Jump to ContentJump to Main Navigation
AlcoholScience, Policy and Public Health$

Peter Boyle, Paolo Boffetta, Albert B. Lowenfels, Harry Burns, Otis Brawley, Witold Zatonski, and Jürgen Rehm

Print publication date: 2013

Print ISBN-13: 9780199655786

Published to Oxford Scholarship Online: May 2013

DOI: 10.1093/acprof:oso/9780199655786.001.0001

Show Summary Details
Page of

PRINTED FROM OXFORD SCHOLARSHIP ONLINE (www.oxfordscholarship.com). (c) Copyright Oxford University Press, 2019. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a monograph in OSO for personal use (for details see www.oxfordscholarship.com/page/privacy-policy). Subscriber: null; date: 15 February 2019

Opioid pharmacogenetics of alcohol addiction

Opioid pharmacogenetics of alcohol addiction

Chapter:
(p.97) Chapter 11 Opioid pharmacogenetics of alcohol addiction
Source:
Alcohol
Author(s):

Wade Berrettini

Publisher:
Oxford University Press
DOI:10.1093/acprof:oso/9780199655786.003.0011

Abstract and Keywords

This chapter reviews clinical studies of naltrexone in alcoholism and pharmacogenetic studies of naltrexone clinical trials for alcohol addiction. There is growing interest in the association between μ-opioid receptors and addiction. Extensive data, across species, suggest that the 118G form of the μ-opioid receptor is characterized by decreased transcription and translation. Murine, primate, and human laboratory studies show that the 118G (or its species-specific homologue) variant permits alcohol to have a greater rewarding valence, leading to increased alcohol consumption. The human and rhesus data are equally convincing that naltrexone is able to blunt this greater rewarding signal.

Keywords:   opioids, alcohol reward, alcohol abuse, alcoholism, alcohol consumption, naltrexone, clinical studies

Introduction: the role of opioids in alcohol reward

There is growing interest in the relationship between mu opioid receptors and addiction to various substances. Ventral tegmental neurons release dopamine at nerve terminals in ventral striatum and medial prefrontal cortex. Activation of this circuit is a common element of abused drugs, including alcohol (1, 2). Thus, alcohol shares in common with nicotine, cocaine, amphetamine, morphine, etc., this property of enhancing dopamergic transmission in ventral striatum and medial prefrontal cortex. Both animal model and human studies are in agreement on this point (3, 4, 5). This release of dopamine in the ventral striatum and medial prefrontal cortex is partially enhanced by stimulation of mu opioid receptors (for which endorphin is the primary ligand) located on inhibitory gamma-aminobutyric acid (GABA)ergic interneurons in the ventral tegmental area. The GABAergic interneurons inhibit the dopaminergic ventral tegmental neurons, whose activation signals reward. Thus, mu opioid receptor agonists enhance the likelihood of ventral tegmental dopaminergic neuron activation (and the experience of reward) by lessening the tonic inhibition of the associated GABAergic interneurons (6, 7, 8).

Given this circuitry, it has been consistently shown that endogenous opioids play a role in ethanol reinforcement in various animal paradigms. Endorphin elevations after alcohol consumption are seen in discrete reward regions of the hypothalamus (9), ventral tegmentum, and ventral striatum (10). It is important to note that endorphin-deficient rats continue to self-administer alcohol, indicating that endorphin is not the sole mechanism of alcohol reward (11). The importance of mu opioid receptor activation as a mechanism for alcohol reward is underscored by the fact that alcohol consumption in alcohol-preferring rats is persistently reduced after inactivating mu opioid receptors in the ventral striatum (12). Similarly, decreased alcohol self-administration is observed in primates after pre-treatment with opioid antagonists (13). C57Bl/6J mice, an inbred strain which prefers alcohol, has increased endorphin release in the hypothalamus after alcohol administration (14). Alcohol-preferring rats have high levels of opioid gene messenger RNA (mRNA) species in the hypothalamus, prefrontal cortex, and mediodorsal nucleus of the thalamus (15), as well as increased mu opioid receptor density in the ventral striatum and medial prefrontal cortex.

