Association of a Functional Polymorphism in the μ-Opioid Receptor Gene With Alcohol Response and Consumption in Male Rhesus Macaques

Barr, Christina S.; Schwandt, Melanie; Lindell, Stephen G.; Chen, Scott A.; Goldman, David; Suomi, Stephen J.; Higley, J. Dee; Heilig, Markus

doi:10.1001/archpsyc.64.3.369

Cited by 105Neurotransmitter Receptor Influence on BehaviorNeuropeptides and Animal PhysiologySubstance Abuse Treatment and Outcomes

Association of a Functional Polymorphism in the μ-Opioid Receptor Gene With Alcohol Response and Consumption in Male Rhesus Macaques

Barr, Christina S., Schwandt, Melanie, Lindell, Stephen G., Chen, Scott A., Goldman, David, Suomi, Stephen J., Higley, J. Dee, Heilig, Markus·2007·Archives of General Psychiatry

DOI 10.1001/archpsyc.64.3.369

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Abstract

CONTEXT: Innate differences in opioid neurotransmission are hypothesized to influence abuse liability of alcohol. In humans, a variant of the mu-opioid receptor gene (OPRM1A118G) increases receptor affinity, alcohol-induced euphoria, and risk for alcohol use disorders. OBJECTIVE: To determine whether a variant in the mu-opioid receptor gene (OPRM1C77G) that increases affinity of the receptor is associated with alcohol response and consumption in macaques. DESIGN: Young adult rhesus macaques (Macaca mulatta) were intravenously administered 2.0 to 2.1 g of ethanol per kilogram of body weight and assessed for alcohol response. Animals were later given simultaneous access to an aspartame-sweetened 8.4% (vol/vol) ethanol solution and a vehicle for 1 hour per day, 5 days a week, for a period of 6 weeks. Animals (N = 82) were genotyped for the OPRM1C77G polymorphism; the effects of the genotype on alcohol response and consumption were determined by analysis of variance, with sex included as a nominal independent variable. MAIN OUTCOME MEASURES: Alcohol response (ataxia, stimulation, and sedation), average alcohol consumption, the percentage of days during which an animal consumed alcohol at a level sufficient to produce intoxication (> or =0.67 g of alcohol per kilogram of body weight), and alcohol preference (calculated as 100 x {alcoholic solution/[alcoholic solution + nonalcoholic solution]}). RESULTS: Increased alcohol-induced stimulation was observed among male macaques carrying the OPRM1C77G allele. OPRM1C77G allele carriers consumed more ethanol and exhibited increased ethanol preference. Male carriers of the OPRM1C77G allele exhibited higher alcohol preference and consumption, and drank to intoxication more frequently than did C/C males. CONCLUSIONS: These findings demonstrate that the rhesus macaques' equivalent of the OPRM1A118G variant is associated with increased alcohol response, consumption, and preference. Our results reveal effects of the OPRM1C77G genotype to be male-restricted or more marked among male macaques. This is of interest, given the fact that early-onset type II alcoholism is more common among men and that, among addicted individuals, men are more responsive to mu-opioid receptor blockade.

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Rhesus macaques have a functionally similar variant of the MOR gene, C77G, which also results in increased alcohol intake.
“Rhesus macaques also have a functionally similar variant of the MOR gene, C77G, which also results in increased alcohol intake (Barr et al 2007).”
From The behavioral, anatomical and pharmacological parallels between social attachment, love and addiction (2012) · cites this paper as Barr et al 2007
The same MOR gene polymorphisms linked to increased alcoholism risk in humans and Rhesus macaques are also related to maternal behavior in both species.
“Additionally, the same polymorphisms of the MOR gene that are associated with increased risk for alcoholism in humans and Rhesus macaques are also related to maternal behavior in both species (Barr et al 2007; Barr et al 2008; Higham et al 2011; Troisi et al 2011b).”
From The behavioral, anatomical and pharmacological parallels between social attachment, love and addiction (2012) · cites this paper as Barr et al 2007

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Translating the neuroscience of alcoholism into clinical treatments: From blocking the buzz to curing the blues
Heilig, M., Thorsell, A., Sommer, W. H., Hansson, A. C., Ramchandani, V. A., George, D. T., Hommer, D., & Barr, C. S. (2010) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2009.11.018 · Cited by 117 · see citing works
“Using this model, we found increased psychomotor stimulation in response to alcohol, increased alcohol preference, and increased frequency of alcohol consumption at a level leading to intoxication in carriers of the rhesus (rh) OPRM1 77G variant (Barr et al., 2007).”
