Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the antipsychotic drug perospirone: role of serotonin 5-HT1A receptors.
Accumulating evidence suggests that the serotonin 5-HT(1A) receptor may play a role in the pathophysiology of schizophrenia. The present study was undertaken to examine the effects of perospirone, an atypical antipsychotic drug with 5-HT(1A) receptor agonism, on cognitive deficits in mice after repeated administration of the NMDA receptor antagonist phencyclidine (PCP). Subsequent subchronic (14 days) administration of perospirone (1.0, 3.0, or 10 mg/kg) significantly attenuated PCP (10 mg/kg)-induced cognitive deficits in mice, in a dose-dependent manner. The effects of perospirone (10 mg/kg) were significantly antagonized by co-administration of the selective 5-HT(1A) receptor antagonist WAY100635 (1.0 mg/kg). Furthermore, hypothermia by the 5-HT(1A) receptor agonist 8-OH DPAT (0.25 mg/kg) was significantly attenuated in mice treated with PCP. Moreover, a receptor binding assay using [(3)H]WAY100635 revealed that levels of 5-HT(1A) receptors in the hippocampus, but not in the frontal cortex, of PCP-treated mice were significantly lower than those of saline-treated mice. These findings suggest that repeated PCP administration alters 5-HT(1A) receptor function in the mouse brain, and that subsequent subchronic administration of perospirone ameliorates PCP-induced cognitive deficits via 5-HT(1A) receptors. Therefore, perospirone could be a potential therapy for the cognitive deficits observed in schizophrenic patients.
Hagiwara
Hiroko
H
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
Fujita
Yuko
Y
Ishima
Tamaki
T
Kunitachi
Shinsui
S
Shirayama
Yukihiko
Y
Iyo
Masaomi
M
Hashimoto
Kenji
K
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage*; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007279:Injections, Subcutaneous / Q000379:methods; D054833:Isoindoles / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010364:Pattern Recognition, Visual / Q000187:drug effects; D010622:Phencyclidine; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013844:Thiazoles / Q000008:administration & dosage*; D013997:Time Factors
D014150:Antipsychotic Agents; D054833:Isoindoles; D010879:Piperazines; D011725:Pyridines; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013844:Thiazoles; D044282:Receptor, Serotonin, 5-HT1A; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D010622:Phencyclidine; C065533:perospirone