COCAINE-INDUCED BEHAVIORAL SENSITIZATION DECREASES THE EXPRESSION OF ENDOCANNABINOID SIGNALING-RELATED PROTEINS IN THE MOUSE HIPPOCAMPUS

BLANCO CALVO, EDUARDO (CO-FIRST AUTHORSHIP); GALEANO, PABLO (CO-FIRST AUTHORSHIP); PALOMINO, ANA; PAVON, FRANCISCO JAVIER; RIVERA, PATRICIA; SERRANO, ANTONIA; ALEN, FRANCISCO; RUBIO, LETICIA; VARGAS, ANTONIO; CASTILLA ORTEGA, ESTELA; DECARA, JUAN; BILBAO, AINHOA; RODRÍGUEZ DE FONSECA, FERNANDO; SUARÉZ, JUAN

EUROPEAN NEUROPSYCHOFARMACOLOGY

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2016 vol. 26 p. 477 - 492

0924-977X

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 (DAGLalpha). These changes resulted in an overall decrease in endocannabinoid synthesis/degradation ratios, especially NAPE-PLD/fatty acid amide hydrolase and DAGLalpha/monoacylglycerol lipase, suggesting a reduced endocannabinoid production associated with a compensatory CB1 up-expression. 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 specific increase in GluN1 receptor expression observed in the hippocampus of cocaine-sensitized mice.