Non-Human Primate Models of Alcohol-Related Phenotypes: The Influence of Genetic and Environmental Factors

  • Christina S. BarrEmail author
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 13)


Because of their complex social structures, behaviors, and genetic similarities to humans, nonhuman primates are useful for studying how genetic factors influence alcohol consumption. The neurobiological systems that influence addiction vulnerability may do so by acting on alcohol response, reward pathways, behavioral dyscontrol, and vulnerability to stress and anxiety. Rhesus macaques show individual differences in alcohol response and temperament, and such differences are influenced by genetic variants that are similar functionally to those present in humans. Genes at which variation moderates these phenotypes include those encoding monoamine oxidase A (MAOA-LPR), the serotonin transporter (HTTLPR), corticotropin releasing hormone (CRH-248C/T and -2232 C/G), Neuropeptide Y (NPY-1002 T/G), and the μ-opioid receptor (OPRM1 C77G). These provide opportunities for modeling how genetic and environmental factors (i.e., stress, individual’s sex, or alcohol exposure) interact to influence alcohol consumption. Studies in primates may also reveal selective factors have driven maintenance or fixation of alleles that increase risk for alcohol use disorders in modern humans.


Genetic Gene-Environment Stress Macaque Non-human primate Alcohol 


  1. Anton RF, Oroszi G, O'Malley S, Couper D, Swift R, Pettinati H, Goldman D (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):135–144Google Scholar
  2. Badia-Elder NE, Stewart RB, Powrozek TA, Roy KF, Murphy JM, Li TK (2001) Effect of neuropeptide Y (NPY) on oral ethanol intake in Wistar, alcohol- preferring (P), and -nonpreferring (NP) rats. Alcohol Clin Exp Res 25(3):386–390PubMedGoogle Scholar
  3. Badia-Elder NE, Stewart RB, Powrozek TA, Murphy JM, Li TK (2003) Effects of neuropeptide Y on sucrose and ethanol intake and on anxiety-like behavior in high alcohol drinking (HAD) and low alcohol drinking (LAD) rats. Alcohol Clin Exp Res 27(6):894–899PubMedGoogle Scholar
  4. Baerwald CG, Mok CC, Fife MS, Tickly M, Lau CS, Wordsworth BP, Ollier B, Panayi GS, Lanchbury JS (1999) Distribution of corticotropin-releasing hormone promoter polymorphism in different ethnic groups: evidence for natural selection in human populations. Immunogenetics 49:894–899PubMedGoogle Scholar
  5. Barr CS, Goldman D (2006) Nonhuman primate models of inheritance of vulnerability to alcohol abuse and addiction. Addiction Biol 11:374–385Google Scholar
  6. Barr CS, Newman TK, Becker ML, Champoux M, Lesch K-P, Suomi SJ, Goldman D, Higley JD (2003a) Serotonin transporter gene variation is associated with alcohol sensitivity in rhesus macaques exposed to early-life stress. Alc Clin Exp Res 27:812–817Google Scholar
  7. Barr CS, Newman TK, Becker ML, Parker CC, Champoux M, Lesch KP, Goldman D, Suomi SJ, Higley JD (2003b) The utility of the non-human primate; model for studying gene by environment interactions in behavioral research. Genes Brain Behav 2:336–340PubMedGoogle Scholar
  8. Barr CS, Newman TK, Lindell S, Shannon C, Champoux M, Lesch KP, Suomi SJ, Goldman D, Higley JD (2004a) Interaction between serotonin transporter gene variation and rearing condition in alcohol preference and consumption in female primates. Arch Gen Psychiatry 61:1146–1152PubMedGoogle Scholar
  9. Barr CS, Newman TK, Schwandt M, Shannon C, Dvoskin RL, Lindell SG, Taubman H, Thompson B, Champoux M, Lesch KP, Goldman D, Suomi SJ, Higley JD (2004b) Sexual dichotomy of an interaction between early adversity and the serotonin transporter gene promoter variant in rhesus macaques. Proc Natl Acad Sci USA 101:12358–12363PubMedGoogle Scholar
  10. Barr CS, Newman TK, Shannon C, Parker C, Dvoskin RL, Becker ML, Schwandt M, Champoux M, Lesch KP, Goldman D, Suomi SJ, Higley JD (2004c) Rearing condition and rh5-HTTLPR interact to influence limbic-hypothalamic-pituitary-adrenal axis response to stress in infant macaques. Biol Psychiatry 55:733–738PubMedGoogle Scholar
  11. Barr CS, Schwandt M, Newman TK, Higley JD (2004d) The use of adolescent nonhuman primates to model human alcohol intake: neurobiological, genetic and environmental variables. Ann. NY Acad. Sci 1021:221–233PubMedGoogle Scholar