MethodSelf-citation
CRHR1 genotypes, neural circuits and the diathesis for anxiety and depression
Rogers, J., Raveendran, M., Fawcett, G. L., Fox, A. S., Shelton, S. E., Oler, J. A., Cheverud, J. M., Muzny, D. M., Gibbs, R. A., Davidson, R. J., et al. (2012) · Molecular Psychiatry · doi:10.1038/mp.2012.152 · Cited by 114 · see citing works
Non-Human Primates: Model Animals for Developmental Psychopathology
Nelson, E. E., & Winslow, J. (2008) · Neuropsychopharmacology · doi:10.1038/npp.2008.150 · Cited by 110 · see citing works
Searching for Responders to Acamprosate and Naltrexone in Alcoholism Treatment: Rationale and Design of thePredict Study
Mann, K. F., Kiefer, F., Smolka, M. N., Gann, H., Wellek, S., & Heinz, A. (2009) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2008.00884.x · Cited by 94 · see citing works
The Role of the Asn40Asp Polymorphism of the Mu Opioid Receptor Gene (OPRM1) on Alcoholism Etiology and Treatment: A Critical Review
Ray, L. A., Barr, C. S., Blendy, J. A., Oslin, D. W., Goldman, D. A., & Anton, R. F. (2011) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2011.01633.x · Cited by 80 · see citing works
Self-citation
Subjective Response to Alcohol Among Alcohol‐Dependent Individuals: Effects of the Mu‐Opioid Receptor (<scp><i>OPRM1</i></scp>) Gene and Alcoholism Severity
Ray, L. A., Bujarski, S., MacKillop, J., Courtney, K. E., Monti, P. M., & Miotto, K. (2013) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2012.01916.x · Cited by 75 · see citing works
“A study of nonhuman primates has demonstrated that male macaques carrying the SNP that is homologous to the Asp40 allele displayed increased alcohol-induced stimulation, consumed more ethanol (EtOH), and exhibited increased EtOH preference (Barr et al., 2007).”
Mu-opioid receptor (OPRM1) variation, oxytocin levels and maternal attachment in free-ranging rhesus macaques Macaca mulatta
Higham, J. P., Barr, C. S., Hoffman, C. L., Mandalaywala, T. M., Parker, K. J., & Maestripieri, D. (2011) · Behavioral Neuroscience · doi:10.1037/a0022695 · Cited by 69 · see citing works
“Following precedent (e.g., Barr et al., 2007; 2008), analyses were undertaken using just two genotypes (C77/C77 vs. G77/C77 and G77/G77 combined) due to the rarity of homozygous G77 individuals.”
Self-citation
Pharmacogenetic Treatments for Drug Addiction: Alcohol and Opiates
Haile, C. N., Kosten, T. A., & Kosten, T. R. (2008) · The American Journal of Drug and Alcohol Abuse · doi:10.1080/00952990802122564 · Cited by 71 · see citing works
“These primates show greater preference for alcohol, consume more alcohol, and drink to intoxication compared to C77C variants (7).”
Background
Acamprosate in Alcohol Dependence: Implications of a Unique Mechanism of Action
Littleton, J. M. (2007) · Journal of Addiction Medicine · doi:10.1097/adm.0b013e318156c26f · Cited by 68 · see citing works
Initial Evidence of an Association Between OPRM1 and Adolescent Alcohol Misuse
Miranda, R., Ray, L. A., Justus, A. N., Meyerson, L. A., Knopik, V. S., McGeary, J. E., & Monti, P. M. (2009) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2009.01073.x · Cited by 64 · see citing works
“Although additional research is necessary to fully elucidate how variation in the OPRM1 receptor gene relates to the neurobiology of alcoholism, animal studies indicate that this polymorphism is central to the reinforcing effects of alcohol (e.g., Barr et al., 2007; Ghozland et al., 2005).”
