The effects of acute nicotine administration (0.09 mg/kg nicotine), chronic nicotine administration (6.3 mg/kg/d nicotine for 14 d), and withdrawal from chronic nicotine administration on fear conditioning in C57BL/6 mice were examined. Mice were trained using two coterminating conditioned stimulus (30 s; 85 dB white noise)-unconditioned stimulus (2 s; 0.57 mA foot shock) pairings and tested 24 h later for contextual and cued fear conditioning. Acute nicotine administration enhanced contextual fear conditioning, chronic nicotine administration had no effect on contextual fear conditioning, and withdrawal from chronic nicotine administration impaired contextual fear conditioning. Plasma nicotine concentrations were similar after acute and chronic treatment and were within the range reported for smokers. During withdrawal, concentrations of nicotine were undetectable. An acute dose of nicotine (0.09 mg/kg) during withdrawal from chronic nicotine treatment reversed withdrawal-associated deficits in contextual fear conditioning. The results suggest that tolerance to the effects of nicotine on contextual fear conditioning develops with chronic nicotine treatment at a physiologically relevant dose, and withdrawal from this chronic nicotine treatment is associated with impairments in contextual fear conditioning. These findings provide a model of how the effects of nicotine on learning may contribute to the development and maintenance of nicotine addiction.

Executive function is a collection of cognitive processes essential for higher order mental function. Processes involved in executive function include, but are not limited to, working memory, attention, cognitive flexibility, and impulse control. These complex behaviors are largely mediated by prefrontal cortical function but are modulated by dopaminergic, noradrenergic, serotonergic, and cholinergic input. The ability of these neurotransmitter systems to modulate executive function allows for adaption in cognitive behavior in response to changes in the environment. Because of the important role these neurotransmitter systems play in regulating executive function, changes in these systems can also have a grave impact on executive function. In addition, polymorphisms in genes associated with these neurotransmitters are associated with phenotypic differences in executive function. Understanding how these naturally occurring polymorphisms contribute to different executive function phenotypes will advance basic knowledge of cognition and potentially further understanding and treatment of mental illness that involve changes in executive function. In this review, we will examine the influence of dopamine, norepinephrine, serotonin, and acetylcholine on the following measures of executive function: attention, cognitive flexibility, and impulse control. We will also review the effects of polymorphisms in genes associated with these neurotransmitter systems on these measures of executive function.

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A long-standing relationship between nicotinic acetylcholine receptors (nAChRs) and cognition exists. Drugs that act at nAChRs can have cognitive-enhancing effects and diseases that disrupt cognition such as Alzheimer's disease and schizophrenia are associated with altered nAChR function. Specifically, hippocampus-dependent learning is particularly sensitive to the effects of nicotine. However, the effects of nicotine on hippocampus-dependent learning vary not only with the doses of nicotine used and whether nicotine is administered acutely, chronically, or withdrawn after chronic nicotine treatment but also vary across different hippocampus-dependent tasks such as the Morris water maze, the radial arm maze, and contextual fear conditioning. In addition, nicotine has variable effects across different types of hippocampal long-term potentiation (LTP). Because different types of hippocampus-dependent learning and LTP involve different neural and molecular substrates, comparing the effects of nicotine across these paradigms can yield insights into the mechanisms that may underlie the effects of nicotine on learning and memory and aid in understanding the variable effects of nicotine on cognitive processes. This review compares and contrasts the effects of nicotine on hippocampus-dependent learning and LTP and briefly discusses how the effects of nicotine on learning could contribute to nicotine addiction.

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