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

中脑星形胶质细胞能量代谢调节药物诱发的多巴胺释放和行为

• 批准号: 10396967
• 负责人: Matthew J. Wanat
• 金额: $ 23.02万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10396967
• 关键词: Adenosine; Affect; Agonist; Animals; Astrocytes; Attenuated; Behavior; Behavioral; Behavioral Assay; Citric Acid Cycle; Cocaine; Corpus striatum structure; Coupled; Cues; Data; Dopamine; Energy Metabolism; Fluoroacetates; Impairment; Infusion procedures; Injections; Intake; Mediating; Midbrain structure; Neuraxis; Neuroglia; Neurons; Nucleus Accumbens; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Production; Property; Receptor Activation; Regulation; Rewards; Self Administration; Signal Pathway; Signal Transduction; Sum; Testing; Tricarboxylic Acids; Ventral Tegmental Area; Work; base; cocaine self-administration; designer receptors exclusively activated by designer drugs; dopamine system; dopaminergic neuron; experience; experimental study; gamma-Aminobutyric Acid; inhibitor; mesolimbic system; receptor

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.

滥用物质的行为影响部分由星形胶质细胞 - 神经元相互作用介导 中唇多巴胺系统。腹侧对盖区域（VTA）的星形胶质细胞与当地电路进行 抑制多巴胺神经元并减轻可卡因的奖励特性。但是，星形胶质细胞的能力 调节神经元活性取决于星形胶质细胞能量代谢。该提案中包含的数据 证明VTA星形胶质细胞产生的ATP在具有自我管理可卡因的动物中受到了损害。 因此，刺激中脑星形胶质细胞中的ATP产生可以抑制多巴胺神经元并抑制 由多巴胺系统控制的药物依赖性行为。该提议将检验以下假设 增强VTA星形胶质细胞中的能量代谢可减弱可卡因诱发的多巴胺释放，可卡因摄入量， 以及提示引起的可卡因寻求恢复。 激活星形胶质细胞中的GQ信号通路可促进ATP的产生。其中的实验 提案将采用化学遗传学和药理方法来选择性激活GQ信号传导 VTA星形胶质细胞。伏安法记录和行为测定将用于确定是否刺激GQ VTA星形胶质细胞中的信号传导减弱了多巴胺释放到可卡因奖励（AIM 1），并引起减少 可卡因的摄入量和提示引起的可卡因寻求恢复（AIM 2）。实验将进行 在存在胶质选择性三羧酸周期抑制剂的情况下，以评估能量的参与 星形胶质细胞GQ途径激活如何影响多巴胺释放和行为的代谢。一起，这个 提案将确定VTA星形胶质细胞中的能量代谢如何控制多巴胺释放和药物 - 依赖行为。

项目成果

Mitigating the impact of adolescence isolation on the development of social anxiety: A potential role for oxytocin.

• DOI: 10.3389/fnbeh.2022.1038236
• 发表时间: 2022
• 期刊: Frontiers in behavioral neuroscience
• 影响因子: 3

Critical periods when dopamine controls behavioral responding during Pavlovian learning.

• DOI: 10.1007/s00213-022-06182-w
• 发表时间: 2022-09
• 期刊: PSYCHOPHARMACOLOGY
• 影响因子: 3.4
• 作者: Lefner, Merridee J.;Stelly, Claire E.;Fonzi, Kaitlyn M.;Zurita, Hector;Wanat, Matthew J.
• 通讯作者: Wanat, Matthew J.