Background
CRH Haplotype as a Factor Influencing Cerebrospinal Fluid Levels of Corticotropin-Releasing Hormone, Hypothalamic-Pituitary-Adrenal Axis Activity, Temperament, and Alcohol Consumption in Rhesus Macaques
Barr, C. S., Dvoskin, R. L., Yuan, Q., Lipsky, R. H., Gupte, M., Xian, H., Zhou, Z., Schwandt, M. L., Lindell, S. G., McKee, M. J., et al. (2008) · Archives of General Psychiatry · doi:10.1001/archpsyc.65.8.934 · Cited by 62 · see citing works
“Prior reports from this laboratory have shown that alcohol consumption is higher among peer-reared macaques and that functional genetic variants can interact with early rearing history to influence levels of ethanol selfadministration.(17,36) Because of these established differences and the fact that males generally c…”
BackgroundSelf-citation
FunctionalNPYVariation as a Factor in Stress Resilience and Alcohol Consumption in Rhesus Macaques
Lindell, S. G., Schwandt, M. L., Sun, H., Sparenborg, J. D., Björk, K., Kasckow, J., Sommer, W. H., Goldman, D. A., Higley, J. D., Suomi, S. J., et al. (2010) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2010.23 · Cited by 60 · see citing works
Self-citation
Population-specific effects of the Asn40Asp polymorphism at the μ-opioid receptor gene (OPRM1) on HPA-axis activation
Hernández–Ávila, C. A., Covault, J., Wand, G. S., Zhang, H., Gelernter, J. E., & Kranzler, H. R. (2007) · Pharmacogenetics and Genomics · doi:10.1097/fpc.0b013e3282f0b99c · Cited by 59 · see citing works
Suppression of Alcohol Preference by Naltrexone in the Rhesus Macaque: A Critical Role of Genetic Variation at the μ-Opioid Receptor Gene Locus
Barr, C. S., Chen, S. A., Schwandt, M. L., Lindell, S. G., Sun, H., Suomi, S. J., & Heilig, M. A. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.07.026 · Cited by 59 · see citing works
Self-citation
Naltrexone Modification of Drinking Effects in a Sub-Acute Treatment and Bar-Lab Paradigm: Influence of OPRM1 and Dopamine Transporter (SCL6A3) Genes
Anton, R., Voronin, K., Randall, P., Myrick, H., & Tiffany, A. (2012) · Alcoholism: Clinical and Experimental Research · doi:10.1111/j.1530-0277.2012.01807.x · Cited by 61 · see citing works
“…to that found in humans in the mu opioid receptor gene occurring naturally in nonhuman primates also appears to confer both sensitivity to alcohol response (Barr et al., 2007) and response to naltrexone in the reduction of alcohol effects and consumption (Barr et al., 2010; Vallender et al., 2010).”
A Pharmacogenetic Determinant of Mu-Opioid Receptor Antagonist Effects on Alcohol Reward and Consumption: Evidence from Humanized Mice
Bilbao, A., Robinson, J. E., Heilig, M. A., Malanga, C. J., Spanagel, R., Sommer, W. H., & Thorsell, A. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.08.021 · Cited by 58 · see citing works
Self-citation
Subjective response to alcohol and associated craving in heavy drinkers vs. alcohol dependents: An examination of Koob's allostatic model in humans
Bujarski, S., & Ray, L. A. (2014) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2014.04.015 · Cited by 57 · see citing works
CB1 Receptor Blockade Decreases Ethanol Intake and Associated Neurochemical Changes in Fawn‐Hooded Rats
Femenía, T., García‐Gutiérrez, M. S., & Manzanares, J. (2009) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2009.01074.x · Cited by 56 · see citing works
Increased mesolimbic cue-reactivity in carriers of the mu-opioid-receptor gene OPRM1 A118G polymorphism predicts drinking outcome: A functional imaging study in alcohol dependent subjects
Bach, P., Vollstädt‐Klein, S., Kirsch, M., Hoffmann, S., Jorde, A., Frank, J., Charlet, K., Beck, A., Heinz, A., Walter, H., et al. (2015) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2015.04.013 · Cited by 54 · see citing works
“Only male primates carrying the OPRM1 G-allele equivalent (77G) showed an increased alcohol-induced stimulation and higher alcohol consumption (Barr et al., 2007).”
Background
Child μ-Opioid Receptor Gene Variant Influences Parent–Child Relations
Copeland, W., Sun, H., Costello, E. J., Angold, A. C., Heilig, M. A., & Barr, C. S. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2010.251 · Cited by 50 · see citing works
“In rhesus macaques, a nonsynonymous SNP in the OPRM1 gene (rhOPRM1 C77G) that increases reward sensitivity (Barr et al, 2007) predicts increased vocalization during periods of maternal separation and social preference for the caregiver upon reunion (Barr et al, 2008).”