Clinical studies of naltrexone in alcoholism

The development of a substantial body of evidence, in the 1980s, that naltrexone (an orally-active mu opioid receptor antagonist) diminished alcohol self-administration in animal models (13, 16, 17, 18, 19) led to the first use of naltrexone in alcohol-addicted populations in a controlled clinical trial (19), the promising outcome of which was immediately confirmed in a second controlled (p.98) clinical trial (20). Naltrexone was found to reduce alcohol craving and relapse to heavy drinking (operationally defined as five or more drinks/day for a man, four or more for a woman), but did not change abstinence rates. On the basis of these two controlled trials, naltrexone was approved by the US Food and Drug Administration, in the absence of the usual pharmaceutical industry interest.

In the intervening 20 years, there have been more than 30 clinical trials of naltrexone in alcohol addiction (21, 22, 23). While the majority of these clinical trials demonstrate efficacy of naltrexone in reducing risk for relapse to heavy drinking, the effect size is small, with many patients having no benefit. This has resulted in multiple reports in which the naltrexone arm outcomes are not significantly better than the placebo arm outcomes (24). This is an expected outcome, given the tremendous heterogeneity of clinical alcohol addiction. It is likely that important clinical characteristics, such as compliance, severity and duration of alcohol addiction, co-morbidity (both medical and psychiatric), and/or attendance at psychosocial treatment, may influence outcomes.

In this situation, multiple investigators have attempted to define clinical characteristics which might enhance the probability of naltrexone response. Some clinical measures have shown promise in characterizing a naltrexone responder—high alcohol craving (25, 26, 27) and strong family history of alcohol addiction (25), but family history of alcohol addiction did not predict response to naltrexone in the COMBINE multicentre trial (28). Alcohol addicts who experience greater euphoria after alcohol may have a better response to naltrexone (29).

A118G OPRM1 mis-sense single nucleotide polymorphism: molecular and cellular effects

A common mis-sense single nucleotide polymorphism (SNP; rs 1799971) in the first exon of the mu opioid receptor gene, OPRM1, was described by Bergen et al. (30), A118G, or N40G, reflecting the fact that the A allele encodes asparagine, while the minor G allele encodes aspartate. The A (asparagine) allele is thought to be N-glycosylated (31), whereas this is not possible for the G (aspartate) allele, as there is no free amino group. Subsequent studies (32, 33, 34, 35) revealed large ethnic differences in allele frequencies (Table 11.1).

Table 11.1 Frequency of G allele for A118G SNP in ethnic groups

Ethnic group

Frequency G

Ethnic group

Frequency G

African

1%

Korean

31%

African American

3%

Chinese

35%

Swedish

11%

Malaysian

43%

European American

15%

Indian

47%

This allele has been the subject of multiple molecular investigations to determine its functional consequences, in terms of gene expression, protein translation, receptor signalling, and receptor density. Initially, Bond et al. (36) reported that the minor ‘G’ allele mu opioid receptor resulted in decreased affinity for binding to beta-endorphin, compared to the common ‘A’ allele receptor. There was no change in binding affinity for alkaloid ligands. This result has not been confirmed in subsequent investigations (37, 38). In one such study transfected HEK293 cells (a fibroblastoid cell type) were used (37), but the 118G allele did not differ in binding affinity for beta-endorphin, compared to 118A. Beyer et al. (37) also reported that the 118G allele was not different from the 118A allele in rate of desensitization, internalization, or resensitization, but 118G had decreased (p.99) transcription compared to 118A. Ramchandani et al. (38) also did not report differences in kinetics of binding of beta-endorphin to the 118G, compared to 118A. Mahmoud et al. (39), using a whole-cell patch clamp technique in acutely dissociated trigeminal ganglion neurons, reported that morphine was fivefold less active at the ‘G’ allele receptor form in activating a Ca2+ channel. There was no such difference for fentanyl. Zhang et al. (40) conducted allelic imbalance studies in post-mortem human brain, revealing a marked decrease in 118G allele mRNA. In a second experiment, they showed in vitro evidence of a marked decreased translation of the 118G mRNA (40).

