Neuropeptide Y1 receptor expressing circuit from the central amygdala to lateral hypothalamus modulates binge-like ethanol consumption in a sex-dependent manner.

Background: Alcohol use disorder is characterized by maladaptive patterns of alcohol consumption, with emerging evidence suggesting that neuropeptide Y (NPY) signaling through Y1 and Y2 receptors (Y1R and Y2R) within the central amygdala (CeA) plays a critical role in modulating ethanol intake. The current experiments investigate the neural mechanisms underlying binge-like ethanol drinking, focusing on the involvement of Y1R+ CeA-to-lateral hypothalamus (LH) projections, dynamic interactions between Y1R and Y2R within the CeA, and the impact of chronic ethanol exposure on Y1R protein expression.

Methods: NPY1R-ires-cre mice received LH cannulation, were infused with cre-dependent inhibitory (Gi) Designer Receptor Exclusively Activated by Designer Drug (DREADD) or control virus into the CeA, and went through drinking in the dark (DID). Other animals were treated intra-CeA with an NPY overexpression vector (FIB-NPY) or control, and went through DID, intermittent access to ethanol (IAE), and open-field testing. Viral placements and receptor targets were assessed via qPCR. Finally, mice went through six cycles of DID, and Y1R immunohistochemical (IHC) labeling on neurons was assessed for animals sacrificed after the final DID session or after a 24-h period of abstinence.

Results: Chemogenetic inhibition of Y1R+ CeA-LH projections selectively reduced binge-like ethanol drinking in male mice without affecting female mice. Viral NPY overexpression revealed behavioral effects and predictive relationships between receptor mRNA expression and intake patterns. Although no significant differences were found in Y1R/NeuN colocalization across sex and treatment groups, correlational analyses revealed that Y1R expression varied with individual ethanol consumption.

Conclusions: Collectively, these results support a model wherein Y1R signaling within the CeA regulates ethanol consumption through circuit-specific mechanisms and broader neuroadaptive changes influenced by sex and individual drinking patterns. This research advances our understanding of the neurobiological mechanisms underlying binge-like ethanol intake and highlights the complex, sex-dependent roles of NPY-Y1R and Y2R signaling in the CeA.