Phencyclidine-induced cognitive deficits in mice are ameliorated by subsequent subchronic administration of donepezil: role of sigma-1 receptors.
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.
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
Shinsui
S
Kunitachi
Yuko
Y
Fujita
Tamaki
T
Ishima
Mami
M
Kohno
Mao
M
Horio
Yuko
Y
Tanibuchi
Yukihiko
Y
Shirayama
Masaomi
M
Iyo
Kenji
K
Hashimoto
D000704:Analysis of Variance; D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy*; D000077265:Donepezil; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D007189:Indans / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010622:Phencyclidine; D010830:Physostigmine / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011437:Propylamines / Q000494:pharmacology; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects; D014316:Tritium; D000097605:Sigma-1 Receptor
D000840:Anisoles; D002800:Cholinesterase Inhibitors; D000077265:Donepezil; D007189:Indans; D010622:Phencyclidine; D010830:Physostigmine; D010880:Piperidines; D011437:Propylamines; D017480:Receptors, sigma; D014316:Tritium; D000097605:Sigma-1 Receptor; C083832:N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride