels and cocaine-induced place preference in C57BL/6J mice. Psychopharmacology (Berl) 2004;172:422–429. [PubMed]
23. Walsh SL, Geter-Douglas B, Strain EC, Bigelow GE. Enadoline and butorphanol: evaluation of kappa-agonists on cocaine pharmacodynamics and cocaine self-administration in humans. J Pharmacol Exp Ther. 2001;299:147–158. [PubMed]
24. Bart G, Schluger JH, Borg L, Ho A, Kreek MJ. Nalmefene induced elevation in serum prolactin in normal human volunteers: Partial kappa-opioid agonist activity? Neuropsychopharmacology. 2005;30:2254–2262. [PubMed]
25. Beardsley PM, Howard JL, Shelton KL, Carroll FI. Differential effects of the novel kappa- opioid receptor antagonist, JDTic, on reinstatement of cocaine-seeking induced by footshock stressors vs. cocaine primes and its antidepressant-like effects in rats. Psychopharmacology (Berl) 2005;183:118–126. [PubMed]
26. Uhl GR, Liu QR, Walther D, Hess J, Naiman D. Polysubstance abuse-vulnerability genes: genome scans for association, using 1,004 subjects and 1,494 single-nucleotide polymorphisms. Am J Hum Genet. 2001;69:1290–1300. [PMC free article] [PubMed]
27. Liu QR, Drgon T, Walther D, Johnson C, Poleskaya O, Hess J, Uhl GR. Pooled association genome scanning: validation and use to identify addiction vulnerability loci in two samples. Proc Natl Acad Sci U S A. 2005;102:11864–11869. [PMC free article] [PubMed]
28. Liu QR, Drgon T, Johnson C, Walther D, Hess J, Uhl GR. Addiction molecular genetics: 639,401 SNP whole genome association identifies many “cell adhesion” genes. Am J Med Genet B Neuropsychiatr Genet. 2006;141B:918–925. [PubMed]
•29. Nielsen DA, Ji F, Yuferov V, Ho A, Chen A, Levran O, Ott J, Kreek MJ. Genotype patterns that contribute to increased risk for or protection from developing heroin addiction. Mol Psychiatry. 2008;13:4170–428. [PMC free article] [PubMed]In order to detect joint gene effect and to avoid reliance on statistical inference of haplotypes, this study analyzed genotype patterns and identified association of a 3-SNPs genotype pattern with protection from heroin addiction with population attributable risk of 83%.
••30. Levran O, Londono D, O'Hara K, Nielsen DA, Peles E, Rotrosen J, Casadonte P, Linzy S, Randesi M, Ott J, et al. Genetic susceptibility to heroin addiction; a candidate-gene association study. Genes Brain Behav. 2008;7:720–729. [PMC free article] [PubMed]This study used a hypothesis-driven custom SNP array (Illumina), a selected specific phenotype (former heroin addicts in methadone treatment), stringent control selection criteria, and one ethnicity (Caucasians). It also employed AIMs to exclude population stratification and tests for association of haplotypes.
•31. Levran O, O'Hara K, Peles E, Li D, Barral S, Ray B, Borg L, Ott J, Adelson M, Kreek MJ. ABCB1 (MDR1) genetic variants are associated with methadone doses required for effective treatment of heroin dependence. Hum Mol Genet. 2008;17:2219–27. [PMC free article] [PubMed]This study aims to asses the clinical relevance of genetic variation in an efflux pump protein, at the blood-brain barrier (Pgp), in methadone brain distribution. It revealed a strong LD across most of the ABCB1 gene and low haplotype diversity that may explain some of the contradicting data of different studies.
•32. Yuferov Y, Ji F, Nielsen DA, Levran O, Ho A, Morgello S, Shi R, Ott J, Kreek MJ. A functional haplotype implicated in vulnerability to develop cocaine dependence is associated with reduced PDYN expression in human brain. Neuropsychopharmacology. 2008 in press. [PMC free article] [PubMed]The study provides the first evidence that SNP rs910079 may be a cis-acting polymorphism, related to differential PDYN gene expression in an allele-specific manner. This study uses ex vivo method for quantitative measurements of differential mRNA allelic expression in human brain environment study postmortem.
