Midbrain astrocyte energy metabolism regulating drug-evoked dopamine release and behavior

滥用物质的行为影响部分是通过星形胶质细胞-神经元之间的相互作用 中脑边缘多巴胺系统。腹侧被盖区(VTA)的星形胶质细胞参与局部环路 抑制多巴胺神经元，减轻可卡因的奖赏特性。然而，星形胶质细胞的能力 神经活动的调节依赖于星形胶质细胞的能量代谢。本建议书中包含的数据 证明了在自我注射可卡因的动物中，VTA星形胶质细胞产生的ATP受到损害。 因此，刺激中脑星形胶质细胞产生ATP可以抑制多巴胺神经元并抑制 受多巴胺系统控制的药物依赖行为。这项提议将检验这样一个假设： 增强VTA星形胶质细胞的能量代谢可减少可卡因引起的多巴胺释放，可卡因摄入量， 以及线索诱导的可卡因寻找的恢复。 激活星形胶质细胞中的GQ信号通路可促进三磷酸腺苷的产生。这里面的实验 Proposal将使用化学遗传学和药理学方法选择性地激活GQ信号在 VTA星形胶质细胞。将利用伏安法记录和行为分析来确定是否刺激GQ VTA星形胶质细胞中的信号减弱多巴胺对可卡因奖励的释放(目标1)并引起 可卡因摄取和线索诱导的恢复可卡因寻找(目标2)。我们将进行一些实验 在胶质细胞选择性三羧酸循环抑制剂存在的情况下，评估能量的参与 星形胶质细胞GQ通路激活如何影响多巴胺释放和行为的代谢。总而言之，这 该提案将确定VTA星形胶质细胞的能量代谢如何控制多巴胺的释放和药物- 依赖行为。

The behavioral effects of abused substances are mediated in part by astrocyte-neuron interactions within the mesolimbic dopamine system. Astrocytes in the ventral tegmental area (VTA) engage a local circuit to inhibit dopamine neurons and mitigate the rewarding properties of cocaine. However, the ability for astrocytes to regulate neuronal activity depends upon astrocyte energy metabolism. Data included in this proposal demonstrates that ATP production by VTA astrocytes is impaired in animals that had self-administered cocaine. Stimulating ATP production in midbrain astrocytes could therefore inhibit dopamine neurons and suppress drug-dependent behaviors controlled by the dopamine system. This proposal will test the hypothesis that enhancing energy metabolism in VTA astrocytes attenuates cocaine-evoked dopamine release, cocaine intake, and the cue-induced reinstatement of cocaine seeking. Activating Gq signaling pathways in astrocytes promotes the production of ATP. The experiments in this proposal will employ both chemogenetic and pharmacological approaches to selectively activate Gq signaling in VTA astrocytes. Voltammetry recordings and behavioral assays will be utilized to determine if stimulating Gq signaling in VTA astrocytes attenuates dopamine release to cocaine rewards (Aim 1) and elicits a reduction in cocaine intake and the cue-induced reinstatement of cocaine seeking (Aim 2). Experiments will be performed in the presence of glia-selective tricarboxylic acid cycle inhibitors to assess the involvement of energy metabolism in how astrocyte Gq pathway activation affects dopamine release and behavior. Together, this proposal will establish how energy metabolism in VTA astrocytes controls dopamine release and drug- dependent behavior.