Impaired performance of alpha7 nicotinic receptor knockout mice in the five-choice serial reaction time task

Abstract

Rationale Nicotinic receptors have been implicated in attentional performance. Nicotine can improve attention in animals and humans, but knowledge about relevant receptor subtypes is very limited. Objectives The aim was to examine the role of α7 receptors in attentional performance of mice and in effects of nicotine. Materials and methods Mice with targeted deletion of the gene coding for the α7 subunit of nicotinic receptors and wild-type controls were trained on a five-choice serial reaction time task with food reinforcers presented under varying parametric conditions. Nicotine was administered in a range of doses (0.001-1.0 mg/kg sc), including those reported to enhance attentional performance. Results Initially the α7 −/− (knockout) mice responded less accurately and made more anticipatory responses. After task parameters were altered so that the time allowed for responding was reduced and anticipatory (impulsive) responses were punished by a time-out, the pattern of performance deficits changed; there were increased omission errors in α7 −/− mice but normal levels of accuracy and anticipatory responding. Nicotine did not improve any measure of performance, either with the original training parameters or after retraining; the largest dose used (1.0 mg/kg) produced a general impairment of responding in α7 −/− and wild-type mice. Conclusions α7 nicotinic receptor knockout mice are impaired in performance of the 5-CSRTT, suggesting a possible role for α7 receptors in attentional processing. However, identification of a protocol for assessing attention-enhancing effects of nicotine in mice may require further modifications of test procedures or the use of different strains of animal.

A-582941, cholinergic alpha 7 nicotinic receptor agonist, improved cognitive and negative symptoms of the sub-chronic MK-801 model of schizophrenia in rats

“…It has been considered that patients consume tobacco for their self-medications due to its nicotine content. It was also demonstrated that α7 NAChR knock-out mice showed worse performance than wild-type animals in cognitive tasks [16]. These data have indicated that α7 NAChR dysfunction can be responsible for schizophrenia pathophysiology and a new drug target for the treatment of schizophrenia.…”

Pro-Cognitive and Antipsychotic Efficacy of the α7 Nicotinic Partial Agonist SSR180711 in Pharmacological and Neurodevelopmental Latent Inhibition Models of Schizophrenia

“…Of particular relevance to attentional and sensory gating deficits in schizophrenia (Adler et al, 1998;Heinrichs, 2005;Lubow, 2005), a7-nAChR agonists alleviate both types of deficits in humans and animals Olincy et al, 2006;Timmermann et al, 2007;Wishka et al, 2006). A role for the a7-nAChR in these processes is supported by findings that a7-nAChR knock-out mice show attentional and gating impairments (Adams et al, 2008;Hoyle et al, 2006;Young et al, 2004Young et al, , 2007. Finally, there is a diminished expression of a7-nAChR in the hippocampus and frontal cortex in schizophrenia (Freedman et al, 1995;Guan et al, 1999).…”

Nicotinic actions on neuronal networks for cognition: General principles and long-term consequences

“…However, genetic approaches assessing the role of nAChRs have shown that α7* receptors do have a role in attention. Knockout mice lacking the gene for the α7 nAChR subunits showed impaired task acquisition and a higher rate of omissions in the 5-choice serial reaction time task [45,46]. Since the mice used for these studies lacked α7* nAChR expression throughout their brains, it is not known whether the impairment in 8 attention performance was attributable to the lack of α7* receptors specifically in the PFC, let alone whether the effects were attributable to a specific type of cells in the PFC neuronal circuits.…”