It is not "either/or": activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood

Abstract

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.

Figure 1. Activation and desensitization contribute to physiological effects of nicotine in the mesolimbic circuitry

A. In the absence of nicotine, the endogenous neurotransmitter acetylcholine (ACh) is released in the ventral tegmental area (VTA) from terminals of cholinergic brainstem nuclei including the pedunculopontine tegmental area (Lança et al., 2000). The mixed cholinergic stimulation of glutamatergic (Glu) and GABAergic (GABA) terminals in the VTA supports both tonic and phasic activity of dopaminergic (DA) neurons (Grenhoff and Svensson, 1992). In addition, cholinergic interneurons release ACh onto the terminals of dopaminergic neurons (DA) in the nucleus accumbens (NAc) (Zhou et al., 2001). At baseline, ACh in the striatum allows tonic firing of DA neurons to result in significant DA release (Rice and Cragg, 2004; Zhang and Sulzer, 2004). B. The effect of nicotine in the VTA is initially to increase the firing rate of DA neurons (Grenhoff et al., 1986; Picciotto et al., 1998). The increase in firing rate of VTA neurons involves glutamate release (Grillner and Svensson, 2000; Schilstrom et al., 1998), and the nicotine-mediated increase in glutamate release does not desensitize during continuous administration of nicotine (Mansvelder et al., 2002; Wooltorton et al., 2003). By contrast, the ability of nicotine to increase GABA release in the VTA undergoes rapid desensitization (Mansvelder et al., 2002; Wooltorton et al., 2003). In the NAc, nicotine initially increases release of DA from terminals, but these nAChRs undergo rapid desensitization (Grady et al., 1994; Rowell and Hillebrand, 1994). Desensitization of these nAChRs decreases the ability of tonic firing to release DA in the NAc, but maintains the effect of phasic firing on DA release, thereby acting as a high pass filter for events increasing phasic firing (Rice and Cragg, 2004; Zhang and Sulzer, 2004). Thus, nicotine acts in the VTA to increase phasic firing, and in the NAc to increase the salience of that increase in phasic firing.