33. Kreek MJ, Bart G, Lilly C, LaForge KS, Nielsen DA. Pharmacogenetics and human molecular genetics of opiate and cocaine addictions and their treatments. Pharmacol Rev. 2005;57:1–26. [PubMed]
34. Zhou Y, Spangler R, Ho A, Kreek MJ. Increased CRH mRNA levels in the rat amygdala during acute withdrawal from chronic “binge” cocaine. Brain Res Mol Brain Res. 2003;114:73–79. [PubMed]
35. Bond C, LaForge KS, Tian M, Melia D, Zhang S, Borg L, Gong J, Schluger J, Strong JA, Leal SM, et al. Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci U S A. 1998;95:9608–9613. [PMC free article] [PubMed]
36. Bart G, Heilig M, LaForge KS, Pollak L, Leal SM, Ott J, Kreek MJ. Substantial attributable risk related to a functional mu-opioid receptor gene polymorphism in association with heroin addiction in central Sweden. Mol Psychiatry. 2004;9:547–549. [PubMed]
37. Zhang H, Luo X, Kranzler HR, Lappalainen J, Yang BZ, Krupitsky E, Zvartau E, Gelernter J. Association between two mu-opioid receptor gene (OPRM1) haplotype blocks and drug or alcohol dependence. Hum Mol Genet. 2006;15:807–819. [PMC free article] [PubMed]
38. Yuferov V, Fussell D, LaForge KS, Nielsen DA, Gordon D, Ho A, Leal SM, Ott J, Kreek MJ. Redefinition of the human kappa opioid receptor gene (OPRK1) structure and association of haplotypes with opiate addiction. Pharmacogenetics. 2004;14:793–804. [PubMed]
39. Gerra G, Leonardi C, Cortese E, D'Amore A, Lucchini A, Strepparola G, Serio G, Farina G, Magnelli F, Zaimovic A, et al. Human kappa opioid receptor gene (OPRK1) polymorphism is associated with opiate addiction. Am J Med Genet B Neuropsychiatr Genet. 2007;144:771–775. [PubMed]
40. Zhang H, Kranzler HR, Yang BZ, Luo X, Gelernter J. The OPRD1 and OPRK1 loci in alcohol or drug dependence: OPRD1 variation modulates substance dependence risk. Mol Psychiatry. 2008;13:531–543. [PMC free article] [PubMed]
41. Chen AC, LaForge KS, Ho A, McHugh PF, Kellogg S, Bell K, Schluger RP, Leal SM, Kreek MJ. Potentially functional polymorphism in the promoter region of prodynorphin gene may be associated with protection against cocaine dependence or abuse. Am J Med Genet. 2002;114:429–435. [PubMed]
42. Dahl JP, Weller AE, Kampman KM, Oslin DW, Lohoff FW, Ferraro TN, O'Brien CP, Berrettini WH. Confirmation of the association between a polymorphism in the promoter region of the prodynorphin gene and cocaine dependence. Am J Med Genet B Neuropsychiatr Genet. 2005;139B:106–108. [PubMed]
43. Williams TJ, LaForge KS, Gordon D, Bart G, Kellogg S, Ott J, Kreek MJ. Prodynorphin gene promoter repeat associated with cocaine/alcohol codependence. Addict Biol. 2007;12:496–502. [PubMed]
44. Xuei X, Flury-Wetherill L, Bierut L, Dick D, Nurnberger J, Jr, Foroud T, Edenberg HJ. The opioid system in alcohol and drug dependence: Family-based association study. Am J Med Genet B Neuropsychiatr Genet. 2007;144:877–884. [PubMed]
45. Dahl JP, Kampman KM, Oslin DW, Weller AE, Lohoff FW, Ferraro TN, O'Brien CP, Berrettini WH. Association of a polymorphism in the Homer1 gene with cocaine dependence in an African American population. Psychiatr Genet. 2005;15:277–283. [PubMed]
46. Foroud T, Wetherill LF, Kramer J, Tischfield JA, Nurnberger JI, Jr, Schuckit MA, Xuei X, Edenberg HJ. The tachykinin receptor 3 is associated with alcohol and cocaine dependence. Alcohol Clin Exp Res. 2008;32:1023–1030. [PMC free article] [PubMed]
47. Proudnikov D, Hamon S, Ott J, Kreek MJ. Association of polymorphisms in the melanocortin receptor type 2 (MC2R, ACTH receptor) gene with heroin addiction. Neurosci Lett. 2008;435:234–239. [PMC free article] [PubMed]
48. Xu K, Lichtermann D, Lipsky RH, Franke P, Liu X, Hu Y, Cao L, Schwab SG, Wildenauer DB, Bau CH, et al. Association of specific haplotypes of D2 dopamine receptor gene with vulnerability to heroin dependence in 2 distinct populations. Arch Gen Psychiatry. 2004;61:597–606. [PubMed]
