PPARdelta receptors and alcohol use phenotypes

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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 PPARδ 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.