  12. Barr CS, Newman TK, Lindell S, Becker ML, Shannon CS, Champoux C, Suomi SJ, Higley JD (2004e) Early experience and sex interact to influence LHPA-axis function following both acute and chronic alcohol administration in Rhesus Macaques (Macaca mulatta). Alcohol Clin Exp Res 28(7):1–5Google Scholar
  13. Barr CS, Schwandt ML, Lindell SG, Chen SA, Suomi SJ, Goldman D, Heilig M, Higley JD (2007) Mu opioid receptor gene variation is associated with alcohol response and consumption in rhesus monkeys. Arch Gen Psychiatry 64:369–376PubMedGoogle Scholar
  14. Barr CS, Schwandt ML, Lindell SG, Higley JD, Maestripieri D, Goldman D, Suomi SJ, Heilig M (2008a) A functional OPRM1 variant is associated with attachment behavior in infant rhesus macaques. Proc Natl Acad Sci 105:5277–5281PubMedGoogle Scholar
  15. Barr CS, Dvoskin RL, Yuan Q, Lipsky RH, Gupte M, Hu X, Zhou Z, Schwandt ML, Lindell SG, McKee M, Becker ML, Kling MA, Gold PW, Higley JD, Heilig M, Suomi SJ, Goldman D (2008b) 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. Arch Gen Psychiatry 65(8):934–944PubMedCentralPubMedGoogle Scholar
  16. Barr CS, Dvoskin RL, Gupte M, Sommer W, Sun H, Schwandt ML, Lindell SG, Kasckow JW, Suomi SJ, Goldman D, Higley HD, Heilig M (2009) Functional CRH promoter variation drives stress-induced alcohol consumption in primates. Proc Natl Acad Sci 106:14593–14598PubMedGoogle Scholar
  17. Barr CS, Chen SA, Schwandt ML, Lindell SG, Sun H, Suomi SJ, Heilig M (2010) Suppression of alcohol preference by naltrexone in the rhesus macaque: a critical role of genetic variation at the micro-opioid receptor gene locus. Biol Psychiatry 67:78–80PubMedCentralPubMedGoogle Scholar
  18. Bennett AJ, Lesch K-P, Heils A, Long JC, Lorenz JG, Shoaf SE, Champoux M, Suomi SJ, Linnoila MV, Higley JD (2002) Early experience and serotonin transporter gene variation interact to influence primate CNS function. Mol Psychiatry 7:118–122PubMedGoogle Scholar
  19. Bethea CL, Streicher JM, Coleman K, Pau FKY, Moessner R, Cameron JL (2004) Anxious behavior and fenfluramine-induced prolactin secretion in young rhesus macaques with different alleles of the serotonin reuptake transporter polymorphism (5HTTLPR). Behav Genet 34:295–307PubMedGoogle Scholar
  20. Bethea CL, Streicher JM, Mirkes SJ, Sanchez RL, Reddy AP, Cameron JL (2006) Serotonin-related gene expression in female monkeys with individual sensitivity to stress. Neuroscience 132:151–166Google Scholar
  21. Blomeyer D, Treutlein J, Esser G, Schmidt MH, Schumann G, Laucht M (2008) Interaction between CRHR1 gene and stressful life events predicts adolescent heavy alcohol use. Biol Psychiatry 63:146–151PubMedGoogle Scholar
  22. Bradwejn J, Kosycki D, Deutetre-Couteax A, Bourin M, Palmour RM, Ervin FR (1992) The cholecystokinin hypothesis of panic and anxiety disorders: a review. J Psychopharm 6:345–351Google Scholar
  23. Cale EM, Lilienfeld SO (2002) Sex differences in psychopathy and antisocial personality disorder: a review and integration. Clin Psychol Rev 22:1179–1207PubMedGoogle Scholar
  24. Capitanio JP, Widaman KF (2005) Confirmatory factor analysis of personality structure in adult male rhesus monkeys (Macaca mulatta). Am J Primatol 65:289–294PubMedGoogle Scholar
  25. Caspi A, Moffitt TE (2006) Gene-environment interactions in psychiatry: joining forces with neuroscience. Nat Rev Neurosci 7(7):583–590PubMedGoogle Scholar
  26. Caspi A, McClay J, Moffitt TE, Mill J, Martin J, Craig IW, Taylor A, Poulton R (2002) Role of genotype in the cycle of violence in maltreated children. Science 297:851–854PubMedGoogle Scholar
  27. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R (2003) Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301:386–389PubMedGoogle Scholar
  28. Caspi A, Hariri AR, Holmes A, Uher R, Mofitt TE (2010) Genetic sensitivity to the environment; the case of the serotonin transporter gene and its implications for studying complex diseases and traits. Am J Psychiatry 167(5):509–527PubMedCentralPubMedGoogle Scholar
  29. Chamove AS, Rosenblum LA, Harlow HF (1973) Monkeys (Macaca mulatta) raised only with peers. Animal Behav 21:316–325Google Scholar
  30. Champoux M, Bennett A, Shannon C, Higley JD, Lesch KP, Suomi SJ (2002) Serotonin transporter gene polymorphism, differential early rearing, and behavior in rhesus monkey neonates. Mol Psychiatry 7:1058–1063PubMedGoogle Scholar
