Agonist Response Induced by Nicotinic α-7 Agonist is Inhibited by Antipsychotic Drugs

Nicotinic acetylcholine α7 receptors (nAChRα7) have been implicated in certain pathological conditions associated with memory impairment, including schizophrenia and Alzheimer's disease. In vivo experiments have shown that both nAChRα7 agonist and nAChRα7 positive allosteric modulators (PAMs) can improve cognition in various preclinical models. Following these results there has been a lot of interest in developing new nAChRα7 ligands for the potential use for cognition in both schizophrenia and Alzheimer's disease. The use of new nAChRα7 compounds in schizophrenia would probably be add-on to existing antipsychotics. Therefore it is important to investigate if antipsychotic compounds have any effects on the positive effects of new nAChRα7 compounds. We have previously shown that antipsychotic compounds are inhibitors of ACh induced responses at h-α7 receptors with IC50 values between 2100 and 6500 nM. In this study we have further evaluated the effects of antipsychotic compounds on the agonistic response at h-α7 receptors induced by nAChRα7 agonists i.e. EVP-6124 (EVP) and TC-5619 (TC). All tested antipsychotics compounds showed inhibition of the agonistic response induced by both EVP and TC at h-α7 receptors with the following IC50 values in nM for EVP and TC, respectively: haloperidol (2400, 1900), clozapine (1800, 2700), olanzapine (3000, 2000), quetiapine (3200, 3000), aripiprazole (2300, 1900) and risperidone (2000, 1500). These IC50 values are higher than the clinically plasma concentrations for antipsychotics drugs in stabile out patients. In summary, it was shown that antipsychotic compounds antagonize both EVP-6124 and TC-5619 induced agonistic response at nAChRα7 receptors with IC50 values between 1500 and 3200 nM.