Differential Desensitization and Distribution of Nicotinic Acetylcholine Receptor Subtypes in Midbrain Dopamine Areas

Abstract

Although many psychopharmacological factors contribute to nicotine addiction, midbrain dopaminergic systems have received much attention because of their roles in reinforcement and associative learning. It is generally thought that the mesocorticolimbic dopaminergic system is important for the acquisition of behaviors that are reinforced by the salient drives of the environment or by the inappropriate stimuli of addictive drugs. Nicotine, as obtained from tobacco, can activate nicotinic acetylcholine receptors (nAChRs) and excite midbrain neurons of the mesocorticolimbic system. Using midbrain slices from rats, wild-type mice, and genetically engineered mice, we have found differences in the nAChR currents from the ventral tegmental area (VTA) and the substantia nigra compacta (SNc). Nicotinic AChRs containing the alpha7 subunit (alpha7* nAChRs) have a low expression density. Electrophysiological analysis of nAChR currents, autoradiography of [125I]-alpha-bungarotoxin binding, and in situ hybridization revealed that alpha7* nAChRs are more highly expressed in the VTA than the SNc. In contrast, beta2* nAChRs are move evenly distributed at a higher density in both the VTA and SNc. At the concentration of nicotine obtained by tobacco smokers, the slow components of current (mainly mediated by beta2* nAChRs) become essentially desensitized. However, the minority alpha7* component of the current in the VTA/SNc is not significantly desensitized by nicotine in the range < or =100 nm. These results suggest that nicotine, as obtained from tobacco, can have multiple effects on the midbrain areas by differentially influencing dopamine neurons of the VTA and SNc and differentially desensitizing alpha7* and non-alpha7 nAChRs.

Blockade of central nicotine acetylcholine receptor signaling attenuate ghrelin-induced food intake in rodents

“…However, there are indications that nicotine addiction causes desensitization and a subsequent up regulation of nAChRs (Mansvelder et al, 2002, Wooltorton et al, 2003, Tapper et al, 2006 and that the hyperphagia following smoking cessation could very likely be due to increased expression of and hypersensitivity of nAChRs (Jo et al, 2002), thereby increasing the output of the endogenous cholinergic pathways involved in reinforcement and reward seeking. In line with a role for nAChRs in weight gain following smoking cessation long term treatment with mecamylamine decreases body weight in genetic and hypothalamic lesion models of obesity, effects attributed entirely to a decrease in food intake (Dulloo and Miller, 1986).…”

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

“…a7*-containing receptors in the VTA/SNc are much less susceptible than a4b2* to desensitization at the daily blood and brain nicotine concentrations of smokers. 171 Up to 500 nM concentration of nicotine (beyond the nicotine concentration range of chronic smokers, as discussed above) causes very little desensitization of VTA/SNc a7*-nAChR currents. 171 As mentioned in Section 'nAChR subunits', DA release in the NAc is enhanced by glutamatergic excitatory drive from the laterodorsal tegmentum and pedunculopontine tegmentum.…”

“…As even low levels of nicotine exposure results in substantial occupancy and desensitization of brain a4b2*-nAChRs, it is plausible that high-affinity nicotine binding to a4b2*-receptors is not in itself a sufficient mechanism to explain continued smoking in nicotine-addicted individuals throughout the day. 16,171 On the other hand, nAChRs with low affinity for nicotine are not susceptible to rapid saturation, and can continue functioning and responding throughout the day. Thus, selective desensitization of some nAChR subtypes, while maintaining the activity and functionality of others may play a significant role in ND.…”

α6-Containing Nicotinic Acetylcholine Receptors Dominate the Nicotine Control of Dopamine Neurotransmission in Nucleus Accumbens

“…However, work to date has not previously been able to address the striking functional dominance of a6*-nAChRs in the control of DA release in NAc that we reveal here. For example, nAChR subunit expression data in the DA cell body regions (VTA and SNc) that give rise to ascending DA projections to NAc and CPu appears similar between cell groups (for non-a7 subunits) (Azam et al, 2002;Azam et al, 2007;Champtiaux et al, 2003;Klink et al, 2001;Wooltorton et al, 2003) and studies of nicotine-evoked [ 3 H]-DA release report a a-CtxMII-sensitive fraction of release that is similar in synaptosomes derived from NAc or CPu (rodents: 40-55% (Champtiaux et al, 2003;Grady et al, 2002); monkeys: 70-80% (McCallum et al, 2005)). However, differences between nicotine-evoked [ 3 H]-DA release studies and the physiological nAChR function identified in this study in an endogenous setting should be expected.…”