1. ¹Department of Psychiatry and Psychotherapy, Charité University Medicine, Campus Mitte, Berlin, Germany
2. ²Department of Pharmacology, University of California, Irvine, USA
3. ³Department of Neuroscience, Bernard B Brodie, University of Cagliari, Cagliari, Italy
4. ⁴Department of Biomedical Sciences and Biotechnologies, Brescia University Medical School, Brescia, Italy
5. ⁵Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy

Correspondence: Dr M Ballmaier, Department of Psychiatry and Psychotherapy, Charité University Medicine, Campus Mitte, Schumannstrasse 20/21, 10117 Berlin, Germany. Tel: +49 (030) 450 517001; Fax: +49 (030) 450 517921; E-mail: martina.ballmaier@charite.de

⁶These authors contributed equally to this work.

Received 16 October 2006; Revised 27 December 2006; Accepted 28 December 2006; Published online 14 February 2007.

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.