Self-citation
Endogenous opiates and behavior: 2007
Bodnar, R. J. (2008) · Peptides · doi:10.1016/j.peptides.2008.09.007 · Cited by 51 · see citing works
“Association of a functional polymorphism in the MOR gene increased alcohol sensitivity, consumption and preference in male rhesus macaques carrying the OPRM1C77G allele [64].”
Background
A pharmacogenetic model of naltrexone-induced attenuation of alcohol consumption in rhesus monkeys☆
Vallender, E. J., Rüedi‐Bettschen, D., Miller, G. M., & Platt, D. M. (2010) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2010.01.005 · Cited by 49 · see citing works
“These data are in concordance with earlier studies that found G77 carrying rhesus macaques consumed greater volumes of alcohol and drink to intoxication (Barr et al., 2007).”
BackgroundResultInfluential
Associations of OPRM1 A118G and alcohol sensitivity with intravenous alcohol self‐administration in young adults
Hendershot, C. S., Claus, E. D., & Ramchandani, V. A. (2014) · Addiction Biology · doi:10.1111/adb.12165 · Cited by 48 · see citing works
“Specifically, rhesus monkeys with the 77G variant (proposed as a functional equivalent to 118G) displayed higher alcohol self-administration under simple operant and free-access paradigms (Barr et al. 2007; Vallender et al. 2010).”
Background
The Value of Extended Pedigrees for Next-Generation Analysis of Complex Disease in the Rhesus Macaque
Vinson, A., Prongay, K., & Ferguson, B. M. (2013) · ILAR Journal · doi:10.1093/ilar/ilt041 · Cited by 41 · see citing works
“Similar to humans, macaques carry a nonsynonymous mutation in OPRM1, the mu-opioid receptor gene, that has been associated with increased alcohol-induced stimulation, increased alcohol consumption, and increased frequency of intoxication, particularly in males (Barr et al. 2007), also consistent with findings in human…”
Result
Nalmefene for the treatment of alcohol dependence: a current update
Soyka, M. (2013) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145713001284 · Cited by 42 · see citing works
“Genetic studies in alcoholism have provided conflicting results concerning the relevance of the functional variant 118G allele in exon 1 of the OPRM1 gene for the vulnerability risk for alcoholism (Bart et al., 2005b; Nishizawa et al., 2006; Barr et al., 2007; Gelernter et al., 2007; Job et al., 2007; van den Wildenbe…”
Background
The µ-Opioid Receptor and Treatment Response to Naltrexone
Thorsell, A. (2013) · Alcohol and Alcoholism · doi:10.1093/alcalc/agt030 · Cited by 41 · see citing works
“Male carriers of the rhesus OPRM1 77G allele display increased alcohol preference, increased drinking to intoxication and increased psychomotor stimulation in response to alcohol (Barr et al., 2007, 2010), as well as an increased HPA axis response (Schwandt et al., 2011).”
Background
The Need for Treatment Responsive Translational Biomarkers in Alcoholism Research
Heilig, M. A., Sommer, W. H., & Spanagel, R. (2015) · Current topics in behavioral neurosciences · doi:10.1007/7854_2015_5006 · Cited by 42 · see citing works
Self-citation
Opiate-Induced Dopamine Release Is Modulated by Severity of Alcohol Dependence: An [18F]Fallypride Positron Emission Tomography Study
Spreckelmeyer, K. N., Paulzen, M., Raptis, M., Baltus, T., Schaffrath, S., Waesberghe, J. V., Zalewski, M. M., Rösch, F., Vernaleken, I., Schäfer, W. M., et al. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.05.035 · Cited by 41 · see citing works
Alcohol response and consumption in adolescent rhesus macaques: life history and genetic influences
Schwandt, M. L., Lindell, S. G., Chen, S., Higley, J. D., Suomi, S. J., Heilig, M. A., & Barr, C. S. (2010) · Alcohol · doi:10.1016/j.alcohol.2009.09.034 · Cited by 41 · see citing works
“Monkeys tested in the social group, on the other hand, are subject to competition for the alcohol dispensers as well as social pressures that likely influence how much they will drink (Barr et al., 2007).”
