Involvement of 2-arachidonoylglycerol signaling in social challenge responding of male CD1 mice.

Rationale: Endocannabinoids are strong modulators of emotionality and present a novel target for psychotropic drug development. Increasing evidence suggests that endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG) affect behavior differentially. While the roles of anandamide have been investigated extensively, studies regarding the specific roles of 2-AG became possible only recently, and its involvement in social behaviors has not yet been studied.

Objective: We studied the impact of 2-AG signaling on aggression as a first attempt to characterize the role of this endocannabinoid in social behaviors.

Methods: 2-AG signaling was enhanced by the monoacylglycerol lipase inhibitor JZL184 (8, and 16 mg/kg) in mice later submitted to the resident/intruder paradigm.

Results: JZL184 near completely abolished aggressiveness in residents and increased victimization (i.e., attacks by the opponent). Interestingly, the level of defensiveness remained unaltered, despite the large increase in bites received. The CB1 receptor blocker AM251 (0.5 mg/kg) did not influence the effects of JZL184. In intruders, JZL184 near completely suppressed bites and offensive behavior in a fashion similar to residents, but it also increased agitation and defensiveness during, and the corticosterone response to, aggressive encounters. Experiments involving the corticosterone synthesis inhibitor metyrapone (30 mg/kg) suggest that the suppression of biting and offensive behavior is directly influenced by JZL184, whereas increased agitation and defensiveness (seen in intruders only) are a secondary development of the stress-endocrine effects of JZL184.

Conclusions: 2-AG signaling emerges as a surprisingly strong negative modulator of aggressiveness, which warrants further studies into its general role in social behavior and the target receptors involved.