, Volume 231, Issue 8, pp 1503–1515 | Cite as

Amphetamine and cocaine suppress social play behavior in rats through distinct mechanisms

  • E. J. Marijke Achterberg
  • Viviana Trezza
  • Stephen M. Siviy
  • Laurens Schrama
  • Anton N. M. Schoffelmeer
  • Louk J. M. J. Vanderschuren
Original Investigation



Social play behavior is a characteristic form of social behavior displayed by juvenile and adolescent mammals. This social play behavior is highly rewarding and of major importance for social and cognitive development. Social play is known to be modulated by neurotransmitter systems involved in reward and motivation. Interestingly, psychostimulant drugs, such as amphetamine and cocaine, profoundly suppress social play, but the neural mechanisms underlying these effects remain to be elucidated.


In this study, we investigated the pharmacological underpinnings of amphetamine- and cocaine-induced suppression of social play behavior in rats.


The play-suppressant effects of amphetamine were antagonized by the alpha-2 adrenoreceptor antagonist RX821002 but not by the dopamine receptor antagonist alpha-flupenthixol. Remarkably, the effects of cocaine on social play were not antagonized by alpha-2 noradrenergic, dopaminergic, or serotonergic receptor antagonists, administered either alone or in combination. The effects of a subeffective dose of cocaine were enhanced by a combination of subeffective doses of the serotonin reuptake inhibitor fluoxetine, the dopamine reuptake inhibitor GBR12909, and the noradrenaline reuptake inhibitor atomoxetine.


Amphetamine, like methylphenidate, exerts its play-suppressant effect through alpha-2 noradrenergic receptors. On the other hand, cocaine reduces social play by simultaneous increases in dopamine, noradrenaline, and serotonin neurotransmission. In conclusion, psychostimulant drugs with different pharmacological profiles suppress social play behavior through distinct mechanisms. These data contribute to our understanding of the neural mechanisms of social behavior during an important developmental period, and of the deleterious effects of psychostimulant exposure thereon.


Social play Adolescence Amphetamine Cocaine Dopamine Serotonin Noradrenaline Alpha-2 adrenoceptor 



Supported by the National Institute on Drug Abuse Grant R01 DA022628 (L.J.M.J.V.), Netherlands Organization for Scientific Research (NWO) Veni grant 91611052 (V.T.), and Marie Curie Career Reintegration Grant PCIG09-GA-2011-293589 (V.T.).


  1. Aragona BJ, Cleaveland NA, Stuber GD, Day JJ, Carelli RM, Wightman RM (2008) Preferential enhancement of dopamine transmission within the nucleus accumbens shell by cocaine is attributable to a direct increase in phasic dopamine release events. J Neurosci 28:8821–8831PubMedCentralPubMedCrossRefGoogle Scholar
  2. Aston-Jones G, Cohen JD (2005) An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annu Rev Neurosci 28:403–450PubMedCrossRefGoogle Scholar
  3. Baarendse PJJ, Counotte DS, O’Donnell P, Vanderschuren LJMJ (2013) Early social experience is critical for the development of cognitive control and dopamine modulation of prefrontal cortex function. Neuropsychopharmacology 38:1485–1494Google Scholar
  4. Beatty WW, Dodge AM, Dodge LJ, Panksepp J (1982) Psychomotor stimulants, social deprivation and play in juvenile rats. Pharmacol Biochem Behav 16:417–422PubMedCrossRefGoogle Scholar
  5. Beatty WW, Costello KB, Berry SL (1984) Suppression of play fighting by amphetamine: effects of catecholamine antagonists, agonists and synthesis inhibitors. Pharmacol Biochem Behav 20:47–755CrossRefGoogle Scholar
  6. Blakemore SJ, Robbins TW (2012) Decision-making in the adolescent brain. Nat Neurosci 15:1184–1191Google Scholar
  7. Boess FG, Martin IL (1994) Molecular biology of 5-HT receptors. Neuropharmacology 33:275–317PubMedCrossRefGoogle Scholar
  8. Boys A, Marsden J, Strang J (2001) Understanding reasons for drug use amongst young people: a functional perspective. Health Educ Res 16:457–469PubMedCrossRefGoogle Scholar
  9. Casey BJ, Jones RM (2010) Neurobiology of the adolescent brain and behavior: implications for substance use disorders. J Am Acad Child Adolesc Psychiatry 49:1189–1201PubMedCentralPubMedGoogle Scholar
  10. Daberkow DP, Brown HD, Bunner KD, Kraniotis SA, Doellman MA, Ragozzino ME, Garris PA, Roitman MF (2013) Amphetamine paradoxically augments exocytotic dopamine release and phasic dopamine signals. J Neurosci 33:452–463PubMedCentralPubMedCrossRefGoogle Scholar
  11. Eagle DM, Baunez C (2010) Is there an inhibitory-response-control system in the rat? Evidence from anatomical and pharmacological studies of behavioral inhibition. Neurosci Biobehav Rev 34:50–72PubMedCentralPubMedCrossRefGoogle Scholar
  12. Ferguson SA, Frisby NB, Ali SF (2000) Acute effects of cocaine on play behaviour of rats. Behav Pharmacol 11:175–179PubMedCrossRefGoogle Scholar
  13. Field EF, Pellis SM (1994) Differential effects of amphetamine on the attack and defense components of play fighting in rats. Physiol Behav 56:325–330PubMedCrossRefGoogle Scholar
  14. File SE, Seth P (2003) A review of 25 years of the social interaction test. Eur J Pharmacol 463:35–53PubMedCrossRefGoogle Scholar
  15. Heikkila RE, Orlansky H, Mytilineou C, Cohen G (1975) Amphetamine: evaluation of d- and l-isomers as releasing agents and uptake inhibitors for 3H-dopamine and 3H-norepinephrine in slices of rat neostriatum and cerebral cortex. J Pharmacol Exp Ther 194:47–56PubMedGoogle Scholar
  16. Homberg JR, Schiepers OJG, Schoffelmeer ANM, Cuppen E, Vanderschuren LJMJ (2007) Acute and constitutive increases in central serotonin levels reduce social play behaviour in peri-adolescent rats. Psychopharmacology 195:175–182PubMedCentralPubMedCrossRefGoogle Scholar
  17. Kelly PH, Seviour PW, Iversen SD (1975) Amphetamine and apomorphine responses in the rat following 6-OHDA lesions of the nucleus accumbens septi and corpus striatum. Brain Res 94:507–522Google Scholar
  18. Knutson B, Panksepp J, Pruitt D (1996) Effects of fluoxetine on play dominance in juvenile rats. Aggr Behav 22:297–307CrossRefGoogle Scholar
  19. Liu Y, Aragona BJ, Young KA, Dietz DM, Kabbaj M, Mazei-Robison M, Nestler EJ, Wang Z (2010) Nucleus accumbens dopamine mediates amphetamine-induced impairment of social bonding in a monogamous rodent species. Proc Natl Acad Sci U S A 107:1217–1222PubMedCentralPubMedCrossRefGoogle Scholar
  20. Liu Y, Young KA, Curtis JT, Aragona BJ, Wang Z (2011) Social bonding decreases the rewarding properties of amphetamine through a dopamine D1 receptor-mediated mechanism. J Neurosci 31:7960–7966PubMedCentralPubMedCrossRefGoogle Scholar
  21. Lyon M, Robbins TW (1975) The action of central nervous system stimulant drugs: A general theory concerning amphetamine effects. In: Essman WB, Valzelli L (eds) Current developments in psychopharmacology, vol 2. Spectrum, New York, pp 79–163Google Scholar
  22. Miczek KA, Yoshimura H (1982) Disruption of primate social behavior by d-amphetamine and cocaine: differential antagonism by antipsychotics. Psychopharmacology 76:163–171PubMedCrossRefGoogle Scholar
  23. Nelson EE, Leibenluft E, McClure EB, Pine DS (2005) The social re-orientation of adolescence: a neuroscience perspective on the process and its relation to psychopathology. Psychol Med 35:163–174PubMedCrossRefGoogle Scholar
  24. Newcomb MD, Bentler PM (1989) Substance use and abuse among children and teenagers. Am Psy 44:242–248CrossRefGoogle Scholar
  25. Niesink RJM, Van Ree JM (1989) Involvement of opioid and dopaminergic systems in isolation-induced pinning and social grooming of young rats. Neuropharmacology 28:411–418PubMedCrossRefGoogle Scholar
  26. Panksepp J, Beatty WW (1980) Social deprivation and play in rats. Behav Neural Biol 30:197–206PubMedCrossRefGoogle Scholar
  27. Panksepp J, Siviy S, Normansell L (1984) The psychobiology of play: theoretical and methodological perspectives. Neurosci Biobehav Rev 8:465–492PubMedCrossRefGoogle Scholar
  28. Panksepp J, Jalowiec J, DeEskinazi FG, Bishop P (1985) Opiates and play dominance in juvenile rats. Behav Neurosci 99:441–453PubMedCrossRefGoogle Scholar
  29. Pellis SM, McKenna MM (1992) Intrinsic and extrinsic influences on play fighting in rats: effects of dominance, partner’s playfulness, temperament and neonatal exposure to testosterone propionate. Behav Brain Res 50:135–145PubMedCrossRefGoogle Scholar
  30. Pellis SM, Pellis VC (1987) Play-fighting differs from serious fighting in both target of attack and tactics of fighting in the laboratory rat Rattus norvegicus. Aggress Behav 13:227–242CrossRefGoogle Scholar
  31. Pellis SM, Pellis VC (2009) The playful brain: Venturing to the limits of neuroscience. Oneworld, OxfordGoogle Scholar
  32. Pellis SM, Field EF, Smith LK, Pellis VC (1997) Multiple differences in the play fighting of male and female rats. Implications for the causes and functions of play. Neurosci Biobehav Rev 21:105–120PubMedCrossRefGoogle Scholar
  33. Pierce RC, Kumaresan V (2006) The mesolimbic dopamine system: the final common pathway for the reinforcing effect of drugs of abuse? Neurosci Biobehav Rev 30:215–238PubMedCrossRefGoogle Scholar
  34. Poole TB, Fish J (1975) Investigation of playful behavior in Rattus norvegicus and Mus musculus (Mammalia). J Zool 175:61–71CrossRefGoogle Scholar
  35. Potegal M, Einon D (1989) Aggressive behaviors in adult rats deprived of playfighting experience as juveniles. Dev Psychobiol 22:159–172PubMedCrossRefGoogle Scholar
  36. Rademacher DJ, Schuyler AL, Kruschel CK, Steinpreis RE (2002) Effects of cocaine and putative atypical antipsychotics on rat social behavior. An ethopharmacological study. Pharmacol Biochem Behav 73:769–778PubMedCrossRefGoogle Scholar
  37. Ritz MC, Kuhar MJ (1989) Relationship between self-administration of amphetamine and monoamine receptors in brain: comparison with cocaine. J Pharmacol Exp Ther 248:1010–1017PubMedGoogle Scholar
  38. Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI et al (2001) Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. Synapse 39:32–41PubMedCrossRefGoogle Scholar
  39. Sahakian BJ, Robbins TW, Morgan MJ, Iversen SD (1975) The effects of psychomotor stimulants on stereotypy and locomotor activity in socially-deprived and control rats. Brain Res 84:195–205PubMedCrossRefGoogle Scholar
  40. Schiørring E (1979) Social isolation and other behavioral changes in groups of adult vervet monkeys (Cercopithecus aethiops) produced by low, nonchronic doses of d-amphetamine. Psychopharmacology 64:297–302PubMedCrossRefGoogle Scholar
  41. Schramm-Sapyta NL, Walker QD, Caster JM, Levin ED, Kuhn CM (2009) Are adolescents more vulnerable to drug addiction than adults? Evidence from animal models. Psychopharmacology 206:1–21PubMedCentralPubMedCrossRefGoogle Scholar
  42. Siviy SM, Panksepp J (1987) Sensory modulation of juvenile play in rats. Dev Psychobiol 20:39–55PubMedCrossRefGoogle Scholar
  43. Siviy SM, Panksepp J (2011) In search of the neurobiological substrates for social playfulness in mammalian brains. Neurosci Biobehav Rev 35:1821–1830PubMedCrossRefGoogle Scholar
  44. Spear LP (2000) The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 24:417–463PubMedCrossRefGoogle Scholar
  45. Sutton ME, Raskin LA (1986) A behavioral analysis of the effects of amphetamine on play and locomotor activity in the post-weaning rat. Pharmacol Biochem Behav 24:455–461PubMedCrossRefGoogle Scholar
  46. Thor DH, Holloway WR Jr (1983) Play soliciting in juvenile male rats: effects of caffeine, amphetamine and methylphenidate. Pharmacol Biochem Behav 19:725–727PubMedCrossRefGoogle Scholar
  47. Trezza V, Vanderschuren LJMJ (2008a) Cannabinoid and opioid modulation of social play behavior in adolescent rats: differential behavioral mechanisms. Eur Neuropsychopharmacol 18:519–530PubMedCentralPubMedCrossRefGoogle Scholar
  48. Trezza V, Vanderschuren LJMJ (2008b) Bidirectional cannabinoid modulation of social behavior in adolescent rats. Psychopharmacology 197:217–227PubMedCrossRefGoogle Scholar
  49. Trezza V, Baarendse PJJ, Vanderschuren LJMJ (2009) Prosocial effects of nicotine and ethanol in adolescent rats through partially dissociable neurobehavioral mechanisms. Neuropsychopharmacology 34:2560–2573PubMedCentralPubMedCrossRefGoogle Scholar
  50. Trezza V, Baarendse PJJ, Vanderschuren LJMJ (2010) The pleasures of play: pharmacological insights into social reward mechanisms. Trends Pharmacol Sci 31:463–469PubMedCentralPubMedCrossRefGoogle Scholar
  51. Trezza V, Campolongo P, Vanderschuren LJMJ (2011) Evaluating the rewarding nature of social interactions in laboratory animals. Dev Cogn Neurosci 1:444–458PubMedCrossRefGoogle Scholar
  52. Van den Berg CL, Pijlman FT, Koning HA, Diergaarde L, Van Ree JM, Spruijt BM (1999) Isolation changes the incentive value of sucrose and social behaviour in juvenile and adult rats. Behav Brain Res 106:133–142PubMedCrossRefGoogle Scholar
  53. Vanderschuren LJMJ (2010) How the brain makes play fun. Am J Play 2:315–337Google Scholar
  54. Vanderschuren LJMJ, Niesink RJM, Spruijt BM, Van Ree JM (1995a) Effects of morphine on different aspects of social play in juvenile rats. Psychopharmacology 117:225–231PubMedCrossRefGoogle Scholar
  55. Vanderschuren LJMJ, Spruijt BM, Hol T, Niesink RJM, Van Ree JM (1995b) Sequential analysis of social play behavior in juvenile rats: effects of morphine. Behav Brain Res 72:89–95PubMedCrossRefGoogle Scholar
  56. Vanderschuren LJMJ, Niesink RJM, Van Ree JM (1997) The neurobiology of social play behavior in rats. Neurosci Biobehav Rev 21:309–326PubMedCrossRefGoogle Scholar
  57. Vanderschuren LJMJ, Trezza V, Griffioen-Roose S, Schiepers OJG, Van Leeuwen N, De Vries TJ et al (2008) Methylphenidate disrupts social play behavior in adolescent rats. Neuropsychopharmacology 33:2946–2956PubMedCentralPubMedCrossRefGoogle Scholar
  58. Veeneman MMJ, Boleij H, Broekhoven MH, Snoeren EMS, Guitart Masip M, Cousijn J, Spooren W, Vanderschuren LJMJ (2011) Dissociable roles of mGlu5 and dopamine receptors in the rewarding and sensitizing properties of morphine and cocaine. Psychopharmacology 214:863–876PubMedCentralPubMedCrossRefGoogle Scholar
  59. Veeneman MMJ, Broekhoven MH, Damsteegt R, Vanderschuren LJMJ (2012) Distinct contributions of dopamine in the dorsolateral striatum and nucleus accumbens shell to the reinforcing properties of cocaine. Neuropsychopharmacology 37:487–498PubMedCentralPubMedCrossRefGoogle Scholar
  60. Venton BJ, Seipel AT, Phillips PEM, Wetsel WC, Gitler D, Greengard P, Augustine GJ, Wightman RM (2006) Cocaine increases dopamine release by mobilization of a synapsin-dependent reserve pool. J Neurosci 26:3206–3209PubMedCrossRefGoogle Scholar
  61. White FJ, Joshi A, Koeltzow TE, Hu XT (1998) Dopamine receptor antagonists fail to prevent induction of cocaine sensitization. Neuropsychopharmacology 18:26–40PubMedCrossRefGoogle Scholar
  62. Wise RA (2004) Dopamine, learning and motivation. Nat Rev Neurosci 5:483–494PubMedCrossRefGoogle Scholar
  63. Wise RA, Bozarth MA (1987) A psychomotor stimulant theory of addiction. Psychol Rev 94:469–492PubMedCrossRefGoogle Scholar
  64. Young KA, Gobrogge KL, Wang Z (2011) The role of mesocorticolimbic dopamine in regulating interactions between drugs of abuse and social behavior. Neurosci Biobehav Rev 35:498–515PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • E. J. Marijke Achterberg
    • 1
  • Viviana Trezza
    • 2
    • 3
  • Stephen M. Siviy
    • 4
  • Laurens Schrama
    • 5
  • Anton N. M. Schoffelmeer
    • 5
  • Louk J. M. J. Vanderschuren
    • 1
    • 2
  1. 1.Department of Animals in Science and Society, Division of Behavioural Neuroscience, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
  2. 2.Department of Neuroscience and Pharmacology, Brain Center Rudolf MagnusUniversity Medical Center UtrechtUtrechtThe Netherlands
  3. 3.Department of Sciences, Section of Biomedical Sciences and TechnologiesUniversity “Roma Tre”RomeItaly
  4. 4.Department of PsychologyGettysburg CollegeGettysburgUSA
  5. 5.Department of Anatomy and Neurosciences, Neuroscience Campus AmsterdamVU University Medical CenterAmsterdamThe Netherlands

Personalised recommendations