Cholinesterase Inhibitors Ameliorate Behavioral Deficits Induced by MK-801 in Mice

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 Nmethyl-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 physostigmineF0.03, 0.10, or 0.30 mg/kg; donepezilF0.10, 0.30, or 1.00 mg/kg; or galantamineF0.25, 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.

Synergistic Effects of Galantamine and Memantine in Attenuating Scopolamine-Induced Amnesia in Mice

“…*P < 0.05, **P < 0.01, ***P < 0.001 vs. controls (V); # P < 0.05, ## P < 0.01 vs. scopolamine-treated animals (Sc). excitatory circuit receives tonic excitatory cholinergic input from the medial septum and the diagonal band of Broca and glutamate, acting on NMDA receptors located on inhibitory GABAergic interneurons within the septum, inhibits the activity of cholinergic neurons that project to the hippocampus (11). Consistent with this localization, behavioral and electrophysiological studies have shown that memantine increases cholinergic signaling and excitability in mouse hippocampus and that this action is blocked by the muscarinic antagonist scopolamine (7).…”

Galantamine and donepezil attenuate pharmacologically induced deficits in prepulse inhibition in rats

“…The lack of benefit of donepezil in the MK801 (PPI) model contrasts with behavioral studies in mice (Csernansky et al, 2005) where donepezil attenuated MK801-induced deficits in fear conditioning as well as spatial and reversal learning better than galantamine. The basis of the differential effects of the compounds observed in our studies and the one cited above is unclear, although there are some differences in the pharmacology of these compounds (i.e., other than that related to AChEI activity) that may be of importance.…”

Butea superba–Induced Amelioration of Cognitive and Emotional Deficits in Olfactory Bulbectomized Mice and Putative Mechanisms Underlying Its Actions

“…The ameliorative effect of BS on the working memory deficit was further supported by the data obtained from the modified version of the Ymaze test. Previous studies demonstrated that central cholinergic and glutamatergic systems are involved in short-term spatial working memory performance elucidated by the modified Y-maze test since the muscarinicreceptor antagonist scopolamine and the anti-NMDAreceptor antagonist MK-801 interfere with the performance in a manner reversible by AChE inhibitors (9,28). In this study, we found that, consistent with previous reports (8 -10), OBX mice exhibited significantly impaired spatial working memory performance in the modified Y-maze test, and that the impairment was reversed by tacrine and BS but not by imipramine.…”