Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611.
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27101.
eNeuro. 2019 Dec 4;6(6). doi: 10.1523/ENEURO.0298-19.2019. Print 2019 Nov/Dec.
Ventral tegmental area (VTA) neurons receive glutamatergic and/or GABAergic input from other local neurons within the VTA. Nicotinic acetylcholine receptor (nAChR) activity is capable of modulating such intra-VTA transmission, but the mechanisms are unclear. Here, we isolated monosynaptic glutamate or GABA transmission from mouse medial VTA (mVTA) to lateral VTA (latVTA) using pharmacology and optogenetics, and we studied the ability of nicotine to modulate these modes of transmission. The action of nicotine on mVTA to latVTA glutamate transmission was bidirectional; nicotine enhanced glutamate release in half of the recorded latVTA cells and inhibited release in the other half. Nicotine-mediated reduction in glutamate release was reversed by blockade of GABA receptors. This, coupled with expression data demonstrating coexpression of vesicular glutamate transporter 2 (VGluT2) and glutamate decarboxylase 2 (Gad2) in mVTA neurons, suggests that nicotine is able to stimulate GABA corelease from mVTA VGluT2 neurons. Nicotine had an altogether different effect on mVTA to latVTA GABA release from Gad2 cells; nicotine suppressed GABA release from mVTA Gad2 terminals in nearly all cells tested. Together, these data uncover a complex system of local circuitry in the VTA that is modulated by nAChR activity. These actions of nicotine, which occurred at concentrations of nicotine found in the artificial CSF of cigarette smokers, may play a role in the adaptive response of the reward system to repeated nicotine exposure.
腹侧被盖区 (VTA) 神经元接收来自 VTA 内其他局部神经元的谷氨酸能和/或 GABA 能输入。烟碱型乙酰胆碱受体 (nAChR) 活性能够调节这种 VTA 内的传递，但机制尚不清楚。在这里，我们使用药理学和光遗传学从小鼠内侧 VTA (mVTA) 分离出单突触谷氨酸或 GABA 传递到外侧 VTA (latVTA)，并研究了尼古丁调节这些传递模式的能力。尼古丁对 mVTA 到 latVTA 谷氨酸传递的作用是双向的；尼古丁在一半记录的 latVTA 细胞中增强谷氨酸释放，而在另一半细胞中抑制释放。尼古丁介导的谷氨酸释放减少被 GABA 受体阻断所逆转。这一点，加上表达数据表明 mVTA 神经元中囊泡谷氨酸转运体 2 (VGluT2) 和谷氨酸脱羧酶 2 (Gad2) 的共表达，表明尼古丁能够刺激 mVTA VGluT2 神经元的 GABA 共释放。尼古丁对 mVTA 到 Gad2 细胞的 latVTA GABA 释放的影响完全不同；尼古丁几乎抑制了所有测试细胞中 mVTA Gad2 末梢的 GABA 释放。总之，这些数据揭示了 VTA 中局部回路的一个复杂系统，其受到 nAChR 活性的调节。这些尼古丁的作用发生在吸烟者人工脑脊液中发现的尼古丁浓度下，可能在奖励系统对重复尼古丁暴露的适应性反应中发挥作用。