49. Szilagyi A, Boor K, Szekely A, Gaszner P, Kalasz H, Sasvari-Szekely M, Barta C. Combined effect of promoter polymorphisms in the dopamine D4 receptor and the serotonin transporter genes in heroin dependence. Neuropsychopharmacol Hung. 2005;7:28–33. [PubMed]
50. Guindalini C, Howard M, Haddley K, Laranjeira R, Collier D, Ammar N, Craig I, O'Gara C, Bubb VJ, Greenwood T, et al. A dopamine transporter gene functional variant associated with cocaine abuse in a Brazilian sample. Proc Natl Acad Sci U S A. 2006;103:4552–4557. [PMC free article] [PubMed]
51. Lohoff FW, Weller AE, Bloch PJ, Nall AH, Ferraro TN, Kampman KM, Pettinati HM, Oslin DW, Dackis CA, O'Brien CP, et al. Association between the catechol-O-methyltransferase Val158Met polymorphism and cocaine dependence. Neuropsychopharmacology. 2008 Aug 13; Epub ahead of print. [PMC free article] [PubMed]
52. Proudnikov D, LaForge KS, Hofflich H, Levenstien M, Gordon D, Barral S, Ott J, Kreek MJ. Association analysis of polymorphisms in serotonin 1B receptor (HTR1B) gene with heroin addiction: a comparison of molecular and statistically estimated haplotypes. Pharmacogenet Genomics. 2006;16:25–36. [PubMed]
53. Gerra G, Garofano L, Santoro G, Bosari S, Pellegrini C, Zaimovic A, Moi G, Bussandri M, Moi A, Brambilla F, et al. Association between low-activity serotonin transporter genotype and heroin dependence: behavioral and personality correlates. Am J Med Genet B Neuropsychiatr Genet. 2004;126B:37–42. [PubMed]
54. Nielsen DA, Barral S, Proudnikov D, Kellogg S, Ho A, Ott J, Kreek MJ. TPH2 and TPH1: association of variants and interactions with heroin addiction. Behav Genet. 2008;38:1313–150. [PubMed]
55. Loh EW, Tang NL, Lee DT, Liu SI, Stadlin A. Association analysis of GABA receptor subunit genes on 5q33 with heroin dependence in a Chinese male population. Am J Med Genet B Neuropsychiatr Genet. 2007;144:439–443. [PubMed]
56. Comings DE, Muhleman D, Gade R, Johnson P, Verde R, Saucier G, MacMurray J. Cannabinoid receptor gene (CNR1): association with i.v. drug use. Mol Psychiatry. 1997;2:161–168. [PubMed]
57. Zhang PW, Ishiguro H, Ohtsuki T, Hess J, Carillo F, Walther D, Onaivi ES, Arinami T, Uhl GR. Human cannabinoid receptor 1: 5′ exons, candidate regulatory regions, polymorphisms, haplotypes and association with polysubstance abuse. Mol Psychiatry. 2004;9:916–931. [PubMed]
58. Ballon N, Leroy S, Roy C, Bourdel MC, Charles-Nicolas A, Krebs MO, Poirier MF. (AAT)n repeat in the cannabinoid receptor gene (CNR1): association with cocaine addiction in an African-Caribbean population. Pharmacogenomics J. 2006;6:126–130. [PubMed]
59. Luo X, Kranzler HR, Zuo L, Wang S, Blumberg HP, Gelernter J. CHRM2 gene predisposes to alcohol dependence, drug dependence and affective disorders: results from an extended case-control structured association study. Hum Mol Genet. 2005;14:2421–2434. [PubMed]
60. Cheng CY, Hong CJ, Yu YW, Chen TJ, Wu HC, Tsai SJ. Brain-derived neurotrophic factor (Val66Met) genetic polymorphism is associated with substance abuse in males. Brain Res Mol Brain Res. 2005;140:86–90. [PubMed]
61. Zou Y, Liao G, Liu Y, Wang Y, Yang Z, Lin Y, Shen Y, Li S, Xiao J, Guo H, et al. Association of the 54-nucleotide repeat polymorphism of hPer3 with heroin dependence in Han Chinese population. Genes Brain Behav. 2007;7:26–30. [PubMed]
62. Luo X, Kranzler HR, Zuo L, Wang S, Schork NJ, Gelernter J. Multiple ADH genes modulate risk for drug dependence in both African- and European-Americans. Hum Mol Genet. 2007;16:380–390. [PMC free article] [PubMed]
PubReader format: click here to try

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Compound
    Compound
    PubChem Compound links
  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • SNP
    SNP
    PMC to SNP links
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...