, Volume 213, Issue 4, pp 799–808

Behavioral characterization of adult male and female rhesus monkeys exposed to cocaine throughout gestation

  • Lindsey R. Hamilton
  • Paul W. Czoty
  • Michael A. Nader
Original Investigation



In utero cocaine exposure has been associated with alterations in the dopamine (DA) system in monkeys. However, the behavioral outcomes of prenatal cocaine exposure in adulthood are poorly understood.


To assess several behavioral measures in 14-year-old rhesus monkeys exposed to cocaine in utero and controls (n = 10 per group).

Materials and methods

For these studies, two unconditioned behavioral tasks, novel object reactivity and locomotor activity, and two conditioned behavioral tasks, response extinction and delay discounting, were examined. In addition, cerebrospinal fluid (CSF) samples were analyzed for concentrations of the monoamine metabolites homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA).


No differences in CSF concentrations of 5-HIAA and HVA, latencies to touch a novel object or locomotor activity measures were observed between groups or sexes. However, prenatally cocaine-exposed monkeys required a significantly greater number of sessions to reach criteria for extinction of food-reinforced behavior than control monkeys. On the delay-discounting task, male prenatally cocaine-exposed monkeys switched preference from the larger reinforcer to the smaller one at shorter delay values than male control monkeys; no differences were observed in females.


These findings suggest that prenatal cocaine exposure results in long-term neurobehavioral deficits that are influenced by sex of the individual.


Animal model Dopamine Drug abuse Serotonin Sex differences Prenatal cocaine Impulsivity Delay discounting Rhesus monkey 


