title: Cannabinoid receptor antagonists counteract sensorimotor gating deficits in the phencyclidine model of psychosis.
abstract: Clinical and laboratory findings suggest that cannabinoids and their receptors are implicated in schizophrenia. The role of cannabinoids in schizophrenia remains however poorly understood, as data are often contradictory. The primary aim of this study was to investigate whether the cannabinoid CB1 receptor antagonists rimonabant and AM251 are able to reverse deficits of sensorimotor gating induced by phencyclidine and to mimic the 'atypical' antipsychotic profile of clozapine. The prepulse inhibition (PPI) of the startle reflex was used to measure deficits of sensorimotor gating. PPI-disruptive effects of phencyclidine and their antagonism by rimonabant, AM251, and clozapine were studied in rats. The effects of rimonabant were carefully examined taking into account dose ranges, vehicle, and route of administration. We also examined the ability of rimonabant to reduce the PPI-disruptive effects of dizocilpine and apomorphine. Rimonabant as well as AM251 significantly counteracted the phencyclidine-disruptive model of PPI, comparable to the restoring effect of clozapine; no augmentation effect was observed with rimonabant and clozapine as cotreatment. Rimonabant also significantly attenuated the PPI disruptive effects of dizocilpine and apomorphine. Taken together, our results indicate that CB1 receptor antagonists do produce 'atypical' antipsychotic profile mimicking that of clozapine in the phencyclidine disruption of sensorimotor gating. Our findings further suggest that CB1 receptor antagonism may be involved in restoring disturbed interactions between the activity of the endocannabinoid system and glutamate neurotransmitter system implied in schizophrenia.
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité University Medicine, Campus Mitte, Shumannstrasse 20/21, 10117 Berlin, Germany. martina.ballmaier@charite.de
authors.forename: Martina
authors.initials: M
authors.lastname: Ballmaier
authors.forename: Marco
authors.initials: M
authors.lastname: Bortolato
authors.forename: Cristina
authors.initials: C
authors.lastname: Rizzetti
authors.forename: Michele
authors.initials: M
authors.lastname: Zoli
authors.forename: GianLuigi
authors.initials: G
authors.lastname: Gessa
authors.forename: Andreas
authors.initials: A
authors.lastname: Heinz
authors.forename: PierFranco
authors.initials: P
authors.lastname: Spano
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D063387:Cannabinoid Receptor Antagonists; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004357:Drug Synergism; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D010622:Phencyclidine / Q000633:toxicity*; D010880:Piperidines / Q000009:adverse effects / Q000494:pharmacology; D011605:Psychoses, Substance-Induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D011720:Pyrazoles / Q000009:adverse effects / Q000494:pharmacology; D051381:Rats; D043882:Receptors, Cannabinoid / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D000077285:Rimonabant; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D012678:Sensation Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D063387:Cannabinoid Receptor Antagonists; D018691:Excitatory Amino Acid Antagonists; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; C103505:AM 251; D018698:Glutamic Acid; D010622:Phencyclidine; D000077285:Rimonabant