In the reward mesocorticolimbic circuits, the glutamatergic and
endocannabinoid systems are implicated in neurobiological mechanisms underlying
cocaine addiction. However, the involvement of both systems in the hippocampus, a critical region to process relational information relevant for encoding drug-associated memories, in
cocaine-related behaviors remains unknown. In the present work, we studied whether the hippocampal gene/
protein expression of relevant
glutamate signaling components, including
glutamate-synthesizing
enzymes and metabotropic and ionotropic receptors, and the hippocampal gene/
protein expression of
cannabinoid type 1 (
CB1) receptor and
endocannabinoid metabolic
enzymes were altered following acute and/or repeated
cocaine administration resulting in conditioned locomotion and locomotor sensitization. Results showed that acute
cocaine administration induced an overall down-regulation of
glutamate-related gene expression and, specifically, a low phosphorylation level of GluA1. In contrast, locomotor sensitization to
cocaine produced an up-regulation of several
glutamate receptor-related genes and, specifically, an increased
protein expression of the GluN1 receptor subunit. Regarding the
endocannabinoid system, acute and repeated
cocaine administration were associated with an increased gene/
protein expression of CB1 receptors and a decreased gene/
protein expression of the
endocannabinoid-synthesis
enzymes N-acyl
phosphatidylethanolamine D (NAPE-
PLD) and
diacylglycerol lipase alpha (DAGLĪ±). These changes resulted in an overall decrease in
endocannabinoid synthesis/degradation ratios, especially NAPE-
PLD/
fatty acid amide hydrolase and DAGLĪ±/
monoacylglycerol lipase, suggesting a reduced
endocannabinoid production associated with a compensatory up-regulation of
CB1 receptor. Overall, these findings suggest that repeated
cocaine administration resulting in locomotor sensitization induces a down-regulation of the
endocannabinoid signaling that could contribute to the specifically increased GluN1 expression observed in the hippocampus of
cocaine-sensitized mice.