  1. Accornero VH, Amado AJ, Morrow CE, Xue L, Anthony JC, Bandstra ES (2007) Impact of prenatal cocaine exposure on attention and response inhibition as assessed by continuous performance tests. J Dev Behav Pediatr 28:195–205CrossRefPubMedGoogle Scholar
  2. Anderson KG, Woolverton WL (2003) Effects of dose and infusion delay on cocaine self-administration choice in rhesus monkeys. Psychopharmacology 167:424–430PubMedGoogle Scholar
  3. Bandstra ES, Accornero VH, Morrow CE, Xue L, Simpson GR, Glavach MK, Anthony JC (2007) Longitudinal study of visual attention in prenatally cocaine-exposed children and adolescents. Pediatric Academic Societies’ Annual Meeting, Toronto, Canada. 6715.3Google Scholar
  4. Bendersky M, Bennet DS, Lewis M (2006) Aggression at age five as a function of prenatal exposure to cocaine, gender, and environmental risk. J Pediatr Psychol 31:1–14Google Scholar
  5. Bennett D, Bendersky M, Lewis M (2007) Preadolescent health risk behavior as a function of prenatal cocaine exposure and gender. J Dev Behav Pediatr 28:467–472CrossRefPubMedGoogle Scholar
  6. Bolig R, Price CS, O’Neill PL, Suomi SJ (1992) Subjective assessment of reactivity level and personality traits of rhesus monkeys. Int J Primatol 13:287–306CrossRefGoogle Scholar
  7. Cabrera-Vera TM, Garcia F, Pinto W, Battaglia G (2000) Neurochemical changes in brain serotonin neurons in immature and adult offspring prenatally exposed to cocaine. Brain Res 870:1–9CrossRefPubMedGoogle Scholar
  8. Chamberlain SR, Sahakian BJ (2007) The neuropsychiatry of impulsivity. Curr Opin Psychiatry 20:255–261PubMedGoogle Scholar
  9. Clarke AS, Boinski S (1995) Temperament in nonhuman primates. Am J Primatol 37:103–125CrossRefGoogle Scholar
  10. Coleman K, Tully LA, McMillan JL (2005) Temperament correlates with training success in adult rhesus macaques. Am J Primatol 65:63–71CrossRefPubMedGoogle Scholar
  11. Collins GT, Witkin JM, Newman AH, Svensson KA, Grundt P, Cao J, Woods JH (2005) Dopamine agonist-induced yawning in rats: a dopamine D3 receptor-mediated behavior. J Pharmacol Exp Ther 314:310–319CrossRefPubMedGoogle Scholar
  12. Czoty PW, Riddick NV, Gage HD, Sandridge M, Nader SH, Garg S, Bounds M, Garg PK, Nader MA (2009) Effect of menstrual cycle phase on dopamine D2 receptor availability in female cynomolgus monkeys. Psychopharmacology 34:548–554Google Scholar
  13. Czoty PW, Gage HD, Nader MA (2010) Differences in D2 dopamine receptor availability and reaction to novelty in socially housed male monkeys during abstinence from cocaine. Psychopharmacology 208:585–592Google Scholar
  14. Dalley JW, Fryer TD, Brichard L, Robinson ES, Theobald DE, Lääne K, Peña Y, Murphy ER, Shah Y, Probst K, Abakumova I, Aigbirhio FI, Richards HK, Hong Y, Baron JC, Everitt BJ, Robbins TW (2007) Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement. Science 215:1267–1270CrossRefGoogle Scholar
  15. Davis BA, Clinton SM, Akil H, Becker JB (2008) The effects of novelty-seeking phenotypes and sex differences on acquisition of cocaine self-administration in selectively bred high-responder and low-responder rats. Pharmacol Biochem Behav 90:331–338CrossRefPubMedGoogle Scholar
  16. Delaney-Black V, Covington C, Nordstrom B et al (2004) Prenatal cocaine: quantity of exposure and gender moderation. J Dev Behav Pediatr 25:254–263CrossRefPubMedGoogle Scholar
  17. Dellu F, Piazza PV, Mayo W, LeMoal M, Simon H (1996) Novelty-seeking in rats—biobehavioral characteristics and possible relationship with the sensation-seeking trait in man. Neuropsychobiology 34:136–145CrossRefPubMedGoogle Scholar
  18. Dennis-Tiwary T, Bendersky M, Ramsay D et al (2006) Reactivity and regulation in children prenatally cocaine exposed. Dev Psycho 42:688–697CrossRefGoogle Scholar