  31. Chong RY, Oswald L, Yang X, Uhart M, Lin PI, Wand GS (2006) The mu-opioid receptor polymorphism A118G predicts cortisol responses to naloxone and stress. Neuropsychopharmacology 31:204–211PubMedGoogle Scholar
  32. Cloninger CR (1987) Neurogenetic adaptive mechanisms in alcoholism. Science 236:410–416PubMedGoogle Scholar
  33. Contini V, Marques FZ, Farcia CE, Hutz MH, Bau CH (2006) MAOA-uVNTR polymorphism in a Brazilian sample; further support for the association with impulsive behaviors and alcohol dependence. Am J Med Genet B Neuropsychiatr Genet 141:305–308Google Scholar
  34. Copeland WE, Sun H, Costello EJ, Angold A, Heilig MA, Barr CS (2011) Child–opioid receptor gene variant influences parent-child relations. Neuropsychopharmacololgy 36(6):1165–1170Google Scholar
  35. Dudley R (2002) Fermenting fruit and the historical ecology of ethanol ingestion: is alcoholism in modern humans an evolutionary hangover? Addiction 97:381–388PubMedGoogle Scholar
  36. Egli M (2005) Can experimental paradigms and animal models be used to discover clinically effective medications for alcoholism? Addiction Biol 10:309–319Google Scholar
  37. Eme RF (2007) Sex differences in child-onset, life-course-persistent conduct disorder. A review of biological influences. Clin Psychol Rev 27:607–627PubMedGoogle Scholar
  38. Ervin FR, Palmour RM, Young SN, Guzman-Flores C, Juarez J (1990) Voluntary consumption of beverage alcohol by vervet monkeys, population screening, descriptive behavior and biochemical measures. Pharmacol Biochem Behav 36:367–373PubMedGoogle Scholar
  39. Fairbanks LA, Newman TK, Bailey JN, Jorgensen MJ, Breidenthal SE, Ophoff RA, Comuzzie AG, Marin LJ, Rogers J (2004) Genetic contributions to social impulsivity and aggressiveness in vervet monkeys. Biol Psychiatry 55:642–647PubMedGoogle Scholar
  40. Fiskerstrand CE, Lovejoy EA, Quinn JP (1999) An intronic polymorphic domain often associated with susceptibility to affective disorders has allele dependent differential enhancer activity in embryonic stem cells. FEBS Lett 458:171–174PubMedGoogle Scholar
  41. Freeman HD, Gosling SD (2010) Personality in Nonhuman primates: a review and evaluation of past research. Am J Primatol 71:1–19Google Scholar
  42. Gold PW, Chrousos GP (2002) Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Mol Psychiatry 7:254–275PubMedGoogle Scholar
  43. Goldman D, Barr CS (2002) Restoring the addicted brain. N Engl J Med 347:843–845PubMedGoogle Scholar
  44. Goldman D, Oroszi G, Ducci F (2005) The genetics of addictions: uncovering the genes. Nat Rev Genet 6:521–532PubMedGoogle Scholar
  45. Grant KA, Bennett AJ (2003) Advances in nonhuman primate alcohol abuse and alcoholism research. Pharmacol Ther 100:235–255PubMedGoogle Scholar
  46. Hansson AC, Cippitelli A, Sommer WH, Fedeli A, Bjork K, Soverchia L, Terasmaa A, Massi M, Heilig M, Ciccocioppo R (2006) Variation at the rat Crhr1 locus and sensitivity to relapse into alcohol seeking induced by environmental stress. Proc Natl Acad Sci USA 103:15236–15241PubMedGoogle Scholar
  47. Harlow HF, Suomi SJ (1974) Induced depression in monkeys. Behav Biol 12:273–296PubMedGoogle Scholar
  48. Heilig M, Koob GF (2007) A key role for corticotropin-releasing factor in alcohol dependence. Trends Neurosci 30(8):399–406PubMedCentralPubMedGoogle Scholar
  49. Higley JD, Suomi SJ (1989) Temperamental reactivity in non-human primates. In: Kohnstamm D, Bates HE, Rothbart MK (eds) Temperament in childhood. Wiley, ChichesterGoogle Scholar
  50. Higley JD, Hasert MF, Suomi SJ, Linnoila M (1991) Nonhuman primate model of alcohol abuse: effects of early experience, personality, and stress on alcohol consumption. Proc Nat Acad Sci USA 88:7261–7265PubMedGoogle Scholar
  51. Higley JD, King ST, Hasert MF, Campoux M, Suomi SJ, Linnoila M (1996a) Stability of interindividual differences in serotonin function and its relationship to severe aggression and competent social behavior in rhesus macaque females. Neuropsychopharmacology 14:67–76Google Scholar
  52. Higley JD, Suomi SJ, Linnoila M (1996b) A nonhuman primate model of type II excessive alcohol consumption? Part 1. Low cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations and diminished social competence correlate with excessive alcohol consumption. Alcoholism Clin Exp Res 20:629–642Google Scholar
