Distinct roles of the endocannabinoids anandamide and 2-arachidonoylglycerol in social behavior and emotionality at different developmental ages in rats

Abstract

To date, our understanding of the relative contribution and potential overlapping roles of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in the regulation of brain function and behavior is still limited. To address this issue, we investigated the effects of systemic administration of JZL195, that simultaneously increases AEA and 2-AG signaling by inhibiting their hydrolysis, in the regulation of socio-emotional behavior in adolescent and adult rats. JZL195, administered at the dose of 0.01mg/kg, increased social play behavior, that is the most characteristic social activity displayed by adolescent rats, and increased social interaction in adult animals. At both ages, these behavioral effects were antagonized by the CB1 cannabinoid receptor antagonist SR141716A and were associated with increased brain levels of 2-AG, but not AEA. Conversely, at the dose of 1mg/kg, JZL195 decreased general social exploration in adolescent rats without affecting social play behavior, and induced anxiogenic-like effects in the elevated plus-maze test both in adolescent and adult animals. These effects, mediated by activation of CB1 cannabinoid receptors, were paralleled by simultaneous increase in AEA and 2-AG levels in adolescent rats, and by an increase of only 2-AG levels in adult animals. These findings provide the first evidence for a role of 2-AG in social behavior, highlight the different contributions of AEA and 2-AG in the modulation of emotionality at different developmental ages and suggest that pharmacological inhibition of AEA and 2-AG hydrolysis is a useful approach to investigate the role of these endocannabinoids in neurobehavioral processes.

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

“…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. 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).…”

Bioactive lipids as modulators of immunity, inflammation and emotions

“…Thus, eCBs critically modulate both the hypothalamic-pituitary-adrenal axis and the monoamine transmission, as demonstrated through numerous anatomical, electrophysiological and in vivo behavioral studies (for reviews see [58,[60][61][62][63][64][65]). Several preclinical and clinical data strongly suggest that emotional behaviors are associated with altered levels of AEA, PEA and 2-AG, which have distinct roles in the emotion arousal, social behavior and emotionality [66][67][68][69][70][71], with their receptors and metabolic enzymes being potential targets for preventing and treating mood-related and anxiety-related disorders, particularly posttraumatic stress disorder. In particular, inhibition of AEA-degrading enzyme FAAH reduces anxiety-like behaviors [72] and facilitates long-term fear extinction and rescues deficient fear extinction in rodent models by enhancing CB 1 signaling and synaptic plasticity in the basolateral amygdala [64], whereas genetic deletion of 2-AG-degrading enzyme MAGL leads to impaired CB 1 signaling and anxiety-like behavior [73 ].…”

The neurobiology of social play and its rewarding value in rats

“…At a dose that enhanced brain levels of 2-AG, but not anandamide, JZL195 increased social play behaviour. This effect was antagonized by pretreatment with the cannabinoid receptor antagonist/inverse agonist SR141716A (Manduca et al, 2015). 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).…”

“…This effect was antagonized by pretreatment with the cannabinoid receptor antagonist/inverse agonist SR141716A (Manduca et al, 2015). 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.…”