Footshock‐induced abstinence from compulsive methamphetamine self‐administration is associated with increased expression of cannabinoid receptors (CB1 and CB2) in the rat hippocampus

Abstract

Methamphetamine (METH) use disorder is characterized by compulsive and repeated drug intake despite negative life consequences. Large intake of METH in humans and animals is accompanied by dysfunctions in learning and memory and learning and by neurodegenerative changes in several brain regions. Because the endocannabinoid system (eCB) has been implicated in the manifestations of substance use disorders (SUDs), we sought to identify potential changes in various enzymes and the receptors (CB1 and CB2) that are involved in mediating the effects of endocannabinoids. To reach that end, we used a model of METH self-administration (SA) paradigm that includes a punishment phase (footshocks) that has helped to separate rats into a compulsive METH phenotype (shock-resistant, compulsive) that continues to take METH and a non-compulsive METH (shock-sensitive, abstinent) that suppressed or became abstinent in the presence of punishment. We then measured mRNA expression of cannabinoid receptors (CB/Cnr), synthetic (Dagl-a, Dagl-b, Nape-pld), as well as metabolizing enzymes (Mgll, Faah, Cox2) of the eCB signaling cascade in the dorsal striatum (DStr), nucleus accumbens (NAc), midbrain (MBr), and hippocampus (Hip) of rats euthanized two hours after the last METH SA plus footshock session. The abstinent rats exhibited significant increases in the expression of CB1 and CB2 in the hippocampus. The mRNA levels for the synthetic enzyme, Dagl-a, and the metabolic enzymes, Mgll, and Faah, were also increased in the hippocampus. In contrast, compulsive rats exhibited significant decreases in the expression of Faah in both the DStr and MBr but showed increased mRNA expression of Cox2 in the DStr. There were no significant changes in any of these in the nucleus accumbens. Taken together, these observations implicate, in part, the hippocampal endocannabinoid system in the suppression of METH intake in the presence of adverse consequences. Pharmacological agents that augment the activity of this system may be beneficial against METH use disorder in humans.