  53. Hinckers AS, Laucht M, Schmidt MH, Mann KF, Schumann G, Schuckit MA, Heinz A (2006) Low level of response to alcohol as associated with serotonin transporter genotype and high alcohol intake in adolescents. Biol Psychiatry 60(3):282–287Google Scholar
  54. Holmes A, Li Q, Murphy DL, Gold E, Crawley JN (2003) Abnormal anxiety-related behavior in serotonin transporter null mutant mice: the influence of genetic background. Genes Brain Behav 26:365–380Google Scholar
  55. Hu X, Oroszi G, Chun J, Smith TL, Goldman D, Schuckit MA (2005) An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk. Alcohol Clin Exp Res 29(1):8–16PubMedGoogle Scholar
  56. Hu XZ, Lipsky RH, Zhu G, Akhtar L, Taubman J, Greenberg BD, Xu K, Arnold PD, Richter MA, Kennedy JL, Murphy DL, Goldman D (2006) Additional functional variation at the SLC6A4 gene. Am J Hum Genet 78:815–826PubMedCentralPubMedGoogle Scholar
  57. Hundt W, Zimmermann U, Pottig M, Spring K, Holsboer F (2001) The combined dexamethasone-suppression/CRH stimulation test in alcoholics during and after acute withdrawal. Alcohol Clin Exp Res 25:687–691PubMedGoogle Scholar
  58. Jaferi A, Bhatnagar S (2007) Corticotropin-releasing hormone receptors in the medial prefrontal cortex regulate HPA activity and anxiety-related behavior regardless of prior stress experience. Brain Res 1186:212–223PubMedCentralPubMedGoogle Scholar
  59. Johnson B (2010) Medication treatment of different types of alcoholism. Am J Psychiatry 167:630–639PubMedCentralPubMedGoogle Scholar
  60. Kagan J, Resnick JS, Snidman N (1988) Biological basis of childhood shyness. Science 240:167–171PubMedGoogle Scholar
  61. Kalin NH, Shelton SE (2003) Nonhuman primate models to study anxiety, emotion regulation and psychopathology. Ann NY Acad Sci 1008:189–200PubMedGoogle Scholar
  62. Kalin NH, Shelton SE, Davidson RJ (2000) Cerebrospinal fluid corticotropin releasing hormone levels are stable in monkeys with patterns of brain activity associated with fearful temperament. Biol Psychiatry 47:579–585PubMedGoogle Scholar
  63. Kendler KS, Prescott CA, Myers J, Neale MC (2003) The structure of genetic and environmental risk factors for common psychiatric and substance use disorders in men and women. Arch Gen Psychiatry 60:929–937PubMedGoogle Scholar
  64. King BR, Nicholson RC (2007) Advances in understanding corticotrophin-releasing hormone gene expression. Front Biosci 12:581–590PubMedGoogle Scholar
  65. Kinnally EL, Capitanio JP, Leibel R, Deng L, Leduc C, Haghighi F, Mann JJ (2010) Epigenetic regulation of serotonin transporter expression and behavior in infant rhesus macaques. Genes Brain Behav 9(6):575–582Google Scholar
  66. Kinoshita H, Jessop D, Finn DP, Coventry TL, DJ Roberts, Ameno K, Jiri I, Harbuz MS (2001) Acetaldehyde, a metabolite of ethanol, activates the HPA axis in the rat. Alcohol Alcohol 36:59–64PubMedGoogle Scholar
  67. Koob GF, Le Moal M (1997) Drug abuse: hedonic homeostatic dysregulation. Science 278:52–58PubMedGoogle Scholar
  68. Koob GF, Le Moal M (2001) Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24:97–129PubMedGoogle Scholar
  69. Koob GF, Roberts AJ, Kieffer BL, Heyser CJ, Katner SN, Ciccocioppo R, Weiss F (2003) Animal models of motivation for drinking in rodents with a focus on opioid receptor neuropharmacology. Recent Dev Alcohol 16:263–281PubMedGoogle Scholar
  70. Korte SM, Koolhaas JM, Wingfield JC, McEwen BS (2005) The Darwinian concept of stress: benefits of allostasis and costs of allostatic load and the trade offs in health and disease. Neurosci Biobehav Rev 29:3–38PubMedGoogle Scholar
  71. Kraemer GW, Moore CF, Newman TK, Barr CS, Schneider ML (2008) Moderate levels of fetal alcohol exposure and serotonin transporter gene promoter polymorphism affect neonatal temperament and LHPA axis regulation in monkeys. Biol Psychiatry 63(3):317–324PubMedCentralPubMedGoogle Scholar
  72. Kranzler H, Lappalainen J, Nellissery M, Gelernter J (2002) Association study of alcoholism subtypes with a functional promoter polymorphism in the serotonin transporter protein gene. Alcohol Clin Exp Res 26:1330–1335PubMedGoogle Scholar