A118G OPRM1 mis-sense single nucleotide polymorphism: animal model studies

In the murine OPRM1 gene, there is no equivalent of the A118G naturally-occurring variation. A homologous variation (A112G, with the A allele encoding asparagines and the G allele encoding aspartate, as in the human OPRM1 gene) was created by bacterial artificial chromosome engineering and murine transgenic techniques by Mague et al. (41). They reported decreased transcription and translation of the G allele in transgenic C57Bl/6 mouse brain, a result congruous with the human post-mortem brain ex vivo results of Zhang et al. (40), as well as the in vitro results of Beyer et al. (37). There was a blunted locomotor response to morphine in the 112G mice, as well as decreased morphine conditioned place preference (CPP) in 112G female mice, the latter being a sexually dimorphic response, with 112G males showing the expected CPP response to morphine.

Two other forms of transgenic mice were produced, using homologous recombination to replace the murine OPRM1 exon 1 with one of the two forms (118A and 118G) of human OPRM1 exon 1 (38). These investigators conducted in vivo microdialysis experiments in the ventral striatum, demonstrating that the 118G mice had the expected elevations in dopamine release after alcohol, while the 118A mice had no significant increase over baseline. These data suggest that the ‘G’ allele conveys an increased rewarding valence to alcohol, compared to the ‘A’ allele.

There have been several studies of a similar SNP in the rhesus monkey, the C77G, which results in a homologous amino acid change, asparagine to aspartate (42, 43, 44). Both groups report that the G allele monkeys consume significantly more alcohol than the CC monkeys. Further, both groups note that naltrexone significantly decreases alcohol intake in the GG monkeys.

These reports, taken together, are consistent with the hypothesis that the 118G allele (or its equivalent in mouse and primate) conveys a greater rewarding effect of alcohol, a difference which is inhibited by naltrexone. These studies are remarkably consistent, given the species, paradigm, technical, and molecular engineering differences among these studies.

A118G OPRM1 mis-sense single nucleotide polymorphism: human pharmacogenetic studies of alcohol

There have been several pharmacogenetic reports of the A118G SNP in human laboratory experiments involving alcohol (38, 45, 46, 47, 48). In a laboratory investigation of the A118G pharmacogenetics of alcohol reward, Ray et al. (45, 46) demonstrated that the G allele carriers experienced significantly greater euphoria after standard oral doses of alcohol (while controlling for breath alcohol concentration), compared to AA persons. Further, naltrexone significantly blunted the euphoria in the G allele carriers and was without effect in the AA group.

In agreement with this result, Ramchandani reported that G allele carriers had a greater striatal release of dopamine after alcohol (using a raclopride positron emission tomography scan technique), compared to AA participants. In a more naturalistic approach, Ray et al. (47) studied (p.100) drinking habits of social drinkers over a five-day period, analysing subjective responses to alcohol by A118G genotype. G allele carriers reported more significantly more ‘vigour’ and less negative mood after drinking, compared to the AA group. Similarly, Setiawan et al. (48) studied the subjective response to alcohol in social drinkers after a dose of naltrexone. Naltrexone significantly decreased the ethanol-induced ‘euphoria’ to a priming dose of alcohol in subjects with the G allele, compared to AA participants.

Taken together, these human laboratory studies of the A118G variant on effect of alcohol are remarkably consistent, with the clear conclusion that the G allele permits people to experience alcohol in a more rewarding manner, compared to AA individuals. It is also notable that naltrexone is able to blunt this euphoria in G allele carriers, but not in AA persons. This latter observation is consistent with subjective reports of the effect of naltrexone in clinical trials for alcohol addiction, in which the medication attenuated alcohol-induced euphoria among responders (29).

Pharmacogenetic studies of naltrexone clinical trials for alcohol addiction

There have been multiple pharmacogenetic studies of naltrexone clinical trials for alcohol addiction published in the last decade. The first such publication (49) was a retrospective analysis of three naltrexone trials of similar design, two conducted at the University of Pennsylvania and one at the University of Connecticut, United States. Compliance was monitored by riboflavin testing and by pill counts. Eighty-two patients (71 of European descent) who were randomized to naltrexone and 59 randomized to placebo (all of European descent) in one of three randomized placebo-controlled clinical trials of naltrexone were genotyped at the A+118G (Asn40Asp) and C+17T (Ala6Val) SNPs in the mu-opioid gene (OPRM1). The association between genotype and drinking outcomes was measured over 12 weeks of treatment. For purposes of examining the pharmacogenetics of naltrexone response, the analysis was limited to those subjects with well-defined outcome data who had at minimum six weeks’ exposure to the medication. The primary drinking outcome considered was relapse to heavy drinking (≥5 drinks in a single day for men or ≥4 drinks for women). This definition of heavy drinking was the primary outcome for each of the trials. The timeline follow-back method was employed (along with self-report) to measure alcohol consumption (50). There was a significantly greater proportion of naltrexone-treated subjects with the G allele variant who did not return to heavy drinking (no relapse) compared to those with those homozygous for the A allele (Wald = 4.04, 1 degree of freedom, odds ratio = 3.47 (95% confidence interval: 1.03–11.67), p = 0.045) (Table 11.2).