  19. Dow-Edwards D (2010) Sex differences in the effects of cocaine abuse across the lifespan. Physiol Behav 100(3):208–215CrossRefPubMedGoogle Scholar
  20. Evenden J (1999) Impulsivity: a discussion of clinical and experimental findings. J Psychopharmacol 13:180–192CrossRefPubMedGoogle Scholar
  21. Fairbanks LA, Fontenot MB, Phillips-Conroy JE, Jolly CJ, Kaplan JR, Mann JJ (1999) CSF monoamines, age, and impulsivity in wild grivet monkeys (Cercopithecus aethiops). Brain Behav Evol 53:305–312CrossRefPubMedGoogle Scholar
  22. Fairbanks LA, Melega WP, Jorgensen MJ, Kaplan JR, McGuire MT (2001) Neuropsychopharmacology 24:370–378CrossRefPubMedGoogle Scholar
  23. Fairbanks LA, Jorgensen MJ, Huff A, Blau K, Hung YY, Mann JJ (2004) Adolescent impulsivity predicts adult dominance attainment in male vervet monkeys. Am J Primatol 64:1–17CrossRefPubMedGoogle Scholar
  24. Fang Y, Janowsky A, Ronnekleiv OK (1997) Cocaine exposure in fetal rhesus monkey: consequences for dopamine D1- and D2-like receptor binding densities. Brain Res Dev Brain Res 104:163–174CrossRefPubMedGoogle Scholar
  25. Freeman KB, Green L, Myerson J, Woolverton WL (2009) Delay discounting of saccharin in rhesus monkeys. Behav Processes 82:214–218CrossRefPubMedGoogle Scholar
  26. Hacia JG, Makalowski W, Edgemon K, Erdos MR, Robbins CM, Fodor SP, Brody LC, Collins FS (1998) Evolutionary sequence comparisons using high-density oligonucleotide arrays. Nat Genet 18:155–158CrossRefPubMedGoogle Scholar
  27. Hamilton LR, Czoty PW, Gage HD, Nader MA (2010) Characterization of the dopamine receptor system in adult rhesus monkeys exposed to cocaine throughout gestation. Psychopharmacology 210:481–488CrossRefPubMedGoogle Scholar
  28. Heidbreder C (2008) Selective antagonism at dopamine D3 receptors as a target for drug addiction pharmacotherapy: a review of preclinical evidence. CNS Neurol Disord Drug Targets 7:410–421CrossRefPubMedGoogle Scholar
  29. Higley JD, Mehlman PT, Poland RE, Taub DM, Vickers J, Suomi SJ, Linnoila M (1996) CSF testosterone and 5-HIAA correlate with different types of aggressive behaviors. Biol Psychiatry 40:1067–1082CrossRefPubMedGoogle Scholar
  30. Hooks MS, Jones GH, Smith AD, Neill DB, Justice DB Jr (2001) Response to novelty predicts the locomotor and nucleus accumbens dopamine response to cocaine. Synapse 9:121–128CrossRefGoogle Scholar
  31. Howell LL, Sachama KF, Ellis JE, Grrimley PJ, Kitchens AJ, Byrd LD (2001) Fetal development in rhesus monkeys exposed prenatally to cocaine. Neurotoxicol Teratol 23:133–140CrossRefPubMedGoogle Scholar
  32. Jewitt DA, Dukelow WR (1972) Cyclicity and gestation length of Macaca fascicularis. Primates 13:327–330CrossRefGoogle Scholar
  33. Johns JM, Lubin DA, Lieberman JA, Lauder JM (2002) Developmental effects of prenatal cocaine exposure on 5-HT1A receptors in male and female rat offspring. Dev Neurosci 24:522–530CrossRefPubMedGoogle Scholar
  34. Klebaur JE, Bevins RA, Segar TM, Bardo MT (2001) Individual differences in behavioral responses to novelty and amphetamine self-administration in male and female rats. Behav Pharmacol 12:267–275PubMedGoogle Scholar
  35. Kraemer S (2000) The fragile male. Br Med J 321:1609–1612CrossRefGoogle Scholar
  36. Le Foll B, Goldberg SR, Sokoloff P (2005) The dopamine D3 receptor and drug dependence: effects on reward or beyond? Neuropharmacology 49:525–541CrossRefPubMedGoogle Scholar
  37. Lidow MS (1998) Nonhuman primate model of the effect of prenatal cocaine exposure on cerebral cortical development. Ann NY Acad Sci 846:182–193CrossRefPubMedGoogle Scholar
  38. Lidow MS (2003) Consequences of prenatal cocaine exposure in nonhuman primates. Dev Brain Res 147:23–36CrossRefGoogle Scholar
