The Effects of Overexpression of Neuropeptide Y (NPY) in Binge-Like Alcohol Consumption

Abstract

Abstract

Binge drinking is a risky pattern of alcohol (ethanol) consumption associated with a variety of negative outcomes, including the development of alcohol use disorder (AUD). Neuropeptide Y (NPY) signaling in the insular cortex is thought to be involved in modulating this behavior. However, the precise effects of increased NPY release from neurons in the insular cortex on binge-like ethanol consumption and dependence remain an important area of investigation. Male and female mice were used to model binge-like ethanol and sucrose consumption. A viral vector containing NPY bound to fibronectin, an extracellular matrix protein, was utilized to force the secretion of NPY, thereby increasing NPY signaling in the insular cortex. To model consumption and dependence, mice underwent a two-bottle choice paradigm (ethanol and water) for 4 weeks, followed by 2 weeks of the "Drinking in the Dark" (DID) paradigm for ethanol, and 2 weeks of DID for sucrose. Blood Ethanol Concentrations (BECs) were collected at multiple time points to monitor intoxication levels. Brain tissue was subsequently extracted and sectioned using a cryostat, and quantitative polymerase chain reaction (qPCR) was performed to assess RNA and validate/quantify virus expression. Daily body weights and fluid