Table 11.2 A118G genotype and good outcome in naltrexone studies (49, 51) of pharmacotherapy for alcohol addiction

Genotype at A118G

(49)

(51)

Naltrexone

Placebo

Naltrexone

Placebo

G allele carriers

85%a

55%

89%b

54%

Homozygous A

56%

46%

56%

50%

a P = 0.04, odds ratio = 3.5.

b P = 0.005, genotype × medication interaction; odds ratio = 5.8.

This finding was confirmed in a larger multisite study of naltrexone, acamprosate, and placebo for alcohol addiction (51). Alcohol-addicted subjects were treated for 16 weeks with 100 mg of (p.101) naltrexone. All participants received medical management alone or with combined behavioural intervention. When considering only those patients receiving medical management alone, there was a significant effect of naltrexone on ‘good outcome’ among the 118G carriers, while there was no such effect for the patients receiving naltrexone who were homozygous A118 (Table 11.2). However, there was no such effect in the naltrexone group receiving medical management with combined behavioural intervention. The combined behavioural intervention was delivered by licensed behavioural health specialists in up to 20 flexible participant need-adjusted 50-minute sessions. Combined behavioural intervention, an intensive and specific alcohol intervention, may have compensated for the placebo effect, thereby suppressing the chances of observing a main effect of naltrexone or a genetic interaction. The data presented by Anton et al. (51) are consistent with this thinking. A gene × medication interaction may be observable only in patients who can show obvious benefit from the medication over placebo.

In a small Korean study of naltrexone in alcohol addiction (52), subjects adherent to naltrexone treatment with one or two copies of the Asp40 allele took a significantly longer time than the Asn40 group to relapse to heavy drinking (p = 0.014). Although not significant, the Asn40 group treated with naltrexone had a 10.6 times greater relapse rate than the Asp40 variant group. There was no effect on abstinence.

In the Veterans Administration multisite study of naltrexone in alcohol addiction, Gelernter et al. (53) reported that the 118G allele did not predict outcome among 149 participants in the naltrexone group and 64 in the placebo group. There are several possible explanations for this result. Firstly, the efficacy of naltrexone is certainly influenced by compliance, and the compliant population was defined as those who opened the medication bottle a minimum of 50% of the time, so that medication compliance was defined liberally. Secondly, it is likely that high levels of co-morbidity influence response to naltrexone. The study population had substantial rates of recurrent unipolar illness, antisocial personality, and anxiety disorders and had severe alcohol addiction of long duration. These factors might overwhelm any genetic predisposition to respond to naltrexone. Thirdly, the study had limited power: for example, there were only nine 118G carriers in the placebo group.

Coller et al. (54) recently reported the results of a naltrexone and cognitive-behavioural therapy trial in 100 Australian alcohol-addicted persons. They reported an overall effect of naltrexone on relapse to heavy drinking, but no influence of the A188G variants. The absence of a control group makes this study less ideal, as does the small sample size, with 68 study completers.

Taken together, the A118G clinical trials in naltrexone treatment for alcohol addiction remain promising, but there are clear unanswered questions, including the influence of counselling, compliance, and co-morbidity on outcome. Available depot formulations of naltrexone may reduce non-compliance, but the influence of co-morbidity and counselling may be more difficult to resolve. It will be necessary to conduct pharmacogenetic alcohol addiction naltrexone trials, for which participants are randomized by A118G genotype into the naltrexone or placebo arm to reduce possible sources of bias. These trials should be characterized by:

  • large size (at least about 150 persons per arm, including oversampling of G allele carriers) to ensure adequate power

  • rigorous assessment of compliance

  • randomization stratified by genotype

  • careful assessment of comorbidity

  • modest psychotherapeutic intervention, so as to mirror ‘real-world’ clinical practice.

