Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the novel selective alpha7 nicotinic receptor agonist SSR180711.
BACKGROUND
Accumulating evidence suggests that alpha7 nicotinic receptor (alpha7 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 alpha7 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 alpha7 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 alpha7 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 alpha7 nAChRs in the brain and that the alpha7 nAChR agonist SSR180711 could ameliorate cognitive deficits in mice after repeated administration of PCP. Therefore, alpha7 nAChR agonists including SSR180711 are potential therapeutic drugs for treating cognitive deficits in schizophrenic patients.
Hashimoto
Kenji
K
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. hashimoto@faculty.chiba-u.jp
Ishima
Tamaki
T
Fujita
Yuko
Y
Matsuo
Masaaki
M
Kobashi
Tatsuhiro
T
Takahagi
Makoto
M
Tsukada
Hideo
H
Iyo
Masaomi
M
D000157:Aconitine / Q000031:analogs & derivatives / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism / Q000627:therapeutic use*; D003072:Cognition Disorders / Q000139:chemically induced* / Q000188:drug therapy*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018733:Nicotinic Antagonists / Q000627:therapeutic use*; D010622:Phencyclidine / Q000378:metabolism
D019086:Bridged Bicyclo Compounds, Heterocyclic; D018733:Nicotinic Antagonists; C516833:SSR180711; C054634:methyllycaconitine; D010622:Phencyclidine; D000157:Aconitine