title: Positive allosteric modulators of alpha 7 nicotinic acetylcholine receptors reverse ketamine-induced schizophrenia-like deficits in rats.
abstract: Alpha 7 nicotinic acetylcholine receptors (α7-nAChRs) have generated great interest as targets of new pharmacological treatments for cognitive dysfunction in schizophrenia. One promising recent approach is based on the use of positive allosteric modulators (PAMs) of α7-nAChRs, which demonstrate several advantages over direct agonists. Nevertheless, the efficacy of these newly introduced α7-nAChR agents has not been extensively characterised in animal models of schizophrenia. The aim of the present study was to evaluate the efficacy of type I and II PAMs, N-(5-chloro-2,4-dimethoxyphenyl)-N'-(5-methyl-3-isoxazolyl)urea (PNU-120596) and N-(4-chlorophenyl)-[[(4-chlorophenyl)amino]methylene]-3-methyl-5-isoxazoleacet-amide (CCMI), respectively, and galantamine, an acetylcholinesterase inhibitor (AChE) that also allosterically modulates nAChRs, against ketamine-induced cognitive deficits and social withdrawal in rats. The orthosteric α7-nAChR agonist octahydro-2-methyl-5-(6-phenyl-3-pyridazinyl)-pyrrolo[3,4-c]pyrrole (A-582941) was used as a positive control. Additionally, the antipsychotic activities of the tested compounds were assessed using the conditioned avoidance response (CAR) test. PNU-120596, CCMI, galantamine and A-582941 reversed ketamine-induced cognitive inflexibility, as assessed in the attentional set-shifting task (ASST). The tested compounds were also effective against ketamine-induced impairment in the novel object recognition task (NORT). PNU-120596, CCMI, and A-582941 ameliorated ketamine-induced social interaction deficits, whereas galantamine was ineffective. Moreover, all tested compounds selectively suppressed the CAR. The positive allosteric modulation of α7-nAChRs demonstrates preclinical efficacy not only against schizophrenia-like cognition impairments but also positive and negative symptoms. Therefore, the use of α7-nAChR PAMs as a potential treatment strategy in schizophrenia is supported.
authors.affiliation: Department of Behavioral Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland. Electronic address: nikifor@if-pan.krakow.pl.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Nikiforuk
authors.affiliation: Department of Behavioral Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Kos
authors.affiliation: Department of Behavioral Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Hołuj
authors.affiliation: Department of Behavioral Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Potasiewicz
authors.affiliation: Department of Behavioral Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Popik
mesh_terms: D000495:Allosteric Site / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D001288:Attention / Q000187:drug effects; D001362:Avoidance Learning / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D007398:Interpersonal Relations; D007649:Ketamine / Q000633:toxicity*; D008297:Male; D018722:Nicotinic Agonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D021641:Recognition, Psychology / Q000187:drug effects; D012559:Schizophrenia / Q000139:chemically induced*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018722:Nicotinic Agonists; D064569:alpha7 Nicotinic Acetylcholine Receptor; D007649:Ketamine
keywords: Alpha 7 nicotinic acetylcholine receptors; Animal models; Cognition; Ketamine; Positive allosteric modulators; Schizophrenia