Nicotine can both activate and desensitize/inactivate nicotinic acetylcholine receptors (nAChRs). An ongoing controversy in the field is to what extent the behavioral effects of nicotine result from activation of nAChRs, and to what extent receptor desensitization is involved in these behavioral processes. Recent electrophysiological studies have shown that both nAChR activation and desensitization contribute to the effects of nicotine in the brain, and these experiments have provided cellular mechanisms that could underlie the contribution of both these processes to nicotine-mediated behaviors. For instance, desensitization of nAChRs may contribute to the salience of environmental cues associated with smoking behavior and activation and desensitization of nAChRs may contribute to both primary and conditioned drug reward. Similarly, studies of the antidepressant-like effects of nicotinic agents have revealed a balance between activation and desensitization of nAChRs. This review will examine the evidence for the contribution of these two very different consequences of nicotine administration to behaviors related to nicotine addiction, including processes related to drug reinforcement and affective modulation. We conclude that there are effects of nAChR activation and desensitization on drug reinforcement and affective behavior, and that both processes are important in the behavioral consequences of nicotine in tobacco smoking.

Nicotine has been shown to have effects on anxiety and depression in both human and animal studies. These studies suggest that nicotinic acetylcholine receptors (nAChRs) can modulate the function of pathways involved in stress response, anxiety and depression in the normal brain, and that smoking can result in alterations of anxiety level and mood. The effects of nicotine are complex however, and nicotine treatment can be either anxiolytic or anxiogenic depending on the anxiety model tested, the route of nicotine administration and the time course of administration. The paradoxical effects of nicotine on emotionality are likely due to the broad expression of nAChRs throughout the brain, the large number of nAChR subtypes that have been identified and the ability of nicotine treatment to both activate and desensitize nAChRs. Activation of nAChRs has been shown to modulate many systems associated with stress response including stress hormone pathways, monoaminergic transmission and release of classical neurotransmitters throughout the brain. Local administration studies in animals have identified brain areas that may be involved in the anxiogenic and anxiolytic actions of nicotine including the lateral septum, the dorsal raphe nuclei, the mesolimbic dopamine system and the hippocampus. The ensemble of studies to date suggest that under certain conditions nicotine can act as an anxiolytic and an antidepressant, but that following chronic use, adaptations to nicotine can occur resulting in increased anxiety and depression following withdrawal.

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The extracellular regulated kinase (ERK) pathway was studied to determine its role in neuronal plasticity related to the development of nicotine dependence. Levels and phosphorylation state of ERK, cAMP response element binding protein (CREB) and proline-rich/Ca 2+ -activated tyrosine kinase (PYK2), and levels of tyrosine hydroxylase (TH), were determined using western blotting. C57Bl/6J mice received acute or chronic nicotine (200 lg/mL) in their drinking water or were withdrawn from nicotine for 24 h following chronic exposure. CREB phosphorylation was reduced in the nucleus accumbens following chronic nicotine, consistent with previous reports that decreased accumbens CREB activity increases drug reinforcement. In contrast, CREB phosphorylation was increased in the prefrontal cortex following chronic nicotine exposure and in the ventral tegmental area during nicotine withdrawal. In addition, total and phosphorylated ERK decreased in the amygdala following chronic nicotine exposure, but ERK phosphorylation increased in the prefrontal cortex. TH levels increased in both the amygdala and prefrontal cortex, supporting the hypothesis that increased catecholaminergic tone contributes to nicotine reinforcement. Overall, these results support a role for ERK and CREB activity in neural plasticity associated with nicotine dependence.

The ␣6 nicotinic acetylcholine receptor (nAChR) subunit is involved in nicotine-stimulated dopamine release in the striatum. It is expressed in brain regions and coexpressed with nAChR subtypes implicated in nicotine dependence behaviors; hence, this subunit may play a role in nicotine dependence. Using the ␣6-selective antagonist ␣-conotoxin H9A;L15A (MII[H9A; L15A]), we determined the role of ␣6* nAChRs in the pharmacological and behavioral effects of nicotine. We measured effects of pretreatment with MII[H9A;L15A] on analgesia, locomotion, and body temperature after a single injection of nicotine. Effects of MII[H9A;L15A] on nicotine reward were measured using the conditioned place preference (CPP) paradigm. We further measured physical (somatic signs and hyperalgesia) and affective [anxiety-related behavior and conditioned place aversion (CPA)] nicotine withdrawal behaviors after extended nicotine exposure. Results showed that MII[H9A;L15A] did not block acute nicotine effects on the behaviors measured. Conversely, MII[H9A:l15A] blocked the expression of nicotine CPP, as well as withdrawal-associated CPA and anxiety-related behavior in the elevated plus maze, but not withdrawalinduced somatic signs or hyperalgesia. These results suggest a role for the ␣6 nAChR subunit in nicotine reward and affective nicotine withdrawal but not acute nicotine-induced or physical withdrawal behaviors.