Friday, April 19, 2024
4/19/2024
Abstract New neurobiological understanding of and therapeutic targets for alcohol use disorder (AUD) are needed. Advances in the biology of AUD indicate that lipid signaling is a key regulator of ethanol use and withdrawal behavior via specialized G-protein coupled membrane receptors, transport proteins, and, more recently, nuclear transcription factors. PPARs are lipid-sensing transcription factors encoded by 3 genes (PPAR¿, PPAR¿, PPAR¿¿¿) that were identified for their roles in peripheral regulation of fuel homeostasis. PPAR¿ and PPAR¿¿ have received intense attention for their anti-addiction-like actions. Yet, the central role of the more abundantly expressed brain PPAR¿¿receptor isotype in the control of compulsive alcohol use behaviors is entirely unknown. Here, we test the overarching hypothesis that brain peroxisome proliferator-activated receptors-delta subtype (PPAR¿) inhibits compulsive ethanol use and negative emotional withdrawal. Studies use the chronic intermittent ethanol vapor exposure model to elicit escalated and aversion-resistant ethanol intake and withdrawal anxiety- and irritability-like behavior to yield new translational insights into AUD. We combine novel brain-penetrant and translatable PPAR¿ agonist (KD3010, T3D-959) and brain-restricted and site-specific cre/lox conditional PPAR¿ knockouts to test the causal role and central sites of PPAR¿¿action in compulsive-like alcohol use phenotypes. The resulting data and novel genetic and translationally-relevant pharmacological tools for this understudied PPARd isotype will lay the groundwork for cell type- and anatomically-specific mechanistic studies and may lead to interventions for people affected by compulsive alcohol use and other forms of addiction.
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