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 N-(4-hydroxyphenyl)-arachidonamide (AM404) reduced social play, whereas its more selective analog N-arachidonoyl-(2methyl- 4-hydroxyphenyl) amine (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 N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3- carboxamide hydrochloride (SR141716A), the CB 2 cannabinoid receptor antagonist N-(1,3,3-trimethylbicyclo(2.2.1)heptan-2-yl)-5-(4-chloro-3-methyl-phenyl)1-( 4-methylbenzyl) pyrazole-3-carboxamide (SR144528), or by the transient receptor potential vanilloid 1 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 CB 1 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 they 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.