BackgroundMethodInfluentialSelf-citation
Nonhuman Primate Models of Neuropsychiatric Disorders: Influences of Early Rearing, Genetics, and Epigenetics
Dettmer, A. M., & Suomi, S. J. (2014) · ILAR Journal · doi:10.1093/ilar/ilu025 · Cited by 40 · see citing works
“…is assessed by quantifying ethanol consumption over some period of time, whereas intoxication is assessed by measuring blood alcohol levels and impaired motor function (Barr et al. 2003, 2007; Heinz et al. 1998; Henningfield and Meisch 1979; Higley, Suomi, Linnoila 1996b; Kornet et al. 1990, 1991).”
BackgroundSelf-citation
Stimulant and motivational effects of alcohol: Lessons from rodent and primate models
Brabant, C., Guarnieri, D. J., & Quertemont, É. (2014) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2014.03.006 · Cited by 38 · see citing works
“These monkeys also drank more alcohol than animals that do not carry the OPRM1C77G allele under nonoperant (Barr et al., 2007) and operant conditions (Vallender et al., 2010).”
BackgroundInfluential
OPRM1 gene variation influences hypothalamic–pituitary–adrenal axis function in response to a variety of stressors in rhesus macaques
Schwandt, M. L., Lindell, S. G., Higley, J. D., Suomi, S. J., Heilig, M. A., & Barr, C. S. (2011) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2011.03.002 · Cited by 37 · see citing works
“Of note, we see lower levels of cortisol among 77G allele carriers, despite the fact that this allele predicts higher levels of alcohol-induced stimulation as measured by locomotor behavior, which can also activate the HPA axis (Barr et al., 2007).”
InfluentialSelf-citation
Interactive Effects of OPRM1 and DAT1 Genetic Variation on Subjective Responses to Alcohol
Ray, L. A., Bujarski, S., Squeglia, L. M., Ashenhurst, J. R., & Anton, R. F. (2014) · Alcohol and Alcoholism · doi:10.1093/alcalc/agt183 · Cited by 37 · see citing works
Polymorphisms in the µ-Opioid Receptor Gene ( OPRM1 ) and the Implications for Alcohol Dependence in Humans
van der Zwaluw, C. S., Wildenberg, E. V. D., Wiers, R. W. H. J., Franke, B., Buitelaar, J. K., Scholte, R. H. J., & Engels, R. C. M. E. (2007) · Pharmacogenomics · doi:10.2217/14622416.8.10.1427 · Cited by 35 · see citing works
Proton Magnetic Resonance Spectroscopy in Alcohol Use Disorders: A Potential New Endophenotype?
Meyerhoff, D. J., & Durazzo, T. C. (2008) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2008.00695.x · Cited by 35 · see citing works
“…have a significant impact on cueinduced craving for alcohol in heavy drinkers (van den Wildenberg et al., 2007), response to naltrexone treatment in alcohol dependent patients (McGeary et al., 2006; Oslin et al., 2003), as well as responses to alcohol (Barr et al., 2007; Ray and Hutchison, 2004).”
Background
Nonhuman primate genetic models for the study of rare diseases
Vallender, E. J., Hotchkiss, C. E., Lewis, A. D., Rogers, J., Stern, J. A., Peterson, S. M., Ferguson, B. M., & Sayers, K. (2023) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-023-02619-3 · Cited by 36 · see citing works
Consensus paper of the WFSBP task force on biological markers: Biological markers for alcoholism
Hashimoto, E., Riederer, P. F., HESSELBROCK, V. M., Hesselbrock, M. N., Mann, K. F., Ukai, W., Sohma, H., Thibaut, F., Schuckit, M. A., & Saito, T. (2013) · The World Journal of Biological Psychiatry · doi:10.3109/15622975.2013.838302 · Cited by 32 · see citing works
“…are other major psychiatric disorders (primarily schizophrenia and bipolar disorder), alcohol craving, the opioid peptide system, and characteristics of at-risk populations derived from electrophysiological and neuroimaging assessments (Winokur et al. 1996; D ’ Souza et al. 2006; Barr et al. 2007).”
