Marijuana exerts profound effects on human social behavior, but the neural substrates underlying such effects are unknown. Here we report that social contact increases, whereas isolation decreases, the mobilization of the endogenous marijuana-like neurotransmitter, anandamide, in the mouse nucleus accumbens (NAc), a brain structure that regulates motivated behavior. Pharmacological and genetic experiments show that anandamide mobilization and consequent activation of CB 1 cannabinoid receptors are necessary and sufficient to express the rewarding properties of social interactions, assessed using a socially conditioned place preference test. We further show that oxytocin, a neuropeptide that reinforces parental and social bonding, drives anandamide mobilization in the NAc. Pharmacological blockade of oxytocin receptors stops this response, whereas chemogenetic, site-selective activation of oxytocin neurons in the paraventricular nucleus of the hypothalamus stimulates it. Genetic or pharmacological interruption of anandamide degradation offsets the effects of oxytocin receptor blockade on both social place preference and cFos expression in the NAc. The results indicate that anandamidemediated signaling at CB 1 receptors, driven by oxytocin, controls social reward. Deficits in this signaling mechanism may contribute to social impairment in autism spectrum disorders and might offer an avenue to treat these conditions. endocannabinoid | oxytocin | reward | social behavior | anandamide

Introduction: We recently uncovered a signaling mechanism by which the endocannabinoid anandamide mediates the action of oxytocin, a neuropeptide that is crucial for social behavior, to control social reward. Oxytocin signaling has been implicated in autism spectrum disorder (ASD), and social reward is a key aspect of social functioning that is thought to be disrupted in ASD. Therefore, as a proof of principle for the core component of ASD-social impairment-we tested an endocannabinoid-enhancing compound on two widely studied mouse models of ASD, the BTBR and fmr1À/À (model of Fragile X Syndrome). Methods:We used the established three-chambered social approach test. We specifically increased the activity of anandamide by administering the compound URB597, a selective inhibitor of fatty acid amide hydrolase (FAAH), the hydrolytic enzyme for anandamide.Results: Remarkably, we found that FAAH blockade completely reversed the social impairment in both mouse models. CB 1 receptor blockade prevented the prosocial action of FAAH inhibition in BTBR mice. These results were likely independent of effects on anxiety, as FAAH inhibition did not alter the performance of BTBR mice in the elevated plus maze. Conclusions:The results suggest that increasing anandamide activity at CB 1 receptors improves ASD-related social impairment and identify FAAH as a novel therapeutic target for ASD.

Many mammalian species, including humans, exhibit social behavior and form complex social groups. Mechanistic studies in animal models have revealed important roles for the endocannabinoid signaling system—consisting of G protein-coupled cannabinoid receptors and their endogenous lipid-derived agonists—in the control of neural processes that underpin social anxiety and social reward, two key aspects of social behavior. An emergent insight from these studies is that endocannabinoid signaling in specific circuits of the brain is context-dependent and selectively recruited. These insights open new vistas on the neural basis of social behavior and social impairment.

Highlights d Neurons in dmPFC respond selectively to male versus female social interaction d Male mice exhibit a bias toward stronger encoding of female versus male cues d Sex encoding in dmPFC predicts behavioral sex preference in individuals d Activation of sex-encoding cells controls male versus female preference behavior

SUMMARY The second messenger hydrogen peroxide transduces changes in cellular redox state by reversibly oxidizing protein cysteine residues to sulfenic acid. This signaling event regulates many cellular processes, but has been never shown to occur in the brain. Here we report that hydrogen peroxide heightens endocannabinoid signaling in brain neurons through sulfenylation of cysteines C201 and C208 in monoacylglycerol lipase (MGL), a serine hydrolase that deactivates the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG) in nerve terminals. The results suggest that MGL sulfenylation may provide a presynaptic control point for 2-AG-mediated endocannabinoid signaling.