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

滥用物质的行为效应部分是由脑内星形胶质细胞-神经元相互作用介导的。 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回路， 抑制多巴胺神经元并减轻可卡因的奖赏特性。然而，星形胶质细胞 调节神经元活动依赖于星形胶质细胞的能量代谢。本提案中包括的数据 证明了VTA星形胶质细胞产生的ATP在自我施用可卡因的动物中受损。 因此，刺激中脑星形胶质细胞中ATP的产生可以抑制多巴胺神经元， 由多巴胺系统控制的药物依赖行为。这一提议将检验以下假设： 增强腹侧被盖区星形胶质细胞的能量代谢减弱可卡因诱发的多巴胺释放，可卡因摄入， 以及线索诱导的可卡因寻求的恢复。 激活星形胶质细胞中的Gq信号通路促进ATP的产生。这个实验 该提案将采用化学发生学和药理学方法来选择性地激活Gq信号传导， 腹侧被盖区星形胶质细胞。伏安法记录和行为测定将用于确定刺激Gq 腹侧被盖区星形胶质细胞中的信号传导减弱了可卡因奖赏的多巴胺释放（Aim 1）， 可卡因摄入和线索诱导的可卡因寻求恢复（目标2）。将进行实验 在存在胶质细胞选择性三羧酸循环抑制剂的情况下， 研究星形胶质细胞Gq通路活化如何影响多巴胺释放和行为。在一起，这 该提案将确定腹侧被盖区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.