(p.102) Summary

There is a growing interest in the association between mu opioid receptors and addiction. There are extensive data, across species, to suggest that the 118G form of the mu opioid receptor is characterized by decreased transcription and translation. There are convincing data, from murine, primate, and human laboratory studies, that the 118G (or its species-specific homologue) variant permits alcohol to have a greater rewarding valence, leading to increased alcohol consumption. Further, the human and rhesus data are equally convincing that naltrexone is able to blunt this greater rewarding signal. Lastly, the possibility that A118G alleles can be used clinically to identify alcohol-addicted persons with a greater probability to have a beneficial response to naltrexone is a hypothesis that deserves testing on a large scale, with the characteristics noted earlier.

References

Bibliography references:

1 Di Chiara G and Imperato A (1988). Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci U S A, 85(14), 5274–8.

2 Koob GF and Volkow ND (2010). Neurocircuitry of addiction. Neuropsychopharmacology, 35(1), 217–38.

3 Spanagel R (2009). Alcoholism: a systems approach from molecular physiology to addictive behavior. Physiol Rev, 89(2), 649–705.

4 Boileau I, Assaad JM, Pihl RO, et al. (2003). Alcohol promotes dopamine release in the human nucleus accumbens. Synapse, 49(4), 226–31.

5 Gilman JM, Ramchandani VA, Davis MB, Bjork JM, and Hommer DW (2008). Why we like to drink: a functional magnetic resonance imaging study of the rewarding and anxiolytic effects of alcohol. J Neurosci, 28(18), 4583–91.

6 Spanagel R, Herz A, and Shippenberg TS (1992). Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway. Proc Natl Acad Sci U S A, 89(6), 2046–50.

7 Johnson SW and North RA (1992). Opioids excite dopamine neurons by hyperpolarization of local interneurons. J Neurosci, 12(2), 483–8.

8 Tanda GL and Di Chiara G (1998). A dopamine mu(1) opioid link in the rat ventral tegmentum shared by palatable food (Fonzies) and non-psychostimulant drugs of abuse. Eur J Neurosci, 10(3), 1179–87.

9 Popp RL and Erickson CK (1998). The effect of an acute ethanol exposure on the rat brain POMC opiopeptide system. Alcohol, 16(2), 139–48.

10 Rasmussen DD, Bryant CA, Boldt BM, Colasurdo EA, Levin N, and Wilkinson CW (1998). Acute alcohol effects on opiomelanocortinergic regulation. Alcohol Clin Exp Res, 22(4), 789–801.

11 Grahame NJ, Low MJ, and Cunningham CL (1998). Intravenous self-administration of ethanol in beta-endorphin-deficient mice. Alcohol Clin Exp Res, 22(5), 1093–8.

12 Myers RD and Robinson DE (1999). Mu and D2 receptor antisense oligonucleotides injected in nucleus accumbens suppress high alcohol intake in genetic drinking HEP rats. Alcohol, 18(2-3), 225–33.

13 Altshuler HL, Phillips PA, and Feinhandler DA (1980). Alteration of ethanol self-administration by naltrexone. Life Sci, 26(9), 679–88.

14 De Waele JP, Papachristou DN, and Gianoulakis C (1992). The alcohol-preferring C57BL/6 mice present an enhanced sensitivity of the hypothalamic beta-endorphin system to ethanol than the alcohol-avoiding DBA/2 mice. J Pharmacol Exp Ther, 261(2), 788–94.

15 Marinelli PW, Kiianmaa K, and Gianoulakis C (2000). Opioid propeptide mRNA content and receptor density in the brains of AA and ANA rats. Life Sci, 66(20), 1915–27.

16 Myers RD, Borg S, and Mossberg R (1986). Antagonism by naltrexone of voluntary alcohol selection in the chronically drinking macaque monkey. Alcohol, 3(6), 383–8.

(p.103) 17 Volpicelli JR, Davis MA, and Olgin JE (1986). Naltrexone blocks the post-shock increase of ethanol consumption. Life Sci, 38(9), 841–7.

