Divergent effects of anandamide transporter inhibitors with different target selectivity on social play behavior in adolescent rats

The endocannabinoid system plays an important role in the modulation of affect, motivation and emotion. Social play behavior is a natural reinforcer in adolescent rats, and we have recently shown that interacting endocannabinoid, opioid and dopamine systems modulate social play. In the present study, we tested the hypothesis that, in contrast to administration of exogenous cannabinoid agonists, increasing local endocannabinoid signaling through anandamide transporter inhibition enhances social play. To this aim, we tested the effects of two anandamide transporter inhibitors with different target selectivity on social play behavior in adolescent rats. Interestingly, we found that the prototypical anandamide transporter inhibitor AM404 reduced social play, whereas its more selective analogue VDM11 enhanced it. The effects of AM404 were not mediated through its known pharmacological targets, since they were not blocked by the CB1 cannabinoid receptor antagonist SR141716A, the CB2 cannabinoid receptor antagonist SR144528, or by the TRPV1 vanilloid receptor antagonist capsazepine. In contrast, the increase in social play induced by VDM11 was dependent on cannabinoid, opioid and dopaminergic neurotransmission, since it was blocked by the CB1 cannabinoid receptor antagonist SR141716A, the opioid receptor antagonist naloxone and the dopamine receptor antagonist alpha-flupenthixol. These findings support the notion that anandamide plays an important role in the modulation of social interaction in adolescent rats, and suggest that selective anandamide transporter inhibitors might be useful for the treatment of social dysfunctions. Furthermore, these results suggest that off-target effects may be responsible for some of the conflicting effects of anandamide transporter inhibitors on behavior.