A role for the endocannabinoid 2-arachidonoyl-sn-glycerol for social and high-fat food reward in male mice

Abstract

Rationale The endocannabinoid system is an important modulator of brain reward signaling. Investigations have focused on cannabinoid (CB1) receptors, because dissection of specific contributions of individual endocannabinoids has been limited by the available toolset. While we recently described an important role for the endocannabinoid anandamide in the regulation of social reward, it remains to be determined whether the other major endocannabinoid, 2-arachidonoyl-sn-glycerol (2-AG), serves a similar or different function. Objectives To study the role of 2-AG in natural reward, we used a transgenic mouse model (MGL-Tg mice) in which forebrain 2-AG levels are selectively reduced. We complemented behavioral analysis with measurements of brain 2-AG levels. Methods We tested male MGL-Tg mice in conditioned place preference tasks (CPP) for high-fat food, social contact and cocaine. We measured 2-AG content in brain regions of interest by liquid chromatography/mass spectrometry. Results Male MGL-Tg mice are impaired in developing CPP for high-fat food and social interaction, but do develop CPP for cocaine. Furthermore, compared to isolated mice, levels of 2-AG in socially stimulated wild-type mice are higher in the nucleus accumbens and ventral hippocampus (183% and 140% of controls, respectively), but unchanged in the medial prefrontal cortex. Conclusions The results suggest that reducing 2-AG-mediated endocannabinoid signaling impairs social and high-fat food reward in male mice, and that social stimulation mobilizes 2-AG in key brain regions implicated in the control of motivated behavior. The time course of this response differentiates 2-AG from anandamide, whose role in mediating social reward was previously documented.

The neurobiology of social play and its rewarding value in rats

“…The effects of JZL195 were behaviourally specific, since at the dose that increased social play, JZL195 did not alter social exploration, anxiety or locomotor activity, nor did it induce other cannabimimetic effects, such as catalepsy or hypothermia (Manduca et al, 2015). These findings provide the first evidence for a role of 2-AG in social play behaviour in rats, which resonates well with recent studies showing an involvement of 2-AG signaling in social reward (Wei et al, 2016) and social defeat stress (Tomas-Roig et al, 2016) in adult mice.…”

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 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. Furthermore, 2-AG levels have been shown to be higher in the NAc of socially stimulated mice compared to isolated mice (Wei et al, 2016), and 2-AG decreases aggressive behavior in a resident/intruder test in adult mice, suggesting a role in social challenge (Aliczki et al, 2014). In the present study, we found that JZL184, which produces a long-lasting elevation of brain 2-AG by inhibiting 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.…”

Endocannabinoid Signaling in the Control of Social Behavior

“…The non-selectivity of this effect stands in contrast to the results obtained with the anandamide-modulating manipulations described above, which selectively heighten social over high-fat-food reward [56]. Also in contrast to social contact at 3 h, prolonged social contact for 6 h was found to stimulate 2-AG mobilization without changing levels of anandamide [58]. These results argue in favor of a role for 2-AG in social reward, which may be more generalizable to other natural rewards.…”

“…To address this question, we used a transgenic mouse model with a specific forebrain reduction in 2-AG (produced by overexpression of the 2-AG- hydrolyzing enzyme, monoacylglycerol lipase [57]). We found that these transgenic mice show impaired conditioned place preference to both social and high-fat-food stimuli [58]. The non-selectivity of this effect stands in contrast to the results obtained with the anandamide-modulating manipulations described above, which selectively heighten social over high-fat-food reward [56].…”