1. ¹Neurosciences Graduate Program, University of Cincinnati, Cincinnati, OH, USA
2. ²Department of Neurology and the Neurosciences Program, M.I.N.D. Institute, University of California at Davis, Sacramento, CA, USA

Correspondence: Professor FR Sharp, Department of Neurology and the Neurosciences Program, M.I.N.D. Institute, University of California at Davis, 2805 50th Street, Room 2416, Sacramento, CA 95817, USA. Tel: +1 916 703 0368; Fax: +1 916 703 0369; E-mail: frsharp@ucdavis.edu

Received 24 March 2005; Revised 5 May 2005; Accepted 12 July 2005; Published online 17 August 2005.

Abstract

Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine, ketamine, and MK-801 produce schizophrenia-like psychosis in humans. The same NMDA antagonists injure retrosplenial cortical neurons in adult rats. We examined the effects of atypical antipsychotics and an inhibitor of nonreceptor tyrosine kinase pp60 (Src) on the cortical injury produced by MK-801. An atypical antipsychotic (either clozapine, ziprasidone, olanzapine, quetiapine, or risperidone) or vehicle was administered to adult female Sprague–Dawley rats. PP1 (Src inhibitor), PP3 (nonfunctional analog of PP1) or vehicle (DMSO) was administered to another group of animals. After pretreatment, animals were injected with MK-801, killed 24 h after the MK-801, and injury to retrosplenial cortex assessed by neuronal Hsp70 protein expression. All atypical antipsychotics examined significantly attenuated MK-801-induced cortical damage. PP1 protected compared to vehicle, whereas PP3 did not protect. The ED50s (decrease injury by 50%) were as follows: PP1 <0.1 mg/kg; olanzapine 0.8 mg/kg; risperdal 1 mg/kg; clozapine 3 mg/kg; ziprasidone 32 mg/kg; and quetiapine 45 mg/kg. The data show that the atypical antipsychotics tested as well as a Src kinase inhibitor prevent the injury produced by the psychomimetic MK-801, and the potency of the atypical antipsychotics for preventing cortical injury was roughly similar to the potency of these drugs for treating psychosis in patients.