Bidirectional cannabinoid modulation of social behavior in adolescent rats

Rationale Marijuana use in adolescents is a highly social activity, and interacting endocannabinoid and opioid systems may modulate social reward. However, cannabinoid exposure has been reported to reduce social behavior. Objectives The aim of this study was to elucidate the mechanisms underlying the paradoxical relationship between cannabinoid exposure and sociability. Materials and methods We investigated the effect of cannabinoid agonists with a different mechanism of action on social play behavior in adolescent rats. In addition, we examined whether endocannabinoid neurotransmission interacts with opioid and dopaminergic neurotransmission in the modulation of social play behavior. Results The direct CB₁ cannabinoid receptor agonist WIN55,212-2 reduced social play. However, the indirect cannabinoid agonist URB597, which inhibits the hydrolysis of the endocannabinoid anandamide, enhanced social play. This effect of URB597 depended upon stimulation of opioid and dopamine receptors. The well-known stimulatory effect of morphine on social play was attenuated by the CB₁ cannabinoid receptor antagonist SR141716A, but independent of dopamine receptor stimulation. Combined treatment with ineffective doses of URB597 and morphine increased social play. Conclusions Cannabinoid neurotransmission can both enhance and inhibit social interaction in adolescent rats depending on how the endocannabinoid system is stimulated. Activation of cannabinoid receptors throughout the brain, which occurs during cannabis use, inhibits sociability. In contrast, on-demand release of endocannabinoids facilitates social interaction, which is magnified by indirect cannabinoid agonists through an interaction with opioid and dopaminergic neurotransmission. These results shed light on the paradoxical relationship between cannabis exposure and sociability and suggest that endocannabinoid degradation inhibitors hold promise for the treatment of social dysfunctions.