Footshock-Induced Abstinence from Compulsive Methamphetamine Self-administration in Rat Model Is Accompanied by Increased Hippocampal Expression of Cannabinoid Receptors (CB1 and CB2)

Abstract

Methamphetamine (METH) use disorder (MUD) is characterized by compulsive and repeated drug taking despite negative life consequences. Large intake of METH in humans and animals is accompanied by dysfunctions in learning and memory processes. The endocannabinoid system (ECS) is known to modulate synaptic plasticity and cognitive functions. In addition, the ECS has been implicated in some of the manifestations of substance use disorders (SUDs). We therefore sought to identify potential changes in the expression of various enzymes and of the receptors (CB1 and CB2) that are members of that system. Herein, we used a model of METH self-administration (SA) that includes a punishment phase (footshocks) that helps to separate rats into a compulsive METH phenotype (compulsive) that continues to take METH and a non-compulsive METH (abstinent) group that suppressed or stopped taking METH. Animals were euthanized 2 h after the last METH SA session and their hippocampi were used to measure mRNA levels of cannabinoid receptors (CB/Cnr), as well as those of synthesizing (DAGL-A, DAGL-B, NAPEPLD) and metabolizing (MGLL, FAAH, PTGS2) enzymes of the endocannabinoid cascade. Non-compulsive rats exhibited significant increased hippocampal expression of CB1/Cnr1 and CB2/Cnr2 mRNAs. mRNA levels of the synthesizing enzyme, DAGL-A, and of the metabolic enzymes, MGLL and FAAH, were also increased. Non-compulsive rats also exhibited a significant decrease in hippocampal Ptgs2 mRNA levels. Taken together, these observations implicate the hippocampal endocannabinoid system in the suppression of METH intake in the presence of adverse consequences.

GPR55 activation improves anxiety- and depression-like behaviors of mice during methamphetamine withdrawal

“…The endocannabinoid system has been extensively investigated in substance use disorder. For example, intervening in the endocannabinoid system affected METH self-administration withdrawal [ 35 ] and conditioned place preference [ 36 ]. The endocannabinoid system may be involved in the development of depression by regulating hippocampal neurogenesis and neuroinflammation [ 37 ].…”

Biochemical Neuroadaptations in the Rat Striatal Dopaminergic System after Prolonged Exposure to Methamphetamine Self-Administration

“…This progression of footshock intensity occurred over a total of 11 punishment days. This model has been successfully used in previous publications from this laboratory [ 15 , 16 , 17 , 18 , 19 , 20 , 71 ].…”

“…This approach has helped to separate rats into two groups based on their METH intake in the presence of punishment [ 15 ]. These groups have been labeled: (i) shock-resistant (SR, compulsive, vulnerable to METH addiction) and (ii) shock-sensitive (SS, abstinent, not vulnerable to addiction) groups [ 15 , 16 , 17 , 18 , 19 ]. This model was employed successfully to document important differences between the vulnerable and non-vulnerable phenotypes [ 15 , 16 , 17 , 18 , 19 , 20 , 21 ].…”

Molecular Insights into Epigenetics and Cannabinoid Receptors

“…Although the mechanism is unclear, these findings suggest that already constitutively expressed genes were not regulated in these cells. Altogether, these limited studies suggest that CB 2 expression could be regulated by DNA methylation of its promoter and warrant future studies, especially during inflammation [ 91 , 92 , 93 ], fear memory [ 94 ], nerve injury [ 52 ], and compulsive drug abuse [ 95 ] conditions in which CB 2 expression was found to be heightened.…”