Background
Gender Differences in Predictors of Treatment Attrition with High Dose Naltrexone in Cocaine and Alcohol Dependence
Suh, J. J., Pettinati, H., Kampman, K., & O'Brien, C. (2008) · American Journal on Addictions · doi:10.1080/10550490802409074 · Cited by 33 · see citing works
The serotonin transporter gene is a substrate for age and stress dependent epigenetic regulation in rhesus macaque brain: Potential roles in genetic selection and Gene × Environment interactions
Lindell, S. G., Yuan, Q., Zhou, Z., Goldman, D. A., Thompson, R. C., López, J. F., Suomi, S. J., Higley, J. D., & Barr, C. S. (2012) · Development and Psychopathology · doi:10.1017/s0954579412000788 · Cited by 28 · see citing works
“…contexts can also render individuals more or less sensitive to particular environmental variables, ultimately driving potentially maladaptive responses (Barr, 2011; Barr et al., 2007, 2008, 2009; Barr & Goldman, 2006; Barr, Newman, Shannon, et al., 2004; Bennett et al., 2002; Lindell et al., 2010).”
BackgroundSelf-citation
Functional Polymorphism of the Mu-Opioid Receptor Gene (OPRM1) Influences Reinforcement Learning in Humans
Lee, M. R., Gallen, C. L., Zhang, X., Hodgkinson, C. A., Goldman, D., Stein, E. A., & Barr, C. S. (2011) · PLoS ONE · doi:10.1371/journal.pone.0024203 · Cited by 27 · see citing works
Self-citation
Non-Human Primate Models of Alcohol-Related Phenotypes: The Influence of Genetic and Environmental Factors
Barr, C. S. (2011) · Current topics in behavioral neurosciences · doi:10.1007/7854_2011_142 · Cited by 27 · see citing works
Self-citation
Nalmefene for treatment of alcohol dependence
Soyka, M., & Rösner, S. (2010) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2010.522990 · Cited by 26 · see citing works
“Results of studies in alcoholism are conflicting concerning the relevance of the functional variant 118G allele in exon 1 of the OPRM1 gene l, and most studies indicate that an association is not likely [22-27].”
Background
What the alcohol doctor ordered from the neuroscientist
Heilig, M., & Leggio, L. (2016) · Progress in Brain Research · doi:10.1016/bs.pbr.2015.07.023 · Cited by 25 · see citing works
Self-citation
Influence of theOPRM1A118G Polymorphism on Alcohol-Induced Euphoria, Risk for Alcoholism and the Clinical Efficacy of Naltrexone
Setiawan, E., Pihl, R. O., Benkelfat, C., & Leyton, M. (2012) · Pharmacogenomics · doi:10.2217/pgs.12.99 · Cited by 23 · see citing works
The effect of the OPRM1 and DRD4 polymorphisms on the relation between attentional bias and alcohol use in adolescence and young adulthood
Pieters, S., van der Vorst, H., Burk, W. J., Schoenmakers, T. M., Wildenberg, E. V. D., Smeets, H. J. M., Lambrichs, E., Field, M., Engels, R. C. M. E., & Wiers, R. W. H. J. (2011) · Developmental Cognitive Neuroscience · doi:10.1016/j.dcn.2011.07.008 · Cited by 22 · see citing works
“In this study, only male heavy drinkers were included for two reasons: first, heavy drinking is far more prevalent in male late adolescents and young adults, and second, some evidence points to a more pronounced role in the development of problem drinking in males (Barr et al., 2007).”
Human Expression Variation in the Mu-Opioid Receptor is Paralleled in Rhesus Macaque
Vallender, E. J., Priddy, C. M., Chen, G., & Miller, G. M. (2008) · Behavior Genetics · doi:10.1007/s10519-008-9207-2 · Cited by 22 · see citing works
“Additional studies have also found that animals with the G allele show greater responses to alcohol and greater levels of alcohol consumption ( Barr et al. 2007 ) similar to findings in humans.”
Result
Neurogenetics of Aggressive Behavior: Studies in Primates
Barr, C. S., & Driscoll, C. A. (2013) · Current topics in behavioral neurosciences · doi:10.1007/7854_2013_267 · Cited by 21 · see citing works
“Studies examining intermediate phenotypes likely to be under the control of this receptor (for example, HPA axis activity) also suggest gain-of-function roles for these polymorphisms (Ray and Hutchison 2004; Chong et al. 2006; Barr et al. 2007; Schwandt et al. 2011).”
