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.