Involvement of 2‐arachidonoyl glycerol in the increased consumption of and preference for ethanol of mice treated with neurotoxic doses of methamphetamine

Abstract

Background and purpose: Methamphetamine (METH) is a psychostimulant amphetamine that causes long-term dopaminergic neurotoxicity in mice. Hypodopaminergic states have been demonstrated to increase voluntary ethanol (EtOH) consumption and preference. In addition, the endocannabinoid system has been demonstrated to modulate EtOH drinking behaviour. Thus, we investigated EtOH consumption in METH-lesioned animals and the role of cannabinoid (CB) signalling in this EtOH drinking. Experimental approach: Mice were treated with a neurotoxic regimen of METH, and 7 days later exposed to increasing concentrations of drinking solutions of EtOH (3, 6, 10 and 20%). Seven days after neurotoxic METH, the following biochemical determinations were carried out in limbic forebrain: CB1 receptor density and stimulated activity, 2-arachidonoyl glycerol (2-AG) and monoacylglycerol lipase (MAGL) activity, dopamine levels and dopamine transporter density. Key results: EtOH consumption and preference were increased in METH-treated mice. Seven days after METH, a time at which both dopamine levels and density of dopamine transporters in limbic forebrain were decreased, CB1 receptor density and activity were unaltered, but 2-AG levels were increased. At this same time-point, MAGL activity was reduced. The CB1 receptor antagonist AM251 prevented the METH-induced increase in EtOH consumption and preference, while N-arachidonoyl maleimide, an inhibitor of MAGL, increased EtOH consumption and preference in both saline-and METH-treated mice. Conclusions and implications:An increase in endocannabinoid tone may be involved in the increased consumption of and preference for EtOH displayed by METH-lesioned mice as blockade of the CB1 receptor decreased EtOH-seeking behaviours, whereas the MAGL inhibitor increased EtOH consumption.

Distinct functions of endogenous cannabinoid system in alcohol abuse disorders

“…In other investigations, the self‐administration of alcohol was demonstrated to increase the extracellular level of 2‐AG in the NAc, which is linked to the amount of alcohol consumed, but not of AEA in the same region (Caille, Alvarez‐Jaimes, Polis, Stouffer, & Parsons, ). Furthermore, a mouse model of methamphetamine‐induced neurotoxic lesioning of nigrostriatal dopaminergic projections exhibited increased alcohol intake and enhanced 2‐AG levels in the limbic forebrain tissues comprising the anterior cingulate and the NAc (Gutierrez‐Lopez et al, ). The pharmacological blockade of MAGL also enhanced alcohol consumption and preference (Serrano et al, ; Figure ).…”

A review of the interactions between alcohol and the endocannabinoid system: Implications for alcohol dependence and future directions for research

“…Notably, self-administration of ethanol increases interstitial levels of 2-AG in the NAc that are correlated with the amount of ethanol consumed, but does not alter levels of AEA in this brain region (Caillé et al, 2007). Additionally, a methamphetamine-induced neurotoxic lesion of nigrostriatal dopaminergic projections (Granado et al, 2010; Sanchez et al, 2003) is associated with increased levels of ethanol consumption and preference, and this mouse model of enhanced ethanol intake displays increased tissue concentrations of 2-AG in limbic forebrain sections containing anterior cingulate and NAc (Gutierrez-Lopez et al, 2010). Furthermore, these investigators found that enhanced ethanol consumption and preference were also observed in intact mice treated with the MAGL inhibitor N- arachidonyl maleimide.…”

Paradoxical effects of the endocannabinoid uptake inhibitor VDM11 on accumbal neural encoding of reward predictive cues

“…Although both anandamide and 2‐AG function as reinforcers in their own right when tested in squirrel monkeys (Justinova et al,2005; Justinova et al,2011), a growing body of evidence suggests that these molecules may exert opposing effects during particular circumstances of reward‐directed behavior. Augmenting 2‐AG levels increases dopamine neurotransmission (Oleson et al,2012) and facilitates reward‐directed behavior (Gutierrez‐Lopez et al,2010; Oleson et al,2012; Wakley and Rasmussen,2009). By contrast, augmenting anandamide levels reduces the potency of cues to motivate reward‐directed behavior.…”