alpha7-Nicotinic acetylcholine receptors (alpha7-nAChR) have been implicated in a range of cognitive deficits in schizophrenia. Therefore we examined alpha7-nAChR knockout (KO), heterozygote (HT) and wildtype (WT) littermate mice in the 5-CSR (a rodent model of sustained attention) and odour span (a novel mouse working memory paradigm) tasks, and related performance to nAChR density. Whilst there was no difference between groups in baseline 5-CSR task performance, alpha7-nAChR KO's exhibited significantly higher omission levels compared to WT mice on increasing the attentional load, with HT mice performing at an intermediate level. Furthermore, alpha7-nAChR KO mice were significantly impaired in the odour span task when compared to WT mice, in a pattern consistent with impaired attention. These behavioural deficits were associated with the loss of alpha7-nAChRs, as alpha4beta2-nAChR density was unaltered in these mice. Thus these studies intimate that the attentional impairment in alpha7-nAChR transgenic mice maybe core to other deficits in cognition.
Title: Identification of species differences in the pharmacology of the alpha-7 nicotinic receptor using the antagonist radioligand [3H]-methyllycaconitine. Crawford N, Finlayson K, Sharkey J, Kelly JS Ref: Cholinergic Mechanisms, CRC Press, :539, 2004 : PubMed
In humans, nicotine has been shown to improve attention in both normal and impaired individuals. Observations in rats reflect some, but not all aspects of the nicotine-induced improvements in humans. To date these findings have not been replicated in mice. To examine the effect of nicotine on sustained attention in mice, we have established a version of the 5-choice serial reaction-time (5-CSR) task with graded levels of difficulty, based upon spatial displacement and a variable intertrial interval. Using this paradigm, microgram doses of nicotine produced a consistent reduction in the level of omissions and an improvement in proportion correct in normal mice. This improvement in sustained attention was made irrespectively of whether mice had previously received nicotine. In an attempt to elucidate which nicotinic acetylcholine receptor (nAChR) subtype(s) mediate this effect, we examined the performance of alpha7 nAChR knockout (KO) mice in the 5-CSR task. alpha7 nAChR KO mice not only acquired the task more slowly than their wild-type littermates, but on attaining asymptotic performance, they exhibited a higher level of omissions. In conclusion, by increasing the level of task difficulty, the performance of mice was maintained at sufficiently low levels to allow a demonstrable improvement in performance upon nicotine administration. Furthermore, as alpha7 KO mice are clearly impaired in the acquisition and asymptotic performance of this task, the alpha7 nAChR may be involved in mediating these effects of nicotine.
Title: Alzheimer's disease: the tacrine legacy Kelly JS Ref: Trends in Pharmacological Sciences, 20:127, 1999 : PubMed
Title: Acetylcholine as an excitatory and inhibitory transmitter in the mammalian central nervous system Kelly JS, Dodd J, Dingledine R Ref: Prog Brain Res, 49:253, 1979 : PubMed
Title: [Inhibitory post-synaptic potentials in the cerebral cortex] Dreifuss JJ, Kelly JS, Krnjevic K Ref: Journal de Physiologie (Paris), 61 Suppl 2:274, 1969 : PubMed
Title: Anionic permeability of cortical neurones during inhibition Kelly JS, Krnjevic K, Morris ME, Yim GK Ref: The Journal of Physiology, 196:120P, 1968 : PubMed
