Cocaine self-administration differentially modulates the expression of endogenous cannabinoid system-related proteins in the hippocampus of Lewis vs. Fischer 344 rats

Abstract

The endocannabinoids anandamide and 2-arachidonyl glycerol (2-AG) are modulators of glutamate and γ-aminobutyric acid (GABA), two transmitters involved in cocaine addiction. However, little is known on the effects of cocaine on the enzymes that produce and degrade endocannabinoids. The present work addresses the effects of cocaine self-administration on the immunohistochemical expression of endocannabinoid signalling (ECS)-related proteins in the hippocampus. The study has been performed on two different strains of rats, Lewis (Lew) and Fischer 344 (F344), which are characterized for displaying a differential sensitivity to cocaine, thus making them suitable in the study of vulnerability to drug addiction. Both strains showed differences in the expression of ECS-related proteins in the hippocampus, i.e. Lew rats exhibited lower CB1 expression but higher CB2 expression than F344 rats. After setting similar cocaine self-administration, both strains showed clear differences in the expression of ECS-related proteins, which were differentially restricted to either the 2-AG or anandamide signalling pathways in a self-administration training/drug-dependent manner. The decreases observed in CB1 expression and N-acyl phosphatidylethanolamine phospholipase D:fatty acid amino hydrolase ratio after saline self-administration were enhanced only in cocaine self-administered Lew rats. CB2 expression increase and diacylglycerol lipase α:monoacylglycerol lipase ratio decrease detected after saline self-administration were blocked only in cocaine self-administered F344 rats. These findings indicate that cocaine may regulate hippocampal GABA/glutamate synapses by directly modulating endocannabinoid production/degradation enzymes and that these actions are strain-dependent. This differential response suggests that the endogenous cannabinoid system might contribute to genotype/strain differences on the sensitivity to self-administration training and cocaine addiction.

Species Differences in Cannabinoid Receptor 2 and Receptor Responses to Cocaine Self-Administration in Mice and Rats

“…This gene-behavior correlation is also observed in Lewis and Fischer 344 rat strains. For example, Lewis rats display lower PR break points for cocaine self-administration, but have higher CB 2 R expression in hippocampus than those of Fischer 344 rats who display higher PR break points for cocaine self-administration (Rivera et al, 2013), which agrees with our findings in mice and rats. Therefore, quantitative and qualitative changes in the mCB 2 R gene might contribute to differential receptor responses to cocaine self-administration.…”

Effects of acute versus repeated cocaine exposure on the expression of endocannabinoid signaling-related proteins in the mouse cerebellum

“…This finding was associated with enhanced expression of CB1 receptors. In a previous study by our group (Rivera et al, 2013), we demonstrated a similar finding in the Hc of Lewis rats self-administering cocaine. Moreover, we cannot ignore the possibility that the observed changes in NAPE-PLD/FAAH may involve non-CB1-acting endocannabinoids, such as oleoylethanolamide (OEA).…”

Strain Differences in Cannabinoid-Reinforced Lever Press Discrimination

“…In light of the previously observed differences in the endocannabinoid system between strains [6,5], we investigated the effects of these differences on cannabinoid self-administration. Neither LEW nor F344 rats acquired a stable WIN self-administration behavior.…”

“…In light of these results, and given the close relationship between the cannabinoid and opioid systems, we analyzed the levels of endocannabinoid-related proteins in the hippocampus of LEW and F344 rats [5]. LEW rats exhibited weaker CB 1 expression but stronger CB 2 expression than F344 rats.…”