Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the novel selective alpha 7 nicotinic receptor agonist SSR180711

Background: Accumulating evidence suggests that alpha 7 nicotinic receptor (alpha 7 nAChR) agonists could be potential therapeutic drugs for cognitive deficits in schizophrenia. The present study was undertaken to examine the effects of the novel selective alpha 7 nAChR agonist SSR180711 on cognitive deficits in mice after repeated administration of the N-methyl-D-aspartate receptor antagonist phencyclidine (PCP). Methods: Saline or PCP (10 mg/kg/day for 10 days) was administered to mice. Subsequently, vehicle, SSR180711 (.3 or 3.0 mg/kg/day), SSR180711 (3.0 mg/kg/day) + the selective alpha 7 nAChR antagonist methyllycaconitine (MLA; 3.0 mg/kg/day), or MLA (3.0 mg/kg/day) was administered IP for 2 consecutive weeks. Twenty-four hours after the final administration, a novel object recognition test was performed. Results: The PCP-induced cognitive deficits were significantly improved by subsequent subchronic (2-week) administration of SSR180711 (3.0 mg/kg). The effects of SSR180711 (3.0 mg/kg) were significantly antagonized by co-administration of MLA (3.0 mg/kg). Furthermore, Western blot analysis and immunohistochemistry revealed that levels of alpha 7 nAChRs in the frontal cortex and hippocampus of the PCP (10 mg/kg/day for 10 days)-treated mice were significantly lower than those of saline-treated mice. Conclusions: These findings suggest that repeated PCP administration significantly decreased the density of alpha 7 nAChRs in the brain and that the alpha 7 nAChR agonist SSR180711 could ameliorate cognitive deficits in mice after repeated administration of PCP. Therefore, alpha 7 nAChR agonists including SSR180711 are potential therapeutic drugs for treating cognitive deficits in schizophrenic patients.