Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of fluvoxamine: role of sigma-1 receptors.
This study was undertaken to examine the effects of the selective serotonin reuptake inhibitors fluvoxamine and paroxetine on cognitive deficits in mice after repeated administration of the N-methyl-D-aspartate receptor antagonist phencyclidine (PCP). In the novel object recognition test, repeated administration of PCP (10 mg/kg/day, 10 days) significantly decreased the exploratory preference in the retention test session, but not in the training test session. PCP-induced cognitive deficits were significantly improved by subsequent subchronic (2-week) administration of fluvoxamine (20 mg/kg/day), but not paroxetine (10 mg/kg/day). Furthermore, the effect of fluvoxamine on PCP-induced cognitive deficits was antagonized by co-administration of the selective sigma-1 receptor antagonist NE-100 (1 mg/kg/day). Moreover, PCP-induced cognitive deficits were also significantly improved by subsequent subchronic (2-week) administration of the selective sigma-1 receptor agonist SA4503 (1 mg/kg/day) or neurosteroid dehydroepiandrosterone 3-sulfate (DHEA-S; 25 mg/kg/day). The effects of SA4503 or DHEA-S were also antagonized by co-administration of NE-100 (1 mg/kg/day), suggesting the role of sigma-1 receptors in the active mechanisms of these drugs. In contrast, acute single administration of these drugs (fluvoxamine, paroxetine, SA4503) alone or combination with NE-100 did not alter PCP-induced cognitive deficits. The present study suggests that agonistic activity of fluvoxamine at sigma-1 receptors plays a role in the active mechanisms of fluvoxamine on PCP-induced cognitive deficits in mice. Therefore, sigma-1 receptor agonists such as fluvoxamine would be potential therapeutic drugs for the treatment of the cognitive deficits of schizophrenia.
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. hashimoto@faculty.chiba-u.jp
Kenji
K
Hashimoto
Yuko
Y
Fujita
Masaomi
M
Iyo
D000704:Analysis of Variance; D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D002755:Choice Behavior / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced* / Q000188:drug therapy*; D019314:Dehydroepiandrosterone Sulfate / Q000494:pharmacology; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005106:Exploratory Behavior / Q000187:drug effects; D016666:Fluvoxamine / Q000008:administration & dosage*; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D018697:Nootropic Agents / Q000494:pharmacology; D010622:Phencyclidine; D010879:Piperazines / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology; D017480:Receptors, sigma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D012153:Retention, Psychology / Q000187:drug effects; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage*; D000097605:Sigma-1 Receptor
D000840:Anisoles; D014150:Antipsychotic Agents; D019314:Dehydroepiandrosterone Sulfate; D016666:Fluvoxamine; D018697:Nootropic Agents; D010622:Phencyclidine; D010879:Piperazines; D011437:Propylamines; D017480:Receptors, sigma; D017367:Selective Serotonin Reuptake Inhibitors; D000097605:Sigma-1 Receptor; C083832:N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride; C101789:SA 4503