  73. Krawczak M, Trefilov A, Berard J, Bercovitch F, Kessler M, Sauermann U, Croucher P, Nürnberg P, Widdig A, Schmidtke J (2005) Male reproductive timing in rhesus macaques is influenced by the HTTLPR promoter polymorphism of the serotonin transporter gene. Biol Reprod 72:1109–1113PubMedGoogle Scholar
  74. Kreek MJ, LaForge KS, Butelman E (2002) Pharmacotherapy of addictions. Nat Rev Drug Discov; (Review. Erratum in: Nat Rev Drug Discov 2002 Nov;1(11):920. PMID: 12209151) 1(9):710–726Google Scholar
  75. Krishnan-Sarin S, Krystal JH, Shi J, Pittman B, O’Malley SS (2007) Family history of alcoholism influences naltrexone-induced reduction in alcohol drinking. Biol Psychiatry 62:694–697PubMedGoogle Scholar
  76. Lanfumey L, Mannoury La Cour C, Froger N, Hamon (2000) 5-HT-HPA interactions in two models of transgenic mice relevant to major depression. Neurochem Res 25:1199–1206PubMedGoogle Scholar
  77. Lappalainen J, Kranzler HR, Malison R, Price LH, Van Dyck C, Rosenheck RA, Cramer J, Southwick S, Charney D, Krystal J, Gelernter J (2002) A functional neuropeptide Y Leu7Pro polymorphism associated with alcohol dependence in a large population sample from the United States. Arch Gen Psychiatry 59(9):825–831PubMedGoogle Scholar
  78. Lesch KP, Meyer J, Glatz K, Flügge G, Hinney A, Hebebrand J, Klauck S, Poustka A, Poustka F, Bengel D, Mössner R, Riederer P, Heils A (1997) The 5-HT transporter gene-linked polymorphic region (5-HTTLPR) in evolutionary perspective: alternative biallelic variation in rhesus monkeys. J Neural Transm 104:1259–1266PubMedGoogle Scholar
  79. Li Q, Wichems C, Heils A, Van de Dar LD, Lesch K-P, Murphy DL (1999) Reduction of 5-HT1A binding sites in 5-HT transporter knockout mice J. Pharmacol Exp Ther 291:999–1007Google Scholar
  80. Li Z, Kang SS, Lee S, Rivier C (2005) Effect of ethanol on the regulation of corticotropin releasing factor gene expression. Mol Cell Neurosci 29:345–354PubMedGoogle Scholar
  81. Lindell SG, Schwandt ML, Sun H, Sparenborg JD, Bjoerk K, Kasckow JW, Sommer WH, Goldman D, Higley JD, Suomi SJ, Heilig M, Barr CS (2010) Functional NPY variation as a factor in stress resilience in rhesus macaques. Arch Gen Psychiatry 67(4):423–431PubMedCentralPubMedGoogle Scholar
  82. Lopez JF, Higley JD (2002) The effect of early experience on brain corticosteroid and serotonin receptors in rhesus monkeys. Biol Psychiatry 51:294Google Scholar
  83. Lorenz JG, Long JC, Linnoila M, Goldman D, Suomi SJ, Higley JD (2006) Genetic and other contributions to alcohol intake in rhesus macaques (Macaca mulatta). Alcohol Clin Exp Res 30:1–10Google Scholar
  84. Lovinger DM, Crabbe JC (2005) Laboratory models of alcoholism: treatment target identification and insight into mechanisms. Nat Neurosci 8(11):1471–1480PubMedGoogle Scholar
  85. Luo X, Zuo L, Kranzler H, Zhang H, Wang S, Gelernter J (2008) Multiple OPR genes influence personality traits in substance dependent and healthy subjects in two American populations. Am J Med Genet B Neuropsychiatr Genet 147B:1028–1039PubMedCentralPubMedGoogle Scholar
  86. Mazzanti CM, Lappalainen J, Long JC, Bengel D, Naukkarinen H, Eggert M, Virkkunen M, Linnoila M, Goldman D (1998) Role of the serotonin transporter promoter polymorphism in anxiety-related traits. Arch Gen Psychiatry 55:936–940PubMedGoogle Scholar
  87. McEwen BS (2006) Protective and damaging effects of stress mediators: central role of the brain. Dialogues Clin Neurosci 8:367–381PubMedCentralPubMedGoogle Scholar
  88. Mehlman PT, Higley JD, Faucher I, Lilly AA, Taub DM, Vickers J, Suomi SJ, Linnoila M (1994) Low CSF 5-HIAA concentrations and severe aggression and impaired impulse control in nonhuman primates. Am J Psychiatry 151:1485–1491PubMedGoogle Scholar
  89. Mehlman PT, Higley JD, Faucher I, Lilly AA, Taub DM, Vickers J, Suomi SJ, Linnoila M (1995) Correlation of CSF 5-HIAA concentration with sociality and the timing of emigration in free-ranging primates. Am J Psychiatry 152:907–913PubMedGoogle Scholar
  90. Meisch RA, Stewart RB (1994) Ethanol as a reinforcer: a revew of laboratory studies of nonhuman primate. Behavioral Pharmacol 5:425–440Google Scholar
  91. Meyer-Lindenberg A, Buckholtz JW, Koachana B, Hariri A, Pezawas L, Blasi G, Wabnitz A, Honea R, Verchinski B, Callicott JH, Egan M, Mattay V, Weinberger DR (2006) Neural mechanisms of genetic risk for impulsivity and violence in humans. Proc Natl Acad Sci USA 103(16):6269–6274PubMedGoogle Scholar
