Cocaine-induced increases in motivation require 2-arachidonoylglycerol mobilization and CB1 receptor activation in the ventral tegmental area

Role of mesolimbic cannabinoid receptor 1 in stress-driven increases in cocaine self-administration in male rats

“…By contrast, intra-NAc shell AM251 failed to alter SA in non-shocked rats, consistent with findings that intra-NAc shell AM251 reduces SA in rats displaying escalated intake following repeated long-access to cocaine (6-h daily) without affecting SA in short-access rats (1-h daily) [31]. Intra-VTA AM251 did have modest effects on SA in control rats at the highest dose tested; which is consistent with reports that VTA CB1R antagonism attenuates cocaine-induced CPP in mice [54; 55] and cocaine-enhanced motivation assessed in rats self-administering food pellets under a progressive ratio schedule of reinforcement [56]. Additionally, in the VTA, cocaine can mobilize endocannabinoids [43] and cocaine SA upregulates CB1R binding which may also explain why we observe an effect of the high dose of AM251 in the no shock control rats at the high dose of the antagonist.…”

“…Endocannabinoids/CB1R signaling mediate many of the neurobiological and physiological effects of glucocorticoids [56] and our previous studies implicated CB1R/endocannabinoid signaling in the acute effects of corticosterone on cocaine seeking [24]. Thus, we hypothesize that combination of stress and cocaine produces additive or synergistic increases in CB1R activation, which contributes to an escalation of cocaine SA.…”

“…Moreover, increases in glucocorticoids at the time of SA contribute to both escalated intake and long-term heightened susceptibility to cocaine-primed and stressor-induced reinstatement [17; 18]. Endocannabinoids/CB1R signaling mediate many of the neurobiological and physiological effects of glucocorticoids [56] and our previous studies implicated CB1R/endocannabinoid signaling in the acute effects of corticosterone on cocaine seeking [24]. Thus, we hypothesize that combination of stress and cocaine produces additive or synergistic increases in CB1R activation, which contributes to an escalation of cocaine SA.…”

Plasma endocannabinoids in cocaine dependence and their interaction with cocaine craving and metabotropic glutamate receptor 5 density in the human brain

“…Our findings suggest that 2-AG might play a crucial role in cocaine dependence in humans. This is consistent with recent animal models showing elevated 2-AG levels in the VTA after cocaine administration, contributing to the positive reinforcing and motivation-enhancing effects of the substance [40,43,70]. Although human plasma samples can only reflect peripheral eCB/NAE levels and do not allow direct assessment of brain-specific concentrations, we speculate that the elevated 2-AG levels found in individuals with cocaine dependence indicate higher response to the cocaine-rewarding effects as well as higher motivated behavior resulting in increased vulnerability to developing cocaine dependence.…”

“…Preclinical findings showed that acute and repeated cocaine administration facilitates endocannabinoid-mediated LTD at GABAergic interneurons and abolishes endocannabinoid-mediated LTD at glutamatergic neurons, both resulting in increased DA release in the VTA and its projection to the NAc, contributing to the drug reinforcing effects [40][41][42]. Moreover, cocaine-induced activation of the endocannabinoid-LTD mechanism in the VTA has been recently linked to motivational behavior in rats, while the CB 1 receptor inverse agonist rimonabant was able to block reward-seeking behavior [43]. In the NAc, a single in vivo cocaine administration in mice has been shown to abolish endocannabinoid-mediated LTD at terminals of glutamatergic neurons resulting in increased glutamate release and subsequently in increased excitation of DA cells [44].…”