title: Cocaine-induced behavioral sensitization decreases the expression of endocannabinoid signaling-related proteins in the mouse hippocampus.
abstract: 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.
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Universidad de Málaga, Avda. Carlos Haya 82, 29010, Málaga, Spain; Departament de Pedagogia i Psicologia, Facultat d׳Educació, Psicologia i Treball Social, Universitat de Lleida, Avda. de l'Estudi General 4, 25001, Lleida, Spain. Electronic address: eduardo.blanco@pip.udl.cat.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Blanco
authors.affiliation: Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA-CONICET), Fundación Instituto Leloir, Avda. Patricias Argentinas 435, C1405BWE Ciudad Autónoma de Buenos Aires, Argentina. Electronic address: pgaleano@leloir.org.ar.
authors.forename: Pablo
authors.initials: P
authors.lastname: Galeano
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Universidad de Málaga, Avda. Carlos Haya 82, 29010, Málaga, Spain. Electronic address: ana_parris@yahoo.es.
authors.forename: Ana
authors.initials: A
authors.lastname: Palomino
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Universidad de Málaga, Avda. Carlos Haya 82, 29010, Málaga, Spain. Electronic address: javier.pavon@ibima.eu.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Pavón
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Universidad de Málaga, Avda. Carlos Haya 82, 29010, Málaga, Spain. Electronic address: riveragonzalez183@gmail.com.
authors.forename: Patricia
authors.initials: P
authors.lastname: Rivera
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Universidad de Málaga, Avda. Carlos Haya 82, 29010, Málaga, Spain. Electronic address: antonia.serrano@ibima.eu.
authors.forename: Antonia
authors.initials: A
authors.lastname: Serrano
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Universidad de Málaga, Avda. Carlos Haya 82, 29010, Málaga, Spain. Electronic address: p_alen@yahoo.es.
authors.forename: Francisco
authors.initials: F
authors.lastname: Alen
authors.affiliation: Departamento de Anatomía y Medicina Legal, Universidad de Málaga, Campus de Teatinos s/n, 29071 Málaga, Spain. Electronic address: lorubio@uma.es.
authors.forename: Leticia
authors.initials: L
authors.lastname: Rubio
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Universidad de Málaga, Avda. Carlos Haya 82, 29010, Málaga, Spain. Electronic address: antoniovargasfuentes@gmail.com.
authors.forename: Antonio
authors.initials: A
authors.lastname: Vargas
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Universidad de Málaga, Avda. Carlos Haya 82, 29010, Málaga, Spain. Electronic address: estela.castilla@ibima.eu.
authors.forename: Estela
authors.initials: E
authors.lastname: Castilla-Ortega
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Universidad de Málaga, Avda. Carlos Haya 82, 29010, Málaga, Spain. Electronic address: juandecara@uma.es.
authors.forename: Juan
authors.initials: J
authors.lastname: Decara
authors.affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Faculty of Medicine Mannheim, University of Heidelberg, J5, 68159 Mannheim, Heidelberg, Germany. Electronic address: ainhoa.bilbao@zi-mannheim.de.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Bilbao
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Universidad de Málaga, Avda. Carlos Haya 82, 29010, Málaga, Spain. Electronic address: fernando.rodriguez@ibima.eu.
authors.forename: Fernando Rodríguez
authors.initials: FR
authors.lastname: de Fonseca
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Universidad de Málaga, Avda. Carlos Haya 82, 29010, Málaga, Spain. Electronic address: juan.suarez@ibima.eu.
authors.forename: Juan
authors.initials: J
authors.lastname: Suárez
mesh_terms: D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D063388:Endocannabinoids / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D017470:Receptors, Glutamate / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013997:Time Factors; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D003042:Cocaine; D018765:Dopamine Uptake Inhibitors; D063388:Endocannabinoids; D018698:Glutamic Acid; D012333:RNA, Messenger; D017470:Receptors, Glutamate; D000099252:Fatty Acid Amide Hydrolases
keywords: Cannabinoid; Cocaine; Cocaine sensitization; Conditioned locomotion; Glutamate; Hippocampus