  92. Miller GM, Bendor J, Tiefenbacher S, Yang H, Novak MA, Madras BK (2004) A mu-opioid receptor single nucleotide polymorphism in rhesus monkey: association with stress response and aggression. Mol Psychiatry 9(1):99–108PubMedGoogle Scholar
  93. Mottagui-Tabar S, Prince JA, Wahlestedt C, Zhu G, Goldman D, Heilig M (2005) A novel single nucleotide polymorphism of the neuropeptide Y (NPY) gene associated with alcohol dependence. Alcohol Clin Exp Res 29(5):702–707PubMedGoogle Scholar
  94. Nelson EC, Agrawal A, Pergadia ML, Wang JC, Whitfield HB, Saccone FS, Kern J, Grant JD, Schrage AJ, Rice JP, Montgomery GW, Heath AC, Goate AM, Martin NG, Madden PA (2010) H2 haplotype at chromosome 17q21.31 protects against childhood sexual abuse-associated risk for alcohol consumption and dependence. Addict Biol 15:1–11PubMedCentralPubMedGoogle Scholar
  95. Newman TK, Syagailo YV, Barr CS, Wendland JR, Champoux M, Graessle M, Suomi SJ, Higley JD, Lesch KP (2005) Monoamine oxidase A gene promoter variation and rearing experience influences aggressive behavior in rhesus monkeys. Biol Psychiatry 57:167–172PubMedGoogle Scholar
  96. Nie Z, Schweitzer P, Roberts AJ, Madamba SG, Moore SD, Siggins GR (2004) Ethanol augments GABAergic transmission in the central amygdala via CRF1 receptors. Science 303:1512–1514PubMedGoogle Scholar
  97. Oslin DW, Berrettinini W, Kranzler HR, Pettinati H, Gelernter J, Volpicelli JR, O’Brien CP (2003) A functional polymorphism of the nu-opioid receptor gene is associated with naltrexone response in alcohol-dependent patients. Neuropsychopharmacology 28:146–155Google Scholar
  98. Palmour RM, Mulligan J, Howbert JJ, Erivn F (1997) Of monkeys and men: vervets and the genetics of human-like behaviors. Am J Hum Genet 61:481–488PubMedCentralPubMedGoogle Scholar
  99. Pang G, Wang J, Wang Z, Goh C, Lee C (2009) The G allele of SNP E1/A118G at the μ-opioid receptor gene locus shows genomic evidence of recent positive selection. Pharmacogenomics 10:1101–1109PubMedGoogle Scholar
  100. Parsian A, Cloninger CR (2001) Serotonergic pathway genes and subtypes of alcoholism: association studies. Psychiatr Genet 11:89–94PubMedGoogle Scholar
  101. Ramchandani VA, Umhau J, Pavon FJ, Ruiz-Velasco V, Margas W, Sun H, Damadzic R, Eskay R, Schoor M, Thorsell A, Schwandt ML, Sommer WH, George DT, Parsons LH, Herscovitch P, Hommer D, Heilig M (2010) A genetic determinant of striatal dopamine response to alcohol in men. Mol Psychiatry (Epub ahead of print)Google Scholar
  102. Ray LA, 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 28:1789–1795PubMedGoogle Scholar
  103. Reich T, Edenberg HJ, Goate A, Williams JT, Rice JP, Van Eerdewegh P, Foroud T, Hesselbrock V, Schuckit MA, Bucholz KK, Porjesz B, Li TK, Conneally PM, Nurnberger JIJ, Tischfield JA, Crowe RR, Cloninger CR, Wu W, Shears S, Carr K, Crose C, Willig C, Begleiter H (1998) Genome-wide search for genes affecting the risk for alcohol dependence. Am J Med Genet 81(3):207–215PubMedGoogle Scholar
  104. Sabol SZ, Hu S, Hamer D (1998) A functional polymorphism in the monoamine oxidase A gene promoter. Hum Genet 103:273–279PubMedGoogle Scholar
  105. Samochowiec J, Lesch KP, Rottmann M, Smolka M, Syagailo YV, Okladnova O, Rommlspacher H, Winterer G, Schmidt LF, Sander T (1999) Association of a regulatory polymorphism in the promoter region of the monoamine oxidase A gene with antisocial alcoholism. Psychiatry Res 86:67–72PubMedGoogle Scholar
  106. Sanchez MM, Young LJ, Plotsky PM, Insel TR (1999) Autoradiographic and in situ hybridization localization of corticotropin-releasing factor 1 and 2 receptors in nonhuman primate brain. J Comp Neurol 408:365–377PubMedGoogle Scholar
  107. Sapolsky RM (2001) Coping with the environment: neural and endocrine mechanisms. In: McEwen BS, Goodman HM (eds): Handbook of Physiology, Oxford University Press, New YorkGoogle Scholar
  108. Schneider ML, Moore CF, Larson JA, Barr CS, Dejesus OT, Roberts AD (2010) Timing of moderate level prenatal alcohol exposure influences gene expression of sensory processing behavior in rhesus monkeys. Front Integr Neurosci 3:30–38Google Scholar
  109. Schuckit MA (1994) Low level of response to alcohol as a predictor of future alcoholism. Am J Psychiatry 15:184–189Google Scholar
