Endocannabinoid signaling mediates oxytocin-driven social reward

Abstract

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

Interacting Cannabinoid and Opioid Receptors in the Nucleus Accumbens Core Control Adolescent Social Play

“…Our data unequivocally demonstrate that 2-AG stimulated social play depending upon activation of CB1R in the NAcC. Thus both anandamide and 2-AG participate in social reward (Marco et al, 2011; Trezza et al, 2012; Wei et al, 2015, 2016) and social play (Trezza et al, 2012). The endogenous opioid system bidirectionally modulates social behavior in adolescent rats: accumbens MOR and κ-opioid receptors stimulate and inhibit social play, respectively (Trezza et al, 2011b).…”

“…The endocannabinoid system participates in emotional homeostasis from early developmental stages onwards (Viveros et al, 2007; Solinas et al, 2008; Berridge et al, 2010; Campolongo et al, 2011). In adolescent rats, anandamide promotes social play via CB1R in the basolateral amygdala (Trezza et al, 2012) and in adult mice it mediates oxytocin-driven social reward via CB1R located in the NAc (Wei et al, 2015). The main endocannabinoid 2-AG is released in the brain of adolescent rats during social play (Manduca et al, 2015), although the exact brain region where 2-AG modulates social play was unknown.…”

Revealing the role of the endocannabinoid system modulators, SR141716A, URB597 and VDM-11, in sleep homeostasis

“…Along with the CB 1 cannabinoid receptor, the degrading enzyme FAAH for anandamide (Seierstad and Breitenbucher, 2008;Otrubova et al, 2011;Justinova et al, 2015;Wei et al, 2015;Panlilio et al, 2016) also appears to contribute in sleep modulation. Consistent with this idea, expression of FAAH in several brain areas has been described lower after sleep deprivation (Wang et al, 2011).…”

Targeting the Oxytocin System to Treat Addictive Disorders: Rationale and Progress to Date

“…Recently, OT has been shown to promote the endocannabinoid-mediated social reward processes in the NAc core(19). OT also plays a role in emotional regulation, pain and stress.…”