The studies reviewed here show that there is no simple relationship between smoking and nAChR activation or desensitization. Rather, coordinated activation and desensitization of a number of different nAChRs on different neuronal subtypes likely occurs in response to nicotine administration through smoking. Neither desensitization alone nor activation alone is sufficient to explain the behavioral consequences of nicotine intake, just as nicotine reward alone is not sufficient to explain smoking behavior. Instead, activation and desensitization of nAChRs contribute to an ensemble of behavioral effects, including nicotine reward, conditioned reinforcement and modulation of mood, that promote ongoing smoking behavior.
The fact that desensitization contributes significantly to some of the effects of chronic nicotine intake suggests that some of the effects of nicotine are due to disruption of endogenous ACh signaling. While this is easiest to describe with respect to the cholinergic hypothesis of depression, it is also the case that nicotine reward may be the result of disruption of normal ACh signaling in the VTA and other brain regions. This is supported by studies showing that nicotinic antagonists modulate the rewarding effects of drugs of abuse such as cocaine (Levin et al., 2000
; Reid et al., 1999
; Zachariou et al., 2001
; Zanetti et al., 2006
), suggesting a role for ACh in reward circuits more generally than just in nicotine reward.
These studies also suggest that there is a role for tonic ACh signaling in behaviors related to reward and affect. Microdialysis studies using the no-net-flux method have shown that the baseline level of extracellular ACh is in the range of 4.5 nM at rest in the mouse hippocampus (Laplante et al., 2004
). One possibility is that nAChRs act as sensors of tonic ACh levels. The volume transmission hypothesis suggests that basal levels of neurotransmitters can coordinate the excitability of ensembles of neurons across a broad distance (Zoli et al., 1999
). The tonic activation and desensitization of nAChRs in the DA system, the hippocampus or the amygdala could regulate reward and affect by setting an overall tone for neuronal activity in these circuits. Thus, the ability of nAChR antagonists to decrease cfos activity in the amygdala and other brain areas (Mineur et al., 2007
) reflects disruption of cholinergic tone in those brain regions that is likely to contribute to the behavioral effects of these nicotinic agents.
The balance between activation and desensitization of nAChRs has been elegantly explored in a number of studies of the DA system (). In this system, the temporal sequence of activation of β2* nAChRs on DA neurons in the VTA, followed by their desensitization, appears to result in a shift from a brief, direct drive of DA neuronal firing toward presynaptic, α7-mediated activation of glutamate release onto DA neurons (Mansvelder et al., 2002
; Wooltorton et al., 2003
). Combined with desensitization of β2* nAChRs on DA terminals in the NAc leading to decreased transmission of tonic DA neuronal firing, but maintained release of DA in response to phasic DA neuronal firing (Rice and Cragg, 2004
; Zhang and Sulzer, 2004
), this pattern of nAChR activity could result in increased salience of environmental cues that were paired with nicotine intake. Together, this provides a mechanism for a network level effect of nAChR activation and desensitization that could occur more generally throughout the brain. Future studies may reveal a similar network level of nicotinic regulation in other systems, such as the hippocampus and amygdala. Future studies using agonists and antagonists selective for particular nAChR subtypes could clarify the effects of activation and desensitization particular nAChR populations on nicotine-related behaviors.
It is interesting that several of the current therapeutics for smoking cessation have both activating and desensitizing/inhibiting effects on nAChR function. For example, the nicotine patch does deliver nicotine, but it does so with pharmacokinetics which favor desensitization of nAChRs (Gries et al., 1998
). Varenicline is a partial agonist of α4/β2* nAChRs (Coe et al., 2005
), but also activates α7-type nAChRs (Mihalak et al., 2006
). While there are common behavioral effects observed between smoked nicotine, nicotine patch and varenicline, neither patch (Jorenby et al., 1995
) nor varenicline are reinforcing (Rollema et al., 2007
). The observation that nicotine patch or mecamylamine can significantly improve mood in patients affected by Tourette's syndrome (Silver et al., 2001
) supports the idea that this effect of the patch is likely to be a result of nAChR desensitization. Finally, bupropion, while having effects on monoamine transporters, has also been shown to be a non-competitive antagonist of nAChRs (Dwoskin et al., 2006
). Thus, it appears that partial agonism or blockade of nAChRs may be particularly useful for aiding smoking cessation. One potential reason for this possibility is that interference with cholinergic transmission ameliorates negative mood symptoms. It would therefore be predicted that a subset of patients taking varenicline may report that their mood symptoms are decreased by the drug. Further, partial agonism or blockade of nAChRs may be helpful in decreasing cue-induced craving by decreasing the firing rate of VTA neurons, while maintaining the filtering effect on DA terminals that allows other salient reward signals to induce DA release in the NAc.
In summary, both activation and desensitization appear to contribute to the primary rewarding properties of nicotine and to secondary conditioned reinforcement. Further, it appears that blockade of nAChRs can be antidepressant-like in animals and human subjects, through either direct blockade of nAChRs or functional antagonism through desensitization. Thus, agents, like nicotine itself, and partial agonists of nAChRs, have the unique ability to regulate network properties of ensembles of neurons, through differential activation and desensitization of nAChRs on excitatory and inhibitory neuronal cell bodies and terminals. This may be a widespread mechanism underlying the effects of nAChRs on a number of different brain systems.