18 Kiianmaa K, Hoffman PL, and Tabakoff B (1983). Antagonism of the behavioral effects of ethanol by naltrexone in BALB/c, C57BL/6, and DBA/2 mice. Psychopharmacology (Berl), 79(4), 291–4.

19 Volpicelli JR, Alterman AI, Hayashida M, and O’Brien CP (1992). Naltrexone in the treatment of alcohol dependence. Arch Gen Psychiatry, 49(11), 876–80.

20 O’Malley SS, Jaffe AJ, Chang G, Schottenfeld RS, Meyer RE, and Rounsaville B (1992). Naltrexone and coping skills therapy for alcohol dependence, a controlled study. Arch Gen Psychiat, 49(11), 881–7.

21 Bouza C, Angeles M, Muñoz A, and Amate JM (2004). Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence, a systematic review. Addiction, 99(7), 811–28.

22 Srisurapanont M and Jarusuraisin N (2005). Naltrexone for the treatment of alcoholism, a meta-analysis of randomized controlled trials. Int J Neuropsychopharmacol, 8(2), 267–80.

23 Pettinati HM, O’Brien CP, Rabinowitz AR, et al. (2006). The status of naltrexone in the treatment of alcohol dependence, specific effects on heavy drinking. J Clin Psychopharmacol, 26(6), 610–25.

24 Krystal JH, Cramer JA, Krol WF, Kirk GF, Rosenheck RA, and Veterans Affairs Naltrexone Cooperative Study 425 Group (2001). Naltrexone in the treatment of alcohol dependence. N Engl J Med, 345(24), 1734–9.

25 Monterosso JR, Flannery BA, Pettinati HM, et al. (2001). Predicting treatment response to naltrexone, the influence of craving and family history. Am J Addict, 10(3), 258–68.

26 O’Malley SS, Krishnan-Sarin S, Farren C, Sinha R, and Kreek MJ (2002). Naltrexone decreases craving and alcohol self administration in alcohol-dependent subjects and activates the hypothalamo-pituitaryadrenocortical axis. Psychopharmacology (Berl), 160(1), 19–29.

27 Chick J, Anton R, Checinski K, et al. (2000). A multicenter double-blind randomized trial of naltrexone in the treatment of alcohol dependence or abuse. Alcohol Alcoholism, 35(6), 587–93.

28 Capone C, Kahler CW, Swift RM, and O’Malley SS (2011). Does family history of alcoholism moderate naltrexone’s effects on alcohol use? J Stud Alcohol Drugs, 72(1), 135–40.

29 Volpicelli JR, Watson NT, King AC, Sherman CE, and O’Brien CP (1995). Effect of naltrexone on alcohol ‘high’ in alcoholics. Am J Psychiat, 152(4), 613–15.

30 Bergen AW, Kokoszka J, Peterson R, et al. (1997). Mu opioid receptor gene variants, lack of association with alcohol dependence. Mol Psychiatry, 2(6), 490–4.

31 Huang P, Chen C, Mague SD, Blendy JA, and Liu-Chen LY (2012). A common single nucleotide polymorphism A118G of the mu opioid receptor alters its N-glycosylation and protein stability. Biochem J, 441(1), 379–86.

32 Crowley JJ, Oslin DW, Patkar AA, et al. (2003). A genetic association study of the mu opioid receptor and severe opioid dependence. Psychiatr Genet, 13(3), 169–73.

33 Gelernter J, Kranzler H, and Cubells J (1999). Genetics of two m opioid receptor gene (OPRM1) exon I polymorphisms, Population studies, and allele frequencies in alcohol- and drug-dependent subjects. Mol Psychiatry, 4(5), 476–83.

34 Szeto CY, Tang NL, Lee DT, and Stadlin A (2001). Association between mu opioid receptor gene polymorphisms and Chinese heroin addicts. Neuroreport, 12(6), 1103–6.

35 Tan EC, Tan CH, Karupathivan U, and Yap EP (2003). Mu opioid receptor gene polymorphisms and heroin dependence in Asian populations. Neuroreport, 14(4), 569–72.

36 Bond C, LaForge KS, Tian M, et al. (1998). 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, 95(16), 9608–13.

37 Beyer A, Koch T, Schröder H, Schulz S, and Höllt V (2004). Effect of the A118G polymorphism on binding affinity, potency and agonist-mediated endocytosis, desensitization, and resensitization of the human mu-opioid receptor. J Neurochem, 89(3), 553–60.

