McCall Nora M, Kotecki Lydia, Dominguez-Lopez Sergio, Marron Fernandez de Velasco Ezequiel, Carlblom Nicholas, Sharpe Amanda L, Beckstead Michael J, Wickman Kevin
Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, USA.
Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA.
Neuropsychopharmacology. 2017 Feb;42(3):707-715. doi: 10.1038/npp.2016.138. Epub 2016 Jul 29.
The increase in dopamine (DA) neurotransmission stimulated by in vivo cocaine exposure is tempered by G protein-dependent inhibitory feedback mechanisms in DA neurons of the ventral tegmental area (VTA). G protein-gated inwardly rectifying K (GIRK/Kir3) channels mediate the direct inhibitory effect of GABA receptor (GABAR) and D DA receptor (DR) activation in VTA DA neurons. Here we examined the effect of the DA neuron-specific loss of GIRK channels on DR-dependent regulation of VTA DA neuron excitability and on cocaine-induced, reward-related behaviors. Selective ablation of Girk2 in DA neurons did not alter the baseline excitability of VTA DA neurons but significantly reduced the magnitude of DR-dependent inhibitory somatodendritic currents and blunted the impact of DR activation on spontaneous activity and neuronal excitability. Mice lacking GIRK channels in DA neurons exhibited increased locomotor activation in response to acute cocaine administration and an altered locomotor sensitization profile, as well as increased responding for and intake of cocaine in an intravenous self-administration test. These mice, however, showed unaltered cocaine-induced conditioned place preference. Collectively, our data suggest that feedback inhibition to VTA DA neurons, mediated by GIRK channel activation, tempers the locomotor stimulatory effect of cocaine while also modulating the reinforcing effect of cocaine in an operant-based self-administration task.
体内可卡因暴露所刺激的多巴胺（DA）神经传递增加，会受到腹侧被盖区（VTA）DA神经元中G蛋白依赖性抑制反馈机制的调节。G蛋白门控内向整流钾（GIRK/Kir3）通道介导VTA DA神经元中GABA受体（GABAR）和D DA受体（DR）激活的直接抑制作用。在此，我们研究了DA神经元特异性缺失GIRK通道对DR依赖性调节VTA DA神经元兴奋性以及对可卡因诱导的、与奖赏相关行为的影响。DA神经元中Girk2的选择性消融并未改变VTA DA神经元的基线兴奋性，但显著降低了DR依赖性抑制性树突-体细胞电流的幅度，并减弱了DR激活对自发活动和神经元兴奋性的影响。DA神经元中缺乏GIRK通道的小鼠在急性给予可卡因后表现出运动激活增加、运动敏感化特征改变，以及在静脉自我给药试验中对可卡因的反应和摄入量增加。然而，这些小鼠在可卡因诱导的条件性位置偏爱方面未表现出改变。总体而言，我们的数据表明，由GIRK通道激活介导的对VTA DA神经元的反馈抑制，可调节可卡因的运动刺激作用，同时也可在基于操作性的自我给药任务中调节可卡因的强化作用。
