Cocaine-induced behavioral sensitization decreases the expression of endocannabinoid signaling-related proteins in the mouse hippocampus

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• 作者：Eduardo Blanco^a ; ^b ; ¹ ; ^{eduardo.blanco@pip.udl.cat" class="auth_mail" title="E-mail the corresponding author} ; Pablo Galeano^c ; ¹ ; ^{pgaleano@leloir.org.ar" class="auth_mail" title="E-mail the corresponding author} ; Ana Palomino^a ; ^{ana_parris@yahoo.es" class="auth_mail" title="E-mail the corresponding author} ; Francisco J. Pav&oacute ; n^a ; ^{javier.pavon@ibima.eu" class="auth_mail" title="E-mail the corresponding author} ; Patricia Rivera^a ; ^{riveragonzalez183@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Antonia Serrano^a ; ^{antonia.serrano@ibima.eu" class="auth_mail" title="E-mail the corresponding author} ; Francisco Alen^a ; ^{p_alen@yahoo.es" class="auth_mail" title="E-mail the corresponding author} ; Leticia Rubio^d ; ^{lorubio@uma.es" class="auth_mail" title="E-mail the corresponding author} ; Antonio Vargas^a ; ^{antoniovargasfuentes@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Estela Castilla-Ortega^a ; ^{estela.castilla@ibima.eu" class="auth_mail" title="E-mail the corresponding author} ; Juan Decara^a ; ^{juandecara@uma.es" class="auth_mail" title="E-mail the corresponding author} ; Ainhoa Bilbao^e ; ^{ainhoa.bilbao@zi-mannheim.de" class="auth_mail" title="E-mail the corresponding author} ; Fernando Rodrí ; guez de Fonseca^a ; ^{fernando.rodriguez@ibima.eu" class="auth_mail" title="E-mail the corresponding author} ; Juan Suá ; rez^a ; ^{juan.suarez@ibima.eu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Cocaine ; Conditioned locomotion ; Cocaine sensitization ; Cannabinoid ; Glutamate ; Hippocampus
• 刊名：European Neuropsychopharmacology
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：26
• 期：3
• 页码：477-492
• 全文大小：2023 K

文摘

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 (DAGLα). These changes resulted in an overall decrease in endocannabinoid synthesis/degradation ratios, especially NAPE-PLD/fatty acid amide hydrolase and DAGLα/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.