Upregulation of nAChRs and Changes in Excitability on VTA Dopamine and GABA Neurons Correlates to Changes in Nicotine-Reward-Related Behavior

Previous reports indicate that nicotine reward is mediated through alpha 4 beta 2*, alpha 6 beta 2*, and alpha 4 alpha 6 beta 2* nicotinic acetylcholine receptors (nAChRs; * indicates that additional nAChR subunits may be present). Little is known about alpha 4 alpha 6 beta 2* nAChR involvement in reward and reinforcement because of a lack of methods that allow the direct investigation of this particular nAChR subtype. Here, we use male and female mice that contain alpha 4-mCherry and a6- GFP nAChR subunits to show that concentrations of nicotine sufficient to evoke reward-related behavior robustly upregulate alpha 4* and alpha 4 alpha 6* nAChRs on midbrain dopamine (DA) and GABA neurons. Furthermore, the extent of alpha 4 alpha 6* nAChR upregulation on ventral tegmental area (VTA) DA neurons aligns with the magnitude of nicotine reward-related behavior. We also show that the upregulation of nAChRs is accompanied by a functional change in firing frequency of both DA and GABA neurons in the VTA that is directly linked to nicotine reward-related behavior.