title: Differential Pharmacological Regulation of Sensorimotor Gating Deficit in CB1 Knockout Mice and Associated Neurochemical and Histological Alterations.
abstract: The endocannabinoid system has been widely involved in the pathophysiology of sensorimotor gating deficits. This study aimed to evaluate the pharmacological modulation of the sensorimotor gating impairment induced by cannabinoid CB1 receptor (CB1r) deletion. For this purpose, the prepulse inhibition (PPI) paradigm was used to evaluate the effect of two antipsychotics drugs (risperidone and haloperidol) and a psychostimulant (methylphenidate) on the preattentional deficit presented by CB1KO mice. Furthermore, the effects of the CB1r antagonist AM251 on PPI were evaluated in WT mice. Real-time PCR and immunohistochemical studies were carried out to analyze dopamine transporter (DAT) and α-2C adrenergic receptor (ADRA2C) gene expressions and the distribution of parvalbumin (PV) and cholecystokinin-8 (CCK) immunoreactive (ir) cortical neurons, respectively. Neither risperidone nor haloperidol significantly modified the PPI of WT and CB1KO mice, whereas methylphenidate improved the preattentional deficit of CB1KO mice. In addition, treatment with AM251 (3 mg/kg; i.p.) significantly decreased the PPI of WT animals. The administration of methylphenidate increased DAT and ADRA2C gene expressions in CB1KO mice without producing any effect in WT animals. Immunohistochemical studies revealed that there were no significant changes in CCK immunolabeling between WT and CB1KO mice, whereas the radial distribution of PV-ir neurons was abnormal in CB1KO mice. These data further support the important role of CB1r in sensorimotor gating regulation and the therapeutic usefulness of methylphenidate for the treatment of psychiatric disorders with associated preattentional deficits.
authors.affiliation: Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Ortega-Álvaro
authors.affiliation: Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Alicante, Spain.|Red Temática de Investigación Cooperativa en Salud (RETICS-Trastornos Adictivos), Instituto de Salud Carlos III, MICINN and FEDER, Madrid, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Navarrete
authors.affiliation: Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Alicante, Spain.|Red Temática de Investigación Cooperativa en Salud (RETICS-Trastornos Adictivos), Instituto de Salud Carlos III, MICINN and FEDER, Madrid, Spain.
authors.forename: Auxiliadora
authors.initials: A
authors.lastname: Aracil-Fernández
authors.affiliation: Departamento de Histología y Anatomía, Universidad Miguel Hernández, Alacant, Spain.
authors.forename: Daniela
authors.initials: D
authors.lastname: Navarro
authors.affiliation: Departamento de Histología y Anatomía, Universidad Miguel Hernández, Alacant, Spain.
authors.forename: Pere
authors.initials: P
authors.lastname: Berbel
authors.affiliation: Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Alicante, Spain.|Red Temática de Investigación Cooperativa en Salud (RETICS-Trastornos Adictivos), Instituto de Salud Carlos III, MICINN and FEDER, Madrid, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Manzanares
mesh_terms: D000818:Animals; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D002491:Central Nervous System Agents / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology*; D002766:Cholecystokinin / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000502:physiology; D006220:Haloperidol / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010320:Parvalbumins / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D065808:Prepulse Inhibition / Q000187:drug effects* / Q000502:physiology*; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D018967:Risperidone / Q000494:pharmacology; D013997:Time Factors
chemical_list: C547775:Adra2c protein, mouse; C578453:CNR1 protein, mouse; D063387:Cannabinoid Receptor Antagonists; D002491:Central Nervous System Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D010320:Parvalbumins; D010446:Peptide Fragments; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D018341:Receptors, Adrenergic, alpha-2; C410885:cholecystokinin 8; D008774:Methylphenidate; C103505:AM 251; D002766:Cholecystokinin; D006220:Haloperidol; D018967:Risperidone