Nicotinic receptors and lurasidone-mediated reversal of phencyclidine-induced deficit in novel object recognition

• Mecamylamine, a non-selective nAChR antagonist, induced a NOR deficit in normal rats.
• A-85380, a selective α4β2* nAChR agonist, reversed PCP-induced NOR deficit.
• PNU-282987, a selective α7 nAChR agonist, reversed PCP-induced NOR deficit.
• The reversal effect of lurasidone was blocked by mecamylamine.
• Sub-effective dose of A-85380 and PNU-282987 potentiated the effect of lurasidone.

BackgroundEnhancement of cholinergic function via nicotinic acetylcholine (ACh) receptor (nAChR) agonism is a potential approach for the treatment of cognitive impairment associated with schizophrenia (CIAS). Some atypical antipsychotic drugs (AAPDs) enhance ACh release in rodent brain, indirectly stimulating these receptors. Here, we elucidate which nAChR subtypes mediate novel object recognition (NOR) in normal rats and contribute to the ability of the AAPD, lurasidone, to improve the NOR deficit in sub-chronic (sc) phencyclidine (PCP)-treated rats, a model for CIAS.MethodsThe ability of lurasidone and nAChR ligands to reverse the scPCP-induced deficit in NOR was assessed in female, Long-Evans rats.ResultsThe broad acting nAChR antagonist, mecamylamine (MEC), induced a NOR deficit in normal rats. The NOR deficit secondary to scPCP was reversed by either selective α4β2* nAChR agonism (A-85380) or α7 nAChRs agonism (PNU-282987); these effects were blocked by DHβE and MLA, selective antagonists of α4β2* and α7 nAChR, respectively. The ability of lurasidone to reverse the scPCP-induced NOR deficit was blocked by MEC, but not MLA or DHβE. However, sub-effective doses (SED) of either A-85380 or PNU-282987 potentiated the ability of SED lurasidone to reverse the scPCP-induced NOR deficit.ConclusionsThese results identify both α4β2* and α7 nAChRs as candidates for enhancing the ability of lurasidone and other AAPDs, which increase the release of ACh, to improve CIAS.