  110. Schwandt ML, Lindell SG, Sjoberg RL, Chisholm KL, Higley JD, Suomi SJ, Heilig M, Barr CS (2010) Gene-environment interactions and response to social intrusion in male and female rhesus macaques. Biol Psychiatry 67(4):323–330PubMedCentralPubMedGoogle Scholar
  111. Servatius RJ, Beck KD, Moldow RL, Salameh G, Tumminello TP, Short KR (2005) A stress-induced anxious state in male rats: CRH induces persistent changes in associative learning and startle reactivity. Biol Psychiatry 57:865–872PubMedGoogle Scholar
  112. Shannon C, Schwandt ML, Champoux M, Shoaf SE, Suomi SJ, Sinnoila M, Higley JD (2005) Maternal absence and stability of individual differences in CSF 5-HIAA concentrations in rhesus monkey infants. Am J Psychiatry 162:1658–1664PubMedGoogle Scholar
  113. Shimmin LC, Natarajan S, Ibarguen H, Montasser M, Kim DK, Hanis CL, Boerwinkle E, Wadhwa PD, Hixson JE (2007) Corticotropin releasing hormone (CRH) gene variation: comprehensive resequencing for variant and molecular haplotype discovery in monosomic hybrid cell lines. DNA Seq 18(6):432–442Google Scholar
  114. Sinha R, Li CS (2007) Imaging stress- and cue-induced drug and alcohol craving: association with relapse and clinical implications. Drug Alcohol Rev 26(1):25–31PubMedGoogle Scholar
  115. Sjoberg RL, Ducci F, Barr CS, Newman TK, Dell’Osso L, Virkkunen M, Goldman D (2008) A non-additive interaction of a functional MAOA VNTR and testosterone predicts antisocial behavior. Neuropsychopharmacology 33(2):425–430PubMedCentralPubMedGoogle Scholar
  116. Smith MJ, Price GR (1973) The logic of animal conflict. Nature 246:15–18Google Scholar
  117. Smoller JW, Rosenbaum JF, Biederman J, Kennedy J, Dai D, Racette SR, Laird NM, Kagan J, Snidman N, Hirshfeld-Becker D, Tsuang MT, Sklar PB, Slaugenhaupt SA (2003) Association of a genetic marker at the corticotropin-releasing hormone locus with behavioral inhibition. Biol Psychiatry 54(12):1376–1381PubMedGoogle Scholar
  118. Soeby K, Larsen SA, Olsen L, Rasmussen HB, Werge T (2005) Serotonin transporter: evolution and impactof polymorphic transcriptional regulation. Am J Hum Genet 136:53–57Google Scholar
  119. Sommer WH, Rimondini R, Hansson AC, Hipskind PA, Gehlert DR, Barr CS, Heilig M (2008) Up-regulation of voluntary alcohol intake, behavioral sensitivity to stress and amygdala Crhr1 expression following a history of dependence. Biol Psychiatry 63(2):139–145PubMedGoogle Scholar
  120. Sommer WH, Lidström J, Sun H, Passer D, Eskay R, Parker SC, Witt SH, Zimmermann US, Nieratschker V, Rietschel M, Margulies EH, Palkovits M, Laucht M, Heilig M (2010) Human NPY promoter variation rs16147: T > C as a moderator of prefrontal NPY gene expression and negative affect. Hum Mutat 31(8):1594–1608Google Scholar
  121. Southwick SM, Vythilingam M, Charney DS (2005) The psychobiology of depression and resilience to stress: implications for prevention and treatment. Annu Rev Clin Psychol 1:255–291PubMedGoogle Scholar
  122. Spinelli S, Schwandt ML, Lindell SG, Newman TK, Heilig M, Higley JD, Suomi SJ, Goldman D, Barr CS (2007) Association between the rh-5HTTLPR polymorphism and behavior in rhesus macaques during social separation stress. Dev Psychopathol 19(4):977–987PubMedGoogle Scholar
  123. Spinelli S, Chefer S, Suomi SJ, Higley JD, Barr CS, Stein E (2010a) Early life stress induces long-term morphologic changes in primate brain. Arch Gen Psychiatry 66:658–665Google Scholar
  124. Spinelli S, Chefer S, Carson RE, Jagoda E, Lang L, Heilig M, Barr CS, Suomi SJ, Higley JD, Stein E (2010b) Effects of early-life stress on serotonin 1A receptors in juvenile rhesus monkeys measured by PET. Biol Psychiatry (Epub ahead of print)Google Scholar
  125. Strome EM, Wheler GH, Higley JD, Loriaux DL, Suomi SJ, Doudet DJ (2002) Intracerebroventricular corticotropin-releasing factor increases limbic glucose metabolism and has social context-dependent behavioral effects in nonhuman primates. Proc Natl Acad Sci USA 99:15749–15754PubMedGoogle Scholar
  126. Suomi SJ (1982) Abnormal behavior in nonhuman primates. In: King JE (ed) Primate behavior. Fobes JD. New York, Academinc PressGoogle Scholar
  127. Suomi SJ, Collins ML, Harlow HF, Ruppenthal GC (1976) Effects of maternal and peer separations on young monkeys. J Child Psychol Psychiatry 17:101–112PubMedGoogle Scholar
  128. Tabakoff B, Hoffman PL (2000) Animal models in alcohol research. Alcohol Res Health 24:77–84PubMedGoogle Scholar
