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

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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.