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

Subramaniam Jayanthi,Ritvik Peesapati,Jean Lud Cadet,Bruce Ladenheim,Michael T Mccoy

doi:10.1007/s12035-021-02656-8

Subramaniam Jayanthi, Ritvik Peesapati + Show 3 more

Open Access

https://doi.org/10.1007/s12035-021-02656-8

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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.

Highlights

Methamphetamine (METH) is the most commonly used amphetamine-type stimulant (ATS) worldwide
Repeated injections of METH can produce reactive oxygen species (ROS) [7, 8] that can alter the integrity of the brain structures [9] that are important for cognitive functions including learning and memory [10]
The endogenous cannabinoids (eCBs) are synthesized “on demand” by the enzymes diacylglycerol lipases (DAGL-A and DAGL-B) and N-acyl phosphotidylethanolamine phospholipase-D (NAPEPLD) that mediate the synthesis of 2-AG and AEA, respectively [19, 20]. 2-AG and AEA are, in turn, broken down by metabolic enzymes that are monoglyceride lipase (MGLL), fatty acid amide hydrolase (FAAH), and prostaglandin-endoperoxide synthase 2 (PTGS2) [17, 18, 21]

Summary

Introduction

Methamphetamine (METH) is the most commonly used amphetamine-type stimulant (ATS) worldwide. The ECS is a bioactive lipid-based signaling pathway that includes cannabinoid receptors (CB1 and CB2) and the endogenous cannabinoids (eCBs), 2-arachidonoylglycerol (2-AG) and arachidonyl ethanolamide (AEA, anandamide) [14,15,16]. This system includes synthesizing and degrading enzymes [17,18,19,20,21]. 2-AG and AEA are, in turn, broken down by metabolic enzymes that are monoglyceride lipase (MGLL), fatty acid amide hydrolase (FAAH), and prostaglandin-endoperoxide synthase 2 (PTGS2) [17, 18, 21] Both 2-AG and AEA bind to cannabinoid receptors (CB/Cnr) to facilitate downstream molecular changes [22]

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