| First Author | Yang K | Year | 2023 |
| Journal | Neuropharmacology | Volume | 235 |
| Pages | 109547 | PubMed ID | 37116611 |
| Mgi Jnum | J:336157 | Mgi Id | MGI:7487846 |
| Doi | 10.1016/j.neuropharm.2023.109547 | Citation | Yang K, et al. (2023) CHRNA5 gene variation affects the response of VTA dopaminergic neurons during chronic nicotine exposure and withdrawal. Neuropharmacology 235:109547 |
| abstractText | Nicotine is the principal psychoactive component in tobacco that drives addiction through its action on neuronal nicotinic acetylcholine receptors (nAChR). The nicotinic receptor gene CHRNA5, which encodes the alpha5 subunit, is associated with nicotine use and dependence. In humans, the CHRNA5 missense variant rs16969968 (G > A) is associated with increased risk for nicotine dependence and other smoking-related phenotypes. In rodents, alpha5-containing nAChRs in dopamine (DA) neurons within the ventral tegmental area (VTA) powerfully modulate nicotine reward and reinforcement. Although the neuroadaptations caused by long-term nicotine exposure are being actively delineated at both the synaptic and behavioral levels, the contribution of alpha5-containing nAChRs to the cellular adaptations associated with long-term nicotine exposure remain largely unknown. To gain insight into the mechanisms behind the influence of alpha5-containing nAChRs and the rs16969968 polymorphism on nicotine use and dependence, we used electrophysiological approaches to examine changes in nAChR function arising in VTA neurons during chronic nicotine exposure and multiple stages of nicotine withdrawal. Our results demonstrate that CHRNA5 mutation leads to profound changes in VTA nAChR function at baseline, during chronic nicotine exposure, and during short-term and prolonged withdrawal. Whereas nAChR function was suppressed in DA neurons from WT mice undergoing withdrawal relative to drug-naive or nicotine-drinking mice, alpha5-null mice exhibited an increase in nAChR function during nicotine exposure that persisted throughout 5-10 weeks of withdrawal. Re-expressing the hypofunctional rs16969968 CHRNA5 variant in alpha5-null VTA DA neurons did not rescue the phenotype, with alpha5-SNP neurons displaying a similar increased response to ACh during nicotine exposure and early stages of withdrawal. These results demonstrate the importance of VTA alpha5-nAChRs in the response to nicotine and implicate them in the time course of withdrawal. |
