Phencyclidine-induced cognitive deficits in mice are ameliorated by subsequent subchronic administration of donepezil: role of sigma-1 receptors.

Abstract

This study was undertaken to examine the effects of two acetylcholinesterase inhibitors (donepezil and physostigmine) on cognitive deficits in mice after repeated administration of the NMDA receptor antagonist phencyclidine (PCP). In the novel object recognition test, PCP (10 mg/kg/day for 10 days)-induced cognitive deficits were significantly improved by subsequent subchronic (14 days) administration of donepezil (1.0 mg/kg/day), but not donepezil (0.1 mg/kg/day). Furthermore, the effect of donepezil (1.0 mg/kg/day) on PCP-induced cognitive deficits was significantly antagonized by co-administration of the selective sigma-1 receptor antagonist NE-100 (1.0 mg/kg/day), suggesting the role of sigma-1 receptors in the active mechanisms of donepezil. In contrast, PCP-induced cognitive deficits were not improved by subsequent subchronic (14 days) administration of physostigmine (0.25 mg/kg/day). Moreover, repeated administration of PCP significantly caused the reduction of sigma-1 receptors in the hippocampus. The present study suggests that agonistic activity of donepezil at sigma-1 receptors plays a role in the active mechanisms of donepezil on PCP-induced cognitive deficits in mice. Therefore, it is likely that donepezil would be potential therapeutic drugs for the treatment of the cognitive deficits in schizophrenia.

• Authors: Shinsui Kunitachi, Yuko Fujita, Tamaki Ishima, Mami Kohno, Mao Horio, Yuko Tanibuchi, Yukihiko Shirayama, Masaomi Iyo, Kenji Hashimoto
• Journal: Brain research (Brain Res) Vol. 1279 Pg. 189-96 (Jul 07 2009) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 19433073 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anisoles
• Cholinesterase Inhibitors
• Indans
• Piperidines
• Propylamines
• Receptors, sigma
• Tritium
• N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride
• Donepezil
• Physostigmine
• Phencyclidine

Topics

• Analysis of Variance
• Animals
• Anisoles (pharmacology)
• Brain (drug effects, metabolism)
• Cell Membrane (metabolism)
• Cholinesterase Inhibitors (pharmacology)
• Cognition Disorders (chemically induced, drug therapy)
• Donepezil
• Hippocampus (drug effects, metabolism)
• Immunohistochemistry
• Indans (pharmacology)
• Male
• Mice
• Mice, Inbred ICR
• Phencyclidine
• Physostigmine (pharmacology)
• Piperidines (pharmacology)
• Propylamines (pharmacology)
• Receptors, sigma (antagonists & inhibitors, metabolism)
• Recognition, Psychology (drug effects)
• Tritium
• Sigma-1 Receptor