  39. Linares TJ, Singer LT, Kirchner HL, Short EJ, Min MO, Hussey P, Minnes S (2006) Mental health outcomes of cocaine-exposed children at 6 years of age. J Pediatr Psychol 31:85–97CrossRefPubMedGoogle Scholar
  40. Manuck SB, Kaplan JR, Rymeski BA, Fairbanks LA, Wilson ME (2003) Approach to a social stranger is associated with low central nervous system serotonergic responsivity in female cynomologus monkeys (Macaca fascicularis). Am J Primatol 61:187–194CrossRefPubMedGoogle Scholar
  41. Matthys W, van Goozen SH, de Vries H, Cohen-Kettenis PT, van Engeland H (1998) The dominance of behavioural activation over behavioural inhibition in conduct disordered boys with or without attention deficit hyperactivity disorder. J Child Psychol Psychiatry 39:642–651CrossRefGoogle Scholar
  42. McCleary R (1966) Response-modulating function of the limbic system: Initiation and suppression. In: Stellar E, Sprague J (eds) Progress in physiological psychology, Vol 1. Academic, New York, pp 209–271Google Scholar
  43. Moeller FG, Barratt ES, Dougherty DM, Schmitz JM, Swann AC (2001) Psychiatric aspects of impulsvity. Am J Psychiatry 158:1783–1793CrossRefPubMedGoogle Scholar
  44. Morris P, Binienda Z, Gillam MP et al (1996) The effect of chronic cocaine exposure during pregnancy on maternal and infant outcomes in the rhesus monkey. Neurotoxicol Teratol 18:147–154CrossRefPubMedGoogle Scholar
  45. Morris P, Binienda Z, Gillam MP et al (1997) The effect of chronic cocaine exposure throughout pregnancy on maternal and infant outcomes in the rhesus monkey. Neurotoxicol Teratol 19:47–57CrossRefPubMedGoogle Scholar
  46. Morrow CE, Culbertson JL, Accornero VH, Zue L, Anthony JC, Bandstra ES (2006) Learning disabilities and intellectual functioning in school-aged children with prenatal cocaine exposure. Dev Neuropsychol 30:905–931CrossRefPubMedGoogle Scholar
  47. Nair BS, Watson RR (1991) Cocaine and the pregnant woman. J Reprod Med 36:862–867PubMedGoogle Scholar
  48. Newman JL, Perry JL, Carrol ME (2008) Effects of altering reinforce magnitude and reinforcement schedule on phencyclindine (PCP) self-administration in monkeys using an adjusting delay task. Pharmacol Biochem Behav 90:778–786CrossRefPubMedGoogle Scholar
  49. Noland JS, Singer LT, Short EJ, Minnes S, Arendt RE, Kirchner HL, Bearer C (2005) Prenatal drug exposure and selective attention in preschoolers. Neurotoxicol Teratol 27:429–438CrossRefPubMedGoogle Scholar
  50. Paule MG, Gillam MP, Binienda Z, Morris P (1996) Chronic cocaine exposure throughout gestation in the rhesus monkey. Pregnancy outcomes and offspring behavior. Ann NY Acad Sci 801:301–309CrossRefPubMedGoogle Scholar
  51. Perry JL, Larson EB, German JP, Madden GJ, Carroll ME (2005) Impulsivity (delay discounting) as a predictor of acquisition of IV cocaine self-administration in female rats. Psychopharmacology 178:193–201CrossRefPubMedGoogle Scholar
  52. Piazza PV, Le Moal M (1998) The role of stress in drug self-administration. Trends Pharmacol Sci 19:67–74CrossRefPubMedGoogle Scholar
  53. Piazza PV, Deminiere JM, Le Moal M, Simon H (1989) Factors that predict individual vulnerability to amphetamine self-administration. Science 245:1511–1513CrossRefPubMedGoogle Scholar
  54. Piazza PV, Deminiere JM, Maccari S, Mormede P, Le Moal M, Simon H (1990) Individual reactivity to novelty predicts probability of amphetamine self-administration. Behav Pharmacol 1:339–345PubMedGoogle Scholar
  55. Pulsifer MB, Butz AM, O’Reilly FM, Belcher HM (2008) Prenatal drug exposure: effects on cognitive functioning at 5 years of age. Clin Pediatr 47:58–65CrossRefGoogle Scholar
  56. Riddick NV, Czoty PW, Gage HD, Kaplan JR, Nader SH, Icenhower M, Pierre PJ, Bennett A, Garg PK, Garg S, Nader MA (2009) Behavioral and neurobiological characteristics influencing social hierarchy formation in female cynomolgus monkeys. Neuroscience 158:1257–1265CrossRefPubMedGoogle Scholar