(p.104) 38 Ramchandani VA, Umhau J, Pavon FJ, et al. (2011). A genetic determinant of the striatal dopamine response to alcohol in men. Mol Psychiatry, 16(8), 809–17.

39 Mahmoud S, Thorsell A, Sommer WH, et al. (2011). Pharmacological consequence of the A118G μ opioid receptor polymorphism on morphine- and fentanyl-mediated modulation of Ca2+ channels in humanized mouse sensory neurons. Anesthesiology, 115(5), 1054–62.

40 Zhang Y, Wang DX, Johnson AD, Papp AC, and Sadee W (2005). Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G. J Biol Chem, 280(38), 32618–24.

41 Mague SD, Isiegas C, Huang P, et al. (2009). Mouse model of OPRM1 (A118G) polymorphism has sex-specific effects on drug-mediated behavior. Proc Natl Acad Sci U S A, 106(26), 10847–52.

42 Vallender EJ, Ruedi-Bettschen D, Miller GM, and Platt DM (2010). A pharmacogenetic model of naltrexone-induced attenuation of alcohol consumption in rhesus monkeys. Drug Alcohol Depend, 109(1–3), 252–6.

43 Barr CS, Schwandt M, Lindell SG, et al. (2007). Association of a functional polymorphism in the mu-opioid receptor gene with alcohol response and consumption in male rhesus macaques. Arch Gen Psychiatry, 64(3), 369–76.

44 Barr CS, Chen SA, Schwandt ML, et al. (2010). Suppression of alcohol preference by naltrexone in the rhesus macaque: a critical role of genetic variation at the mu-opioid receptor gene locus. Biol Psychiatry, 67(1), 78–80.

45 Ray LA and Hutchison KE (2004). A polymorphism of the mu-opioid receptor gene (OPRM1) and sensitivity to the effects of alcohol in humans. Alcohol Clin Exp Res, 28(12), 1789–95.

46 Ray LA and Hutchison KE (2007). Effects of naltrexone on alcohol sensitivity and genetic moderators of medication response, a double-blind placebo-controlled study. Arch Gen Psychiatry, 64(9), 1069–77.

47 Ray LA, Miranda R Jr, Tidey JW, et al. (2010). Polymorphisms of the mu-opioid receptor and dopamine D4 receptor genes and subjective responses to alcohol in the natural environment. J Abnorm Psychol, 119(1), 115–25.

48 Setiawan E, Pihl RO, Cox SM, et al. (2011). The effect of naltrexone on alcohol’s stimulant properties and self-administration behavior in social drinkers, influence of gender and genotype. Alcohol Clin Ex Res, 35(6), 1134–41.

49 Oslin DW, Berrettini W, Kranzler HR, et al. (2003). A functional polymorphism of the mu-opioid receptor gene is associated with naltrexone response in alcohol-dependent patients. Neuropsychopharmacology, 28(8), 1546–52.

50 Sobell LC and Sobell MB (1992). Timeline follow-back, a technique for assessing self-reported alcohol consumption, in Litten R and Allen J (eds) Measuring alcohol consumption, pp. 41–65. Humana Press Inc., Totowa, NJ.

51 Anton RF, Oroszi G, O’Malley S, et al. (2008). An evaluation of mu-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence: results from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study. Arch Gen Psychiatry, 65(2), 135–44.

52 Kim SG, Kim CM, Choi SW, et al. (2009). A micro opioid receptor gene polymorphism (A118G) and naltrexone treatment response in adherent Korean alcohol-dependent patients. Psychopharmacology (Berl), 201(4), 611–18.

53 Gelernter J, Gueorguieva R, Kranzler HR, et al. (2007). Opioid receptor gene (OPRM1, OPRK1, and OPRD1) variants and response to naltrexone treatment for alcohol dependence, results from the VA Cooperative Study. Alcohol Clin Exp Res, 31(4), 555–63.

54 Coller JK, Cahill S, Edmonds, C, et al. (2011). OPRM1 A118G genotype fails to predict the effectiveness of naltrexone treatment for alcohol dependence. Pharmacogenet Genomics, 21(12), 902–5.