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Subtype-selective nicotinic acetylcholine receptor agonists can improve cognitive flexibility in an attentional set shifting task

Lookup NU author(s): Dr Chris Wood, Emma Malcolm, Dr Claire Allison, Dr Mohammed Shoaib


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Nicotinic acetylcholine receptors (nAChRs) are considered to be viable targets to enhance cognition in patients diagnosed with schizophrenia. Activation of nAChRs with selective nicotinic receptor agonists may provide effective means to pharmacologically treat cognitive deficits observed in schizophrenia. Cognitive flexibility is one aspect of cognition, which can be assessed in a rodent model of the attentional set-shifting task (ASST). The aim of the present study was two-fold, firstly, to evaluate the efficacy of a series of subtype selective nAChR agonists, such as those that target alpha 7 and alpha 4 beta 2 nAChR subtypes in non compromised rodents. Secondly, nicotine as a prototypic agonist was evaluated for its effects to restore attentional deficits produced by sub-chronic ketamine exposure in the ASST. Male hooded Lister rats underwent habituation, consisting of a simple odour and medium discrimination with subsequent assessment 24 h later. In experimentally naive rats, alpha 7 subtype selective agonists, compound-A and SSR180711 along with PNU-120596, an alpha 7 positive allosteric modulator (PAM), were compared against the beta 2* selective agonist, 5IA-85380. All compounds except for PNU-120596 were observed to significantly improve extra-dimensional (ED) shift performance, nicotine, 5IA-85380 and SSR180711 further enhanced the final reversal (REV3) stage of the task. In another experiment, sub-chronic ketamine treatment produced robust deficits during the ED and the REV3 stages of the discriminations; rodents required significantly more trials to reach criterion during these discriminations. These deficits were attenuated in rodents treated acutely with nicotine (0.1 mg/kg SC) 10 min prior to the ED shift. These results highlight the potential utility of targeting nAChRs to enhance cognitive flexibility, particularly the alpha 7 and beta 2* receptor subtypes. The improvement with nicotine was much greater in rodents that were impaired following the sub-chronic ketamine exposure suggesting a greater therapeutic opportunity to target nicotinic receptors for patients diagnosed with schizophrenia. (C) 2016 Elsevier Ltd. All rights reserved.

Publication metadata

Author(s): Wood C, Kohli S, Malcolm E, Allison C, Shoaib M

Publication type: Article

Publication status: Published

Journal: Neuropharmacology

Year: 2016

Volume: 105

Pages: 106-113

Print publication date: 01/06/2016

Online publication date: 06/01/2016

Acceptance date: 03/01/2016

ISSN (print): 0028-3908

ISSN (electronic): 1873-7064

Publisher: Elsevier


DOI: 10.1016/j.neuropharm.2016.01.006


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