1. ¹Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA
2. ²Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, MO, USA
3. ³Department of Psychology, St Louis University, St Louis, MO, USA

Correspondence: Dr JG Csernansky, Department of Psychiatry (Box 8134), Washington University School of Medicine, 660 S. Euclid, St Louis, MO 63110, USA. Tel: +1 314 747 2160; Fax: +1 314 747 2182; E-mail: jgc@conte.wustl.edu

Received 14 December 2004; Revised 1 April 2005; Accepted 1 April 2005; Published online 8 June 2005.

Abstract

Enhancing cholinergic function has been suggested as a possible strategy for ameliorating the cognitive deficits of schizophrenia. The purpose of this study was to examine the effects of acetylcholinesterase (AChE) inhibitors in mice treated with the noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, which has been suggested as an animal model of the cognitive deficits of schizophrenia. Three separate experiments were conducted to test the effects of physostigmine, donepezil, or galantamine on deficits in learning and memory induced by MK-801. In each experiment, MK-801 (0.05 or 0.10 mg/kg) or saline was administered i.p. 20 min prior to behavioral testing over a total of 12 days. At 30 min prior to administration of MK-801 or saline, one of three doses of the AChE inhibitor (ie physostigmine—0.03, 0.10, or 0.30 mg/kg; donepezil—0.10, 0.30, or 1.00 mg/kg; or galantamine—0.25, 0.50, or 1.00 mg/kg) or saline was administered s.c. Behavioral testing was performed in all experimental animals using the following sequence: (1) spatial reversal learning, (2) locomotion, (3) fear conditioning, and (4) shock sensitivity. Both doses of MK-801 produced impairments in spatial reversal learning and in contextual and cued memory, as well as hyperlocomotion. Physostigmine and donepezil, but not galantamine, ameliorated MK-801-induced deficits in spatial reversal learning and in contextual and cued memory in a dose-dependent manner. Also, physostigmine, but not donepezil or galantamine, reversed MK-801-induced hyperlocomotion. Galantamine, but not physostigmine or donepezil, altered shock sensitivity. These results suggest that AChE inhibitors may differ in their capacity to ameliorate learning and memory deficits produced by MK-801 in mice, which may have relevance for the cognitive effects of cholinomimetic drugs in patients with schizophrenia.