Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Neuron. 2023 Apr 5;111(7):1104-1117.e6. doi: 10.1016/j.neuron.2022.12.033. Epub 2023 Jan 20.
Addictive drugs increase ventral tegmental area (VTA) dopamine (DA) neuron activity through distinct cellular mechanisms, one of which involves disinhibition of DA neurons by inhibiting local GABA neurons. How drugs regulate VTA GABA neuron activity and drive addictive behaviors remains poorly understood. Here, we show that astrocytes control VTA GABA neuron activity in cocaine reward via tonic inhibition in mice. Repeated cocaine exposure potentiates astrocytic tonic GABA release through volume-regulated anion channels (VRACs) and augments tonic inhibition of VTA GABA neurons, thus downregulating their activities and disinhibiting nucleus accumbens (NAc) projecting DA neurons. Attenuation of tonic inhibition by either deleting Swell1 (Lrrc8a), the obligatory subunit of VRACs, in VTA astrocytes or disrupting δ subunit of GABA receptors in VTA GABA neurons reduces cocaine-evoked changes in neuron activity, locomotion, and reward behaviors in mice. Together, our findings reveal the critical role of astrocytes in regulating the VTA local circuit and cocaine reward.
成瘾性药物通过不同的细胞机制增加腹侧被盖区（VTA）多巴胺（DA）神经元的活性，其中一种机制涉及通过抑制局部 GABA 神经元来抑制 DA 神经元。然而，药物如何调节 VTA GABA 神经元的活性并驱动成瘾行为仍知之甚少。在这里，我们发现在小鼠中，星形胶质细胞通过持续抑制来控制可卡因奖赏中的 VTA GABA 神经元活性。反复可卡因暴露通过体积调节阴离子通道（VRAC）增强星形胶质细胞持续 GABA 释放，并增强 VTA GABA 神经元的持续抑制，从而下调其活性并去抑制伏隔核（NAc）投射 DA 神经元。通过在 VTA 星形胶质细胞中删除 VRAC 的必需亚基 Swell1（Lrrc8a）或在 VTA GABA 神经元中破坏 GABA 受体的 δ 亚基来减弱持续抑制，可减少可卡因引起的小鼠神经元活动、运动和奖赏行为的变化。总之，我们的研究结果揭示了星形胶质细胞在调节 VTA 局部回路和可卡因奖赏中的关键作用。
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