BackgroundSelf-citation
OPRM1 A118G and serum β-endorphin interact with sex and digit ratio (2D:4D) to influence risk and course of alcohol dependence
Gegenhuber, B., Weinland, C., Kornhuber, J., Mühle, C., & Lenz, B. (2018) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2018.09.002 · Cited by 19 · see citing works
Rapid Tolerance and Locomotor Sensitization in Ethanol‐Naïve Adolescent Rhesus Macaques
Schwandt, M. L., Higley, J. D., Suomi, S. J., Heilig, M. A., & Barr, C. S. (2008) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2008.00676.x · Cited by 18 · see citing works
Self-citation
Nonhuman Primate Research Contributions to Understanding Genetic and Environmental Influences on Phenotypic Outcomes across Development
Bennett, A. J., & Pierre, P. J. (2010) · doi:10.1002/9781444327632.ch12 · Cited by 19 · see citing works
Opioid Antagonists and the A118G Polymorphism in the μ-Opioid Receptor Gene: Effects of GSK1521498 and Naltrexone in Healthy Drinkers Stratified by OPRM1 Genotype
Ziauddeen, H., Nestor, L. J., Subramaniam, N., Dodds, C., Nathan, P. J., Miller, S. R., Sarai, B. K., Maltby, K., Fernando, D., Warren, L. L., et al. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2016.60 · Cited by 17 · see citing works
“In macaques, the G allele of the C77G OPRM1 polymorphism was associated with increased β-endorphin binding affinity, greater alcohol preference and consumption, as well as greater decreases in preference and consumption following naltrexone (NTX) administration (Barr et al, 2007, 2010).”
BackgroundInfluential
A gene-by-sex interaction for nicotine reward: evidence from humanized mice and epidemiology
Bernardi, R. E., Zohsel, K., Hirth, N., Treutlein, J., Heilig, M. A., Laucht, M., Spanagel, R., & Sommer, W. H. (2016) · Translational Psychiatry · doi:10.1038/tp.2016.132 · Cited by 17 · see citing works
Self-citation
Rhesus monkey tryptophan hydroxylase-2 coding region haplotypes affect mRNA stability
Chen, G.-L., & Miller, G. M. (2008) · Neuroscience · doi:10.1016/j.neuroscience.2008.05.050 · Cited by 17 · see citing works
“…example, a nonsynonymous SNP C77G (P26R) in rhesus monkey mu opioid receptor (OPRM1) functionally parallels a non-identical SNP A118G (N40D) in human OPRM1 and in both cases, the SNP associates with common phenotypes (Kroslak et al., 2007; Bond et al., 1998; Miller et al., 2004; Barr et al., 2007).”
Background
Convergent Balancing Selection on the Mu-Opioid Receptor in Primates
Sweeney, C. G., Rando, J. M., Panas, H. N., Miller, G. M., Platt, D. M., & Vallender, E. J. (2017) · Molecular Biology and Evolution · doi:10.1093/molbev/msx105 · Cited by 15 · see citing works
Alcohol addiction and the mu-opioid receptor
Berrettini, W. H. (2015) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2015.07.011 · Cited by 15 · see citing works
Differential sensitivity of human neurons carrying μ opioid receptor (MOR) N40D variants in response to ethanol
Scarnati, M. S., Boreland, A. J., Joel, M., Hart, R. P., & Pang, Z. P. (2020) · Alcohol · doi:10.1016/j.alcohol.2020.05.004 · Cited by 14 · see citing works
“Acute ethanol application causes an increase in the overall inhibitory tone in MOR N40 AD-iNs There have been several studies (Barr et al., 2007; Vallender, Rüedi-Bettschen, Miller, & Platt, 2010; Ramchandani et al., 2011; Bilbao et al., 2015; Henderson-Redmond, Lowe, Tian, & Morgan, 2018)…”
Background
Opioid Pharmacogenetics of Alcohol Addiction
Berrettini, W. H. (2013) · Oxford University Press eBooks · doi:10.1093/acprof:oso/9780199655786.003.0011 · Cited by 13 · see citing works
Opioid neuroscience for addiction medicine
Berrettini, W. H. (2015) · Progress in brain research · doi:10.1016/bs.pbr.2015.07.030 · Cited by 13 · see citing works
DRD1 5′UTR variation, sex and early infant stress influence ethanol consumption in rhesus macaques
Newman, T. K., Parker, C. C., Suomi, S. J., Goldman, D. A., Barr, C. S., & Higley, J. D. (2009) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2009.00507.x · Cited by 12 · see citing works
“…studies in this population of rhesus have examined the effects of sex, rearing, and other candidate genes such as the serotonin transporter (Barr et al. 2004), μ-opioid (Barr et al. 2007), corticotropin-releasing hormone (CRH) (Barr et al. 2008) and monoamine oxidase A (MAOA) (Newman et al. 2005).”
