Neuronal nicotinic receptors as targets for enhancing cognition in schizophrenia

Abstract

Cognitive deficits are a core disabling feature of schizophrenia, yet remain inadequately treated by current pharmacological or behavioural therapies. The non-competitive NMDAR antagonist ketamine can pharmacologically induce cognitive deficits in both rodents and humans, presenting a novel translational approach for examining mechanisms underlying cognitive deficits associated with schizophrenia (CDS). Nicotine can improve working memory in rodents and in smokers with schizophrenia where heavy tobacco use may reflect self-medication to ameliorate CDS. The roles of the two main subtypes of nAChRs, the α7 and α4β2, in mediating cognitive improvement have yet to be determined. Cohorts of male hooded-Lister rats were trained in the Odour Span Task (OST) until demonstrating asymptotic performance and then exposed to a sub-anaesthetic dose of ketamine or vehicle daily for 5 consecutive days. This sub-chronic regimen produced a replicable, dose-dependent impairment in OST performance that was not restored following anti-psychotic treatment. Nicotine, α7 and α4β2 nAChR-selective agonists improved performance in ketamine-treated animals, with nicotine and one α4β2 agonist also improving the performance of control subjects. These data indicate the α4β2 nAChR as the main receptor subtype mediating the effect of nicotine on the OST in control animals, with a lesser role for the α7 nAChR. The α7 nAChR however was shown to have a role in improving the performance of ketamine-treated animals, as demonstrated by the enhancing effect of allosteric modulator PNU-120596 and Compound T on OST performance; an effect that was blocked by the α7 nAChR antagonist methyllycaconitine. When administered locally into the medial prefrontal cortex (mPFC), nicotine improved, and muscimol impaired OST performance; suggesting the mPFC as the neural site of action in the OST. Complementary data using an in-vitro electrophysiological gamma frequency model of network oscillations indicated an enhancing effect of nicotine on normal gamma frequency oscillations in the rat mPFC and is proposed as a potential mechanism behind the behavioural data. Collectively, these results provide further impetus for targeting nAChRs in the treatment of CDS.