title: Positive allosteric modulation of alpha 7 nicotinic acetylcholine receptors enhances recognition memory and cognitive flexibility in rats.
abstract: A wide body of preclinical and clinical data suggests that alpha 7 nicotinic acetylcholine receptors (α7-nAChRs) may represent useful targets for cognitive improvement in schizophrenia and Alzheimer׳s disease. A promising recent approach is based on the use of positive allosteric modulators (PAMs) of α7-nAChRs due to their several advantages over the direct agonists. Nevertheless, the behavioural effects of this class of compounds, particularly with regard to higher-order cognitive functions, have not been broadly characterised. The aim of the present study was to evaluate the procognitive efficacies of type I and type II α7-nAChRs PAMs, N-(4-chlorophenyl)-[[(4-chlorophenyl)amino]methylene]-3-methyl-5-isoxazoleacet-amide (CCMI) and N-(5-Chloro-2,4-dimethoxyphenyl)-N'-(5-methyl-3-isoxazolyl)urea (PNU-120596) in the novel object recognition task (NORT), attentional set-shifting task (ASST) and five-choice serial reaction time task (5-CSRTT) in rats. Additionally, the effects of galantamine, an acetylcholinesterase inhibitor that also allosterically modulates nAChRs, were assessed. We report that CCMI (0.3-3mg/kg), PNU-120596 (0.3-3mg/kg) and galantamine (1-3mg/kg) attenuated the delay-induced impairment in NORT performance and facilitated cognitive flexibility in the ASST. Methyllycaconitine (3mg/kg) blocked the actions of CCMI, PNU-120596 and galantamine in the NORT and ASST, suggesting that the procognitive effects of these compounds are α7-nAChRs-dependent. However, none of the compounds tested affected the rats' attentional performance in the 5-CSRTT. The present findings confirm and extend the observations indicating that the positive allosteric modulation of α7-nAChRs enhances recognition memory and cognitive flexibility in preclinical tasks. Therefore, the present study supports the utility of α7-nAChRs PAMs as a potential cognitive enhancing therapy.
authors.affiliation: Department of Behavioural Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Nikiforuk
authors.affiliation: Department of Behavioural 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 Behavioural 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 Behavioural Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland. Electronic address: nfpopik@cyf-kr.edu.pl.
authors.forename: Piotr
authors.initials: P
authors.lastname: Popik
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001288:Attention / Q000187:drug effects / Q000502:physiology; D018678:Cholinergic Agents / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects / Q000502:physiology*; D056344:Executive Function / Q000187:drug effects / Q000502:physiology; D005702:Galantamine / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010671:Phenylurea Compounds / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: C547642:(N-(4-chlorophenyl))-alpha-((4-chlorophenyl)-aminomethylene)-3-methyl-5-isoxazoleacet-amide; C508388:1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; D018678:Cholinergic Agents; D007555:Isoxazoles; D010671:Phenylurea Compounds; D064569:alpha7 Nicotinic Acetylcholine Receptor; D005702:Galantamine
keywords: Alpha 7 nicotinic acetylcholine receptor; Attention; Galantamine; Positive allosteric modulators; Recognition memory; Set-shifting