Nicotine improves performance in an attentional set shifting task in rats

Abstract

A large number of studies in both humans and experimental animals have demonstrated nicotine-induced improvements in various aspects of cognitive function, including attention and memory. The prefrontal cortex (PFC) is thought to be critically involved in the modulation of executive function and these attentional processes are enhanced by nicotine acting at nicotinic acetylcholine receptors. The involvement of nicotinic processes on cognitive flexibility in particular has not been specifically investigated. The effects of nicotine on attentional flexibility were therefore evaluated using the rodent attentional set shifting task in rats. Nicotine injected both acutely and following repeated pre-exposure significantly improved both intradimensional and extradimensional set shifting performance in the task. Further investigation of the acute effects of nicotine demonstrated this improvement in attentional flexibility to be dose-dependent. These results implicate the nicotinic receptor system in the mediation of processes underlying cognitive flexibility and suggest that nicotine improves attentional flexibility in rats, both within and between perceptual dimensions of a compound stimulus. Nicotine-induced alterations in prefrontal circuitry may underlie these effects on cognitive flexibility.

This article is part of a Special Issue entitled ‘Cognitive Enhancers’.

Introduction

Nicotine is widely accepted as the primary psychoactive agent in tobacco smoke and has been shown to improve cognitive performance across multiple domains (Levin et al., 2006). Interest in the development of nicotinic agonists as cognitive enhancers has gained momentum, since nicotinic receptors (nAChRs) have been implicated in neuropsychiatric diseases characterised by cognitive impairments including Alzheimer's, schizophrenia, attention-deficit hyperactive disorder and mild cognitive impairment (Newhouse et al., 2004, 2012).

Neuronal nAChRs are considered to be involved since they are widely distributed throughout the rat (Clarke et al., 1985; Tribollet et al., 2004) and human brain (Gotti et al., 1997). More specifically, there is evidence that the major nAChR subtypes in rats are highly expressed in brain regions subserving cognitive functions such as the prefrontal cortex (PFC) (Gil et al., 1997; Vidal and Changeux, 1993), a brain region known to play a critical role in the modulation of executive function (Dalley et al., 2004a; Chudasama and Robbins, 2006); the hippocampus and other subcortical limbic structures (Changeux et al., 1998; Gotti et al., 2006, 2007). Furthermore, in the PFC, dopamine and glutamate have been shown to be modulated by nicotine and subtype selective agonists (Livingstone et al., 2009) which further support the role for nAChRs in cognitive function (Vidal, 1996; Mansvelder et al., 2006).

In the preclinical literature, nicotine and other subtype nAChRs agonists have been demonstrated to improve sustained and divided aspects of attention (Stolerman et al., 2000; Hahn et al., 2002) using the five choice serial reaction time task (5CSRTT; developed by Carli et al., 1983). However, another important aspect of executive function based on prefrontal cortical function which has not been systematically studied with respect to nicotinic receptor involvement is attentional flexibility.

Attentional control involves the ability to change behaviour effectively in response to alterations in the significance of environmental stimuli, a process that requires flexibility of attentional set for different dimensional properties of stimuli. Attentional flexibility is commonly measured clinically using the Wisconsin Card Sorting Test (WCST; Milner, 1963). Birrell and Brown (2000) devised an analogous model to the Wisconsin Card Sorting Test (WCST) to be executed in rodents, the Attentional Set Shifting Task (ASST). The ASST is an adaptation of the WCST, utilising the dimensions of odour, medium and texture of the bowl (Birrell and Brown, 2000). The task requires the rodent to learn to associate a food reward with a specific dimension which is later changed during the task (extradimensional shift EDS). Birrell and Brown observed the rodents took more trials to complete the extradimensional shift (switching to a previously irrelevant stimulus, whilst ignoring the previously relevant stimulus) component of the task than the intradimensional shift (switching within the same relevant dimension) component when rodents had bilateral lesions of the prefrontal cortex (Birrell and Brown, 2000). Thus, the ASST assesses a rodent's ability to shift attention to allow investigation of the mechanisms underlying both attentional set formation and maintenance in addition to attentional flexibility and reversal learning. It is formally equivalent to the human and primate versions of the task (Brown and Bowman, 2002; Dias et al., 1996a, 1996b; Owen et al., 1991), but uses more species appropriate stimuli.

In view of nicotine's cognitive-enhancing effects on sustained attention in non-compromised rodents (Hahn et al., 2002), the present studies evaluated a similar dosing regimen of nicotine in the ASST. More specifically, given the relatively short half-life for metabolism of nicotine in rats, tests were applied just prior to the extra-dimensional shift. To gauge the specificity of any improvements, similar tests were conducted on the intra-dimensional shift. These studies would also provide the potential utility of assessing attentional flexibility as a domain sensitive to cognitive enhancement by psychoactive substances.