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

Abstract

Social play behavior is a highly rewarding, developmentally important form of social interaction in young mammals. However, its neurobiological underpinnings remain incompletely understood. Previous work has suggested that opioid and endocannabinoid neurotransmission interact in the modulation of social play. Therefore, we combined behavioral, pharmacological, electrophysiological, and genetic approaches to elucidate the role of the endocannabinoid 2-arachidonoylglycerol (2-AG) in social play, and how cannabinoid and opioid neurotransmission interact to control social behavior in adolescent rodents. Systemic administration of the 2-AG hydrolysis inhibitor JZL184 or the opioid receptor agonist morphine increased social play behavior in adolescent rats. These effects were blocked by systemic pretreatment with either CB1 cannabinoid receptor (CB1R) or mu-opioid receptor (MOR) antagonists. The social play-enhancing effects of systemic morphine or JZL184 treatment were also prevented by direct infusion of the CB1R antagonist SR141716 and the MOR antagonist naloxone into the nucleus accumbens core (NAcC). Searching for synaptic correlates of these effects in adolescent NAcC excitatory synapses, we observed that CB1R antagonism blocked the effect of the MOR agonist DAMGO and, conversely, that naloxone reduced the effect of a cannabinoid agonist. These results were recapitulated in mice, and completely abolished in CB1R and MOR knockout mice, suggesting that the functional interaction between CB1R and MOR in the NAcC in the modulation of social behavior is widespread in rodents. The data shed new light on the mechanism by which endocannabinoid lipids and opioid peptides interact to orchestrate rodent socioemotional behaviors.

Synaptic functions of endocannabinoid signaling in health and disease

“…On a functional level, prolonged (20 min) low frequency (4 Hz) stimulation of glutamatergic afferents to this NAc sub region triggers a form of LTD that requires activation of 5-HT 2 R, CB 1 and L-type VGCCs. Recent work revealed that social play, one of the earliest forms of non-mother directed social behavior observed in mammals, implicates a functional interaction between CB 1 and Mu Opioid Receptors in the NAc of rats and mice (Manduca et al, 2016). Thus, the regulation of positively valenced social behavior by morphine, synthetic cannabinoids and 2-AG implicates reciprocal interaction between the two cognate presynaptic receptors, perhaps within a heterodimer complex.…”

Endocannabinoid Signaling in the Control of Social Behavior

“…Moreover, microinjection of the FAAH inhibitor URB597, which stops anandamide degradation and increases its levels [50], into either of these two brain regions, enhanced social play [49,51]. Endocannabinoid effects on social play may also be extended to 2-AG signaling, and may interact with opioid or dopaminergic signaling in the nucleus accumbens [52,53]. These results with an anandamide-potentiating agent stand in sharp contrast to those obtained using a direct-acting cannabinoid receptor agonist, which decreased social play [51] and other forms of direct interactions (as reviewed in the previous section).…”

Muscarinic M1 receptor modulation of synaptic plasticity in nucleus accumbens of wild-type and fragile X mice

“…The accumbens has been extensively studied in the context of drug abuse and addiction related behaviors 7 . More recently, its role in rewarding social behaviors and social interactions has been highlighted [8][9][10] . Muscarinic and nicotinic receptors in the accumbens are necessary for the acquisition of appetitive tasks 11 , food and drug satiety 12 .…”