Effects of α7 nicotinic acetylcholine receptor agonists on antipsychotic efficacy in a preclinical mouse model of psychosis

Abstract

Antipsychotics normalize responses in the DBA/2 mouse model of prepulse inhibition (PPI), a preclinical model of sensorimotor gating deficits. The α7 nicotinic acetylcholine receptor (nAChR) as a molecular target is considered an attractive approach for improvement of cognitive deficits in schizophrenia (CDS). Assessment of clinical efficacy of novel agents in CDS involves treating patients already on antipsychotic medications. We evaluated the effects of the combination of α7 nAChR agonists ABT-107 (0.1-10.0mg/kgi.p.), A-582941 (0.04-4.0mg/kgi.p.), and PNU282987 (1.0-10.0mg/kgi.p.) with risperidone (0.1-1.0mg/kgi.p.) or haloperidol (0.3-3.0mg/kgi.p.), representative atypical and typical antipsychotic agents in the DBA/2 mouse PPI model. The same α7 agonists were given alone or in combination with a dose of antipsychotic medication that induces a minimal level of catalepsy in rats, an assay with predictive validity for the induction of extrapyramidal symptoms. The α7 nAChR agonists ABT-107, A-582941, and PNU282987 had no effect in DBA/2 mouse PPI when given alone yet increased the effects of haloperidol and risperidone. The α7 nAChR agonists did not cause catalepsy in rats, nor did they enhance antipsychotic-induced catalepsy. When given in combination with either a typical or atypical antipsychotic, α7 nAChR agonists did not impair efficacy in the DBA/2J mouse PPI model. The efficacy but not the motoric side effects of antipsychotics was enhanced, suggesting that adjunctive therapy of α7 nAChR agonists not only could be useful for the treatment of cognitive deficits associated with schizophrenia but also could enhance the efficacy against positive symptoms.