Endocannabinoids in Amygdala and Nucleus Accumbens Mediate Social Play Reward in Adolescent Rats

Abstract

The brain endocannabinoid system plays a crucial role in emotional processes. We have previously identified an important role for endocannabinoids in social play behavior, a highly rewarding form of social interaction in adolescent rats. Here, we tested the hypothesis that endocannabinoid modulation of social play behavior occurs in brain regions implicated in emotion and motivation. Social play increased levels of the endocannabinoid anandamide in the amygdala and nucleus accumbens (NAc), but not in prefrontal cortex or hippocampus of 4–5 week old male Wistar rats. Furthermore, social play increased phosphorylation of CB1 cannabinoid receptors in the amygdala. Systemic administration of the anandamide hydrolysis inhibitor URB597 increased social play behavior, and augmented the associated elevation in anandamide levels in the amygdala, but not the NAc. Infusion of URB597 into the basolateral amygdala (BLA) increased social play behavior, and blockade of BLA CB1 cannabinoid receptors with the antagonist/inverse agonist SR141716A prevented the play-enhancing effects of systemic administration of URB597. Infusion of URB597 into the NAc also increased social play, but blockade of NAc CB1 cannabinoid receptors did not antagonize the play-enhancing effects of systemic URB597 treatment. Last, SR141716A did not affect social play after infusion into the core and shell subregions of the NAc, while it reduced social play when infused into the BLA. These data show that increased anandamide signalling in the amygdala and NAc augments social play, and identify the BLA as a prominent site of action for endocannabinoids to modulate the rewarding properties of social interactions in adolescent rats.

Phencyclidine-Induced Social Withdrawal Results from Deficient Stimulation of Cannabinoid CB1 Receptors: Implications for Schizophrenia

“…As CB 1 receptors are predominantly expressed on CCK þ terminals (Marsicano and Lutz, 1999;Ramikie and Patel, 2011), and CB 1 activation produces a selective inhibition of these cells (Hentges et al, 2005), we postulated that endocannabinoid-induced inhibition of CCK þ interneurons is lost/reduced in PCP-treated rats, thus resulting in social withdrawal (Supplementary Figure S7). In support of this hypothesis, our study and other reports have shown increased AEA (Trezza et al, 2012) and decreased CCK levels (Panksepp et al, 2004) during social interaction in normal rats. In PCP-treated rats, which are characterized by deficient AEA mobilization, endocannabinoid elevation back to control levels, or direct activation of CB 1 receptors or blockade of CCK2 receptors, reverses the social behavior deficit.…”

“…Indeed, we found that the 'on demand' production of AEA occurring during social interaction (Trezza et al, 2012) is significantly reduced in PCP-treated rats in brain areas relevant to social behavior, such as the mPFC and amygdala. The resulting deficient CB 1 activation cannot be attributed to decreased CB 1 expression, nor to disrupted CB 1 function/coupling, as neither one are affected in our animal model (Seillier et al, 2010).…”

Endocannabinoid signaling mediates oxytocin-driven social reward

“…In humans, marijuana can either facilitate or impair social interactions and social saliency, possibly depending on dose and context (1-3). Analogously, in animal models, cannabinoid receptor activation with direct-acting agonist drugs disrupts social interactions, whereas FAAH inhibition enhances them, which is suggestive of a role for anandamide in socialization (9,25,26). Although important, these data leave unanswered two key questions.…”

“…Consistent with this idea, CB 1 receptors are highly expressed in associational cortical regions of the frontal lobe and subcortical structures that underpin human social-emotional functioning (6,7). Moreover, the receptors and their endogenous lipid-derived ligands, anandamide and 2-arachidonoyl-sn-glycerol (2-AG) (8), have been implicated in the control of social play (9) and social anxiety (10,11), two crucial aspects of the social experience. Another essential facet of social behavior, the adaptive reinforcement of interactions among members of a group (i.e., the reward of being social), requires the oxytocin-dependent induction of long-term synaptic plasticity at excitatory synapses of the nucleus accumbens (NAc) (12), a key region in the brain reward circuit.…”

Dopaminergic Neurotransmission in the Nucleus Accumbens Modulates Social Play Behavior in Rats

“…Previous studies have shown that the nucleus accumbens (NAc), a brain region widely implicated in reward and motivation (Berridge and Kringelbach, 2008;Everitt and Robbins, 2005;Floresco, 2015), modulates the positive subjective properties of social play behavior in rats (Gordon et al, 2002;Trezza et al, 2011Trezza et al, , 2012van Kerkhof et al, 2013van Kerkhof et al, , 2014Vanderschuren et al, 1995b). Interestingly, peer-peer interactions in 4-week-old rats increase dopamine activity in the NAc (Robinson et al, 2011).…”