title: Chronic administration of antipsychotics attenuates ongoing and ketamine-induced increases in cortical γ oscillations.
abstract: Noncompetitive N-methyl-d-aspartate receptor (NMDAr) antagonists can elicit many of the symptoms observed in schizophrenia in healthy humans, and induce a behavioural phenotype in animals relevant to psychosis. These compounds also elevate the power and synchrony of gamma (γ) frequency (30-80 Hz) neural oscillations. Acute doses of antipsychotic medications have been shown to reduce ongoing γ power and to inhibit NMDAr antagonist-mediated psychosis-like behaviour in rodents. This study aimed to investigate how a chronic antipsychotic dosing regimen affects ongoing cortical γ oscillations, and the electrophysiological and behavioural responses induced by the NMDAr antagonist ketamine. Male Wistar rats were chronically treated with haloperidol (0.25 mg/kg/d), clozapine (5 mg/kg/d), LY379268 (0.3 mg/kg/d) or vehicle for 28 d, delivered by subcutaneous (s.c.) osmotic pumps. Weekly electrocorticogram (ECoG) recordings were acquired. On day 26, ketamine (5 mg/kg, s.c.) was administered, and ECoG and locomotor activity were simultaneously measured. These results were compared with data generated previously following acute treatment with these antipsychotics. Sustained and significant decreases in ongoing γ power were observed during chronic administration of haloperidol (64%) or clozapine (43%), but not of LY379268 (2% increase), compared with vehicle. Acute ketamine injection concurrently increased γ power and locomotor activity in vehicle-treated rats, and these effects were attenuated in rats chronically treated with all three antipsychotics. The ability of haloperidol or clozapine to inhibit ketamine-induced elevation in γ power was not observed following acute administration of these drugs. These results indicate that modulation of γ power may be a useful biomarker of chronic antipsychotic efficacy.
authors: Department of Medicine, Faculty of Medicine Dentistry and Health Sciences,University of Melbourne,Parkville 3010, Victoria,Australia.
authors: Paul M
authors: PM
authors: Anderson
authors: INSERM U1114, Neuropsychologie cognitive et physiopathologie de la schizophrénie,Université de Strasbourg,Fédération de Médecine Translationnelle de Strasbourg, 11 rue Humann, F-67085 Strasbourg,France.
authors: Didier
authors: D
authors: Pinault
authors: Department of Medicine, Faculty of Medicine Dentistry and Health Sciences,University of Melbourne,Parkville 3010, Victoria,Australia.
authors: Terence J
authors: TJ
authors: O'Brien
authors: Department of Medicine, Faculty of Medicine Dentistry and Health Sciences,University of Melbourne,Parkville 3010, Victoria,Australia.
authors: Nigel C
authors: NC
authors: Jones
mesh_terms: D000704:Analysis of Variance; D000778:Anesthetics, Dissociative / Q000494:pharmacology*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects*; D004569:Electroencephalography; D065818:Gamma Rhythm / Q000187:drug effects*; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D018709:Statistics, Nonparametric; D013997:Time Factors
chemical_list: D000778:Anesthetics, Dissociative; D014150:Antipsychotic Agents; D007649:Ketamine