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.
Highlights
Social play behavior is a highly vigorous form of social interaction, which is abundant in young mammals, including humans (Panksepp et al, 1984; Pellis and Pellis, 2009)
The present study supports the idea that CB1R and mu-opioid receptor (MOR) interact in the nucleus accumbens (NAc) core (NAcC) to underlie the actions of endogenous cannabinoid lipids and opioid peptides on social behavior in adolescent rats and mice
We found that JZL184, which produces a long-lasting elevation of brain 2-AG by inhibiting monoacylglycerol lipase (MAGL) mediated 2-AG hydrolysis (Long et al, 2009; Seillier et al, 2014; Morena et al, 2015), increased the frequency of pinning and pouncing, the two principal characteristic parameters of social play in adolescent rats
Summary
Social play behavior is a highly vigorous form of social interaction, which is abundant in young mammals, including humans (Panksepp et al, 1984; Pellis and Pellis, 2009). Social play has a strong rewarding value (Calcagnetti and Schechter, 1992; Trezza et al, 2011b; Achterberg et al, 2016) It can be used as an incentive for place conditioning, operant conditioning and maze learning in laboratory animals (for a review see Panksepp et al, 1987; Trezza et al, 2011a), and social play is modulated by neurotransmitters implicated in reward and motivation, such as endogenous opioids, endocannabinoids (eCBs), and dopamine (Trezza and Vanderschuren, 2008b; Trezza et al, 2010; Achterberg et al, 2016; Manduca et al, 2016; Vanderschuren et al, 2016). In the CNS, two principal eCBs are thought to be responsible for the neuromodulatory functions of CB1 cannabinoid receptors (CB1R): anandamide and 2-arachidonoylglycerol (2-AG; Katona and Freund, 2012) Both molecules are synthesized on-demand to regulate synaptic transmission (Castillo et al, 2012). We hypothesized that MORs and CB1Rs interact in the modulation of social behavior in young rats and mice
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