Nicotine consumption is regulated by a human polymorphism in dopamine neurons

Abstract

Smoking is the most important preventable cause of morbidity and mortality worldwide. Recent genome-wide association studies highlighted a human haplotype on chromosome 15 underlying the risk for tobacco dependence and lung cancer. Several polymorphisms in the CHRNA3-CHRNA5-CHRNB4 cluster coding for the nicotinic acetylcholine receptor (nAChR) α3, α5 and β4 subunits were implicated. In mouse models, we define a key role in the control of sensitivity to nicotine for the α5 subunit in dopaminergic (DAergic) neurons of the ventral tegmental area (VTA). We first investigated the reinforcing effects of nicotine in drug-naive α5(-/-) mice using an acute intravenous nicotine self-administration task and ex vivo and in vivo electrophysiological recordings of nicotine-elicited DA cell activation. We designed lentiviral re-expression vectors to achieve targeted re-expression of wild-type or mutant α5 in the VTA, in general, or in DA neurons exclusively. Our results establish a crucial role for α5*-nAChRs in DAergic neurons. These receptors are key regulators that determine the minimum nicotine dose necessary for DA cell activation and thus nicotine reinforcement. Finally, we demonstrate that a single-nucleotide polymorphism, the non-synonymous α5 variant rs16969968, frequent in many human populations, exhibits a partial loss of function of the protein in vivo. This leads to increased nicotine consumption in the self-administration paradigm. We thus define a critical link between a human predisposition marker, its expression in DA neurons and nicotine intake.

Nicotinic receptors mediate stress-nicotine detrimental interplay via dopamine cells’ activity

“…To test this hypothesis, we measured DA neuron responses to intravenous nicotine administration in vivo. In naive mice (NoSD), a single intravenous injection of 30 μg kg − 1 of nicotine, 11,18 enhanced the firing and bursting activities of VTA DA cells (Figure 1d and Supplementary Figure S1b-g). In striking contrast, defeated mice exhibited a virtually abolished response to nicotine evidenced by a lack of significant variation from baseline of firing and bursting patterns of DA neurons ( Figure 1d and Supplementary Figure S1b-g).…”

“…We have previously shown that the sensitivity of VTA DA cells to nicotineinduced increase of activity determines the reinforcing dose of nicotine. 18 The reduced response to nicotine exposure of VTA DA cells following SD may explain the high rates of tobacco consumption in stressed people or subjects suffering from mood disorders.…”

“…17 They determine the sensitivity of the reward system to a minimum dose of nicotine necessary for VTA DA cell activation and thus nicotine reinforcement. 18 VTA nAChRs subtypes are present on GABA and DA neurons, as well as on excitatory inputs, which results in a fine tuning of DA neuronal activity. 11,12 Preclinical and clinical studies implicate both high-and low-affinity nAChRs in stress-induced pathologies.…”

Role of β4* Nicotinic Acetylcholine Receptors in the Habenulo–Interpeduncular Pathway in Nicotine Reinforcement in Mice

“…Recordings from a single DA neuron were conducted after one to four injections of nicotine at different doses. DA cell firing was analyzed with respect to the average firing rate and the percentage of spikes within a burst, as previously described (Morel et al, 2014). To quantify nicotine effects, the maximum of fluctuation on a 3-min period after injection was determined.…”

Nicotinic Mechanisms Modulate Ethanol Withdrawal and Modify Time Course and Symptoms Severity of Simultaneous Withdrawal from Alcohol and Nicotine

“…In humans, certain single-nucleotide polymorphisms within this gene cluster represent risk alleles for nicotine dependence (Berrettini and Doyle, 2012), whereas other polymorphisms may influence alcohol-related behaviors (Choquet et al, 2013;Hallfors et al, 2013;Joslyn et al, 2008;Wang et al, 2009). In rodents, α5-, α3-, and β4-containing nAChRs influence the rewarding and aversive properties of nicotine (Fowler et al, 2011;Morel et al, 2013) and the symptoms accompanying its withdrawal (Jackson et al, 2013;Salas et al, 2004;Salas et al, 2009). As the present study also implicates MHB and IPN in ethanol withdrawal, it is tempting to speculate that nAChRs containing the α5, α3, and/or the β4 subunits within these brain structures are responsible for the phenomenon we observed.…”