BackgroundMethodInfluentialSelf-citation
Increased ethanol drinking in “humanized” mice expressing the mu opioid receptor A118G polymorphism are mediated through sex-specific mechanisms
Henderson, A. N., Lowe, T. E., Tian, X., & Morgan, D. J. (2017) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2017.07.017 · Cited by 10 · see citing works
“The functionally homologous C77G SNP within the mu-opioid receptor of rhesus monkeys also causes greater ethanol consumption and increased sensitivity to the suppressive effect of naltrexone on ethanol drinking in non-human primates (Barr et al., 2007; 2010; Vallender et al., 2010).”
Pharmacogenetic approaches in the treatment of alcohol use disorders: addressing clinical utility and implementation thresholds
Hendershot, C. S. (2014) · Addiction Science & Clinical Practice · doi:10.1186/1940-0640-9-20 · Cited by 9 · see citing works
“The identification of a functional equivalent to OPRM1 A118G in rhesus monkeys (C77G) has also allowed investigations in primate models [35-37].”
Background
Genetic polymorphisms in the serotonin, dopamine and opioid pathways influence social attention in rhesus macaques (Macaca mulatta)
Howarth, E., Szott, I. D., Witham, C. L., Wilding, C. S., & Bethell, E. (2023) · PLoS ONE · doi:10.1371/journal.pone.0288108 · Cited by 9 · see citing works
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A Functional Polymorphism of the μ‐Opioid Receptor Gene (OPRM1) Influences Cue‐Induced Craving for Alcohol in Male Heavy Drinkers
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A Functional Polymorphism of the Mu-Opioid Receptor Gene (OPRM1) Influences Cue-Induced Craving for Alcohol in a cue-reactivity paradigm
Wildenberg, E. V. D., Dessers, J., Janssen, R. G. J. H., Lambrichs, E., Smeets, H. J. M., & Wiers, R. W. H. J. (2006) · Radboud Repository (Radboud University)
\nA Functional Polymorphism of the Mu-Opioid Receptor Gene (OPRM1) Influences Cue-Induced Craving for Alcohol in a cue-reactivity paradigm
Wildenberg, E. V. D., Dessers, J., Janssen, R. G. J. H., Lambrichs, E., Smeets, H. J. M., & Wiers, R. W. H. J. (2006) · Radboud Repository (Radboud University)

Authors: Barr, C. S., Schwandt, M., Lindell, S. G., Chen, S. A., Goldman, D., Suomi, S. J., Higley, J. D., & Heilig, M.
Affiliations: National Institutes of Health (US)
ORCID: Barr, Christina S.
Schwandt, Melanie
Goldman, David
Suomi, Stephen J.
Higley, J. Dee
Heilig, Markus
Venue: Archives of General Psychiatry
Publisher: American Medical Association (AMA)
Published: 2007-03-01
Volume: 64
Issue: 3
Pages: 369
ISSN: 0003-990X (ISSN-L)
DOI: 10.1001/archpsyc.64.3.369
OpenAlex: W2069018102
Cited by: 105
References: 58
Citations by year: 2025: 1 · 2024: 1 · 2023: 4 · 2022: 2 · 2021: 1 · 2020: 3 · 2019: 2 · 2018: 1 · 2017: 3 · 2016: 5 · 2015: 5 · 2014: 8 · 2013: 7 · 2012: 10
FWCI: 5.40
Type: journal article
Language: en
Open access: closed
Locations: Archives of General Psychiatry (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
Keywords: OPRM1, alcohol response, alcohol consumption, alcohol preference, rhesus monkeys, sex differences, ethanol intoxication, alcoholism, genetic susceptibility to alcoholism, genotype-phenotype correlation
MeSH terms: Alcohol Drinking, Ethanol, Alcoholism, Animals, Behavior, Animal, Conditioning, Operant, Disease Models, Animal, Drinking Behavior, Genotype, Macaca mulatta, Male, Polymorphism, Genetic, Sex Factors, Genetic Variation, Receptors, Opioid, mu, Age of Onset

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Association of a Functional Polymorphism in the μ-Opioid Receptor Gene With Alcohol Response and Consumption in Male Rhesus Macaques

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