  57. Savage J, Brodsky NL, Malmud E, Giannetta JM, Hurt H (2005) Attentional functioning and impulse control in cocaine-exposed and control children at age 10 years. J Dev Behav Pediatr 26:42–47PubMedGoogle Scholar
  58. Silk J, Short J, Roberts J, Kusnitz J (1993) Gestation length in rhesus macaques (Macaca mulatta). Intern J Primatol 14:95–104CrossRefGoogle Scholar
  59. Silvers JM, Wallace DR, Harrod SB, Mactutus CF, Booze RM (2006) Prenatal cocaine alters dopamine and sigma receptor binding in nucleus accumbens and striatum in dams and adolescent offspring. Neurotoxicol Teratol 28:173–180CrossRefPubMedGoogle Scholar
  60. Singer LT, Arendt R, Minnes S, Farkas K, Salvator A (2000) Neurobehavioral outcomes of cocaine-exposed infants. Neurotoxicol Teratol 22:653–666CrossRefPubMedGoogle Scholar
  61. Singer LT, Hawkins S, Huang J, Davillier M, Baley J (2001) Developmental outcomes and environmental correlates of very low birthweight, cocaine-exposed infants. Early Hum Dev 64:91–103CrossRefPubMedGoogle Scholar
  62. Singer LT, Eisengart LJ, Minnes S, Noland J, Jey A, Lane C, Min MO (2005) Prenatal cocaine exposure and infant cognition. Infant Behav Dev 28:431–444CrossRefPubMedGoogle Scholar
  63. Singer LT, Nelson S, Short E, Min MO, Lewis B, Russ S, Minnes S (2008) Prenatal cocaine exposure: drug and environmental effects at 9 years. J Pediatr 153:105–111CrossRefPubMedGoogle Scholar
  64. Sokoloff P, Diaz J, Le Foll B, Guillin O, Leriche L, Bezard E, Gross C (2006) The dopamine D3 receptor: a therapeutic target for the treatment of neuropsychiatric disorders. CNS Neurol Disord Drug Targets 5:25–43CrossRefPubMedGoogle Scholar
  65. Suto N, Austin JD, Vezina P (2001) Locomotor response to novelty predicts a rat’s propensity to self-administer nicotine. Psychopharmacology 158:175–180CrossRefPubMedGoogle Scholar
  66. United States Department of Health and Human Services, Substance Abuse and Mental Health Services Administration SAMHSA Office of Applied Studies (2009) Results from the 2008 National Survey on Drug Use and Health: National Findings. Ref Type: ReportGoogle Scholar
  67. Weerts EM, Fantegrossi WE, Goodwin AK (2007) The value of nonhuman primates in drug abuse research. Exp Clin Psychopharmacol 15:309–327CrossRefPubMedGoogle Scholar
  68. Westergaard GC, Suomi SJ, Higley JD, Mehlman PT (1999) CSF 5-HIAA and aggression in female macaque monkeys: species and interindividual differences. Psychopharmacology 146:440–446CrossRefPubMedGoogle Scholar
  69. Westergaard GC, Suomi SJ, Chavanne TJ, Houser L, Hurley A, Cleveland A, Snoy PJ, Higley JD (2003) Physiological correlates of aggression and impulsivity in free-ranging female primates. Neuropsychopharmacology 28:1045–1055PubMedGoogle Scholar
  70. Woolverton WL, Anderson KG (2006) Effects of delay to reinforcement on the choice between cocaine and food in rhesus monkeys. Psychopharmacology 186:99–106CrossRefPubMedGoogle Scholar
  71. Woolverton WL, Myerson J, Green L (2007) Delay discounting of cocaine by rhesus monkeys. Exp Clin Psychopharmacol 15:238–244CrossRefPubMedGoogle Scholar
  72. Zuckerman M (1996) The psychobiological model for impulsive unsocialized sensation-seeking: a comparative approach. Neuropsychobiology 34:125–129CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Lindsey R. Hamilton
    • 1
  • Paul W. Czoty
    • 1
  • Michael A. Nader
    • 1
    • 2
  1. 1.Department of Physiology and PharmacologyWake Forest University School of MedicineWinston-SalemUSA
  2. 2.Department of RadiologyWake Forest University School of MedicineWinston-SalemUSA

Personalised recommendations