title: Effects of acute versus repeated cocaine exposure on the expression of endocannabinoid signaling-related proteins in the mouse cerebellum.
abstract: Growing awareness of cerebellar involvement in addiction is based on the cerebellum's intermediary position between motor and reward, potentially acting as an interface between motivational and cognitive functions. Here, we examined the impact of acute and repeated cocaine exposure on the two main signaling systems in the mouse cerebellum: the endocannabinoid (eCB) and glutamate systems. To this end, we investigated whether eCB signaling-related gene and protein expression {cannabinoid receptor type 1 receptors and enzymes that produce [diacylglycerol lipase alpha/beta (DAGLα/β) and N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD)] and degrade [monoacylglycerol lipase (MAGL) and fatty acid amino hydrolase (FAAH)] eCB} were altered. In addition, we analyzed the gene expression of relevant components of the glutamate signaling system [glutamate synthesizing enzymes liver-type glutaminase isoform (LGA) and kidney-type glutaminase isoform (KGA), metabotropic glutamatergic receptor (mGluR3/5), NMDA-ionotropic glutamatergic receptor (NR1/2A/2B/2C) and AMPA-ionotropic receptor subunits (GluR1/2/3/4)] and the gene expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, because noradrenergic terminals innervate the cerebellar cortex. Results indicated that acute cocaine exposure decreased DAGLα expression, suggesting a down-regulation of 2-arachidonylglycerol (2-AG) production, as well as gene expression of TH, KGA, mGluR3 and all ionotropic receptor subunits analyzed in the cerebellum. The acquisition of conditioned locomotion and sensitization after repeated cocaine exposure were associated with an increased NAPE-PLD/FAAH ratio, suggesting enhanced anandamide production, and a decreased DAGLβ/MAGL ratio, suggesting decreased 2-AG generation. Repeated cocaine also increased LGA gene expression but had no effect on glutamate receptors. These findings indicate that acute cocaine modulates the expression of the eCB and glutamate systems. Repeated cocaine results in normalization of glutamate receptor expression, although sustained changes in eCB is observed. We suggest that cocaine-induced alterations to cerebellar eCB should be considered when analyzing the adaptations imposed by psychostimulants that lead to addiction.
authors.affiliation: Laboratorio de Investigación (Unidad de Gestión Clínica de Salud Mental), Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga Málaga, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Palomino
authors.affiliation: Laboratorio de Investigación (Unidad de Gestión Clínica de Salud Mental), Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga Málaga, Spain.
authors.forename: Francisco-Javier
authors.initials: FJ
authors.lastname: Pavón
authors.affiliation: Laboratorio de Investigación (Unidad de Gestión Clínica de Salud Mental), Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga Málaga, Spain ; Departament de Pedagogia i Psicologia, Facultat de Ciències de l'Educació, Universitat de Lleida Lleida, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Blanco-Calvo
authors.affiliation: Laboratorio de Investigación (Unidad de Gestión Clínica de Salud Mental), Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga Málaga, Spain.
authors.forename: Antonia
authors.initials: A
authors.lastname: Serrano
authors.affiliation: Laboratorio de Investigación (Unidad de Gestión Clínica de Salud Mental), Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga Málaga, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Arrabal
authors.affiliation: Laboratorio de Investigación (Unidad de Gestión Clínica de Salud Mental), Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga Málaga, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Rivera
authors.affiliation: Departamento de Psicobiología, Facultad de Psicología, Universidad Complutense Madrid, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Alén
authors.affiliation: Laboratorio de Investigación (Unidad de Gestión Clínica de Salud Mental), Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga Málaga, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Vargas
authors.affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty of Mannheim, University of Heidelberg Mannheim, Germany.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Bilbao
authors.affiliation: Departamento de Anatomía y Medicina Legal y Forense, Facultad de Medicina, Universidad de Málaga Málaga, Spain.
authors.forename: Leticia
authors.initials: L
authors.lastname: Rubio
authors.affiliation: Laboratorio de Investigación (Unidad de Gestión Clínica de Salud Mental), Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga Málaga, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodríguez de Fonseca
authors.affiliation: Laboratorio de Investigación (Unidad de Gestión Clínica de Salud Mental), Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga Málaga, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Suárez
keywords: cannabinoid; cerebellum; cocaine; glutamate; mouse; sensitization; tyrosine hydroxylase