  129. Thorsell A, Repunte-Canonigo V, O’Dell LE, Chen SA, King AR, Lekic D, Koob GF, Sanna PP (2007) Viral vector-induced amygdala NPY overexpression reverses increased alcohol intake caused by repeated deprivations in Wistar rats. Brain 130:1330–1337PubMedCentralPubMedGoogle Scholar
  130. Tikkanen R, Sjoberg RL, Ducci F, Goldman D, Holi M, Tiihonen J, Virkkunen (2009) Effects of MAOA-genotype, alcohol consumption and aging on violent behavior. Alcohol Clin Exp Res 33:428–443PubMedCentralPubMedGoogle Scholar
  131. Trefilov A, Berard J, Krawczak M, Schmidtke J (2000) Natal dispersal in rhesus macaques is related to serotonin transporter gene promoter variation. Behav Genet 30:295–301PubMedGoogle Scholar
  132. Vallender EJ, Priddy CM, Hakim S, Yang H, Chen GL, Miller GM (2008) Functional variation in the 3’ UTR of the serotonin transporter in human and rhesus macaque. Genes Brain Behav 7:690–697PubMedGoogle Scholar
  133. Vallender EJ, Rüedi-Bettschen D, Miller GM, Platt DM (2010) A pharmacogenetic model of naltrexone-induced attenuation of alcohol consumption in rhesus monkeys. Drug Alcohol Depend 109(1–3):252–256Google Scholar
  134. Wagner U, Wahle M, Moritz F, Wagner U, Hantzschel H, Baerwald CG (2006) Promoter polymorphisms regulating corticotrophin-releasing hormone transcription in vitro. Horm Metab Res 38(2):69–75PubMedGoogle Scholar
  135. Way BM, Taylor SE, Eisenberger NL (2009) Variation in the μ-opioid receptor gene is associated with dispositional and neural sensitivity to social rejection. Proc Nat Acad Sci USA 106:15079–15084PubMedGoogle Scholar
  136. Wendland JR, Lesch KP, Newman TK, Timme A, Gachot-Neveu H, Thierry B, Suomi SJ (2005) differential functional variability of serotonin transporter and monoamine oxidase A genes in Macaque species displaying contrasting levels of aggression-related behavior. Behav Genet 30:1–10Google Scholar
  137. Wendland JR, Hampe M, Newman TK, Syagailo Y, Meyer J, Schempp W, Timme A, Suomi SJ, Lesch KP (2006) Structural variation of the monoamine oxidase A gene promoter repeat polymorphism in nonhuman primates. Genes Brain Behav 5:40–45PubMedGoogle Scholar
  138. Westergaard GC, Suomi SJ, Chavanne TJ, Houser L, Hurley A, Cleveland A, Snoy PJ, Higley HD (2003) Physiological correlates of aggression and impulsivity in free-ranging female primates. Neuropsychopharmacology 28:1045–1055PubMedGoogle Scholar
  139. Williams JB, Spitzer RL, Linzer M, Kroenke K, Hahn SR, deGruy FV, Lazev A (1995) Gender differences in depression in primary care. Am J Obstet Gynecol 173:654–659PubMedGoogle Scholar
  140. Williamson DE, Coleman K, Bacanu S, Devlin BJ, Rogers J, Ryan ND, Cameron JL (2003) Heritability of fearful-anxious endophenotypes in infant Rhesus macaques: a preliminary report. Biol Psychiatry 53:284–291PubMedGoogle Scholar
  141. Wood W, Eagly AH (2002) A cross-cultural analysis of the behavior of women and men: implications for the origins of sex differences. Psychol Bull 128:699–727PubMedGoogle Scholar
  142. Zhang H, Luo X, Kranzler HR, Lappalainen J, Yang BZ, Krupitsky E, Zvartau E, Gelernter J (2006) Association between two mu-opioid receptor gene (OPRM1) haplotype blocks and drug or alcohol dependence. Hum Mol Genet 15:807–819PubMedCentralPubMedGoogle Scholar
  143. Zhou Z, Zhu G, Hariri AR, Enoch MA, Scott D, Sinha R, Virkkunen M, Mash DC, Lipsky RH, Hu XZ, Hodgkinson CA, Xu K, Buzas B, Yuan Q, Shen PH, Ferrell RE, Manuck SB, Brown SM, Hauger RL, Stohler CS, Zubieta JK, Goldman D (2008) Genetic variation in human NPY expression affects stress response and emotion. Nature 452(7190):997–1001PubMedCentralPubMedGoogle Scholar
  144. Zhu G, Pollak L, Mottagui-Tabar S, Wahlestedt C, Taubman J, Virkkunen M, Goldman D, Heilig M (2003) NPY leu7pro and alcohol dependence in Finnish and Swedish Populations. Alcohol Clin Exp Res 27(1):19–24PubMedGoogle Scholar
  145. Zill P, Preuss UW, Koller G, Bondy B, Soyka M (2008) Analysis of single nucleotide polymorphisms and haplotypes in the neuropeptide Y gene: no evidence for association with alcoholism in a German population sample. Alcohol Clin Exp Res 32(3):430–434PubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  1. 1.Section of Comparative Behavioral GenomicsRockvilleUSA

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