The widespread use of tobacco and alcohol among adolescents might be related to the ability of nicotine and ethanol to facilitate social interactions. To investigate the neurobehavioral mechanisms underlying the prosocial effects of nicotine and ethanol, we focused on social play behavior, the most characteristic social activity in adolescent rats. Social play behavior is rewarding, and it is modulated through opioid, cannabinoid and dopaminergic neurotransmission, which are also involved in the reinforcing properties of nicotine and ethanol. We found that nicotine and ethanol increased social play, without affecting locomotion or social exploration. Their effects depended on the level of social activity of the partner, and were comparable in familiar and unfamiliar environments. At doses that increased social play, nicotine and ethanol had no anxiolytic effects in the elevated plus-maze. By contrast, the prototypical anxiolytic drug diazepam reduced social play at doses that reduced anxiety. The effects of nicotine on social play were blocked by the opioid receptor antagonist naloxone, the CB(1) cannabinoid receptor antagonist SR141716A, and the dopamine receptor antagonist alpha-flupenthixol. The effects of ethanol were blocked by SR141716A and alpha-flupenthixol, but not by naloxone. Combined administration of subeffective doses of nicotine and ethanol only modestly enhanced social play. These results show that the facilitatory effects of nicotine and ethanol on social play are behaviorally specific and mediated through neurotransmitter systems involved in positive emotions and motivation, through partially dissociable mechanisms. Furthermore, the stimulating effects of nicotine and ethanol on social play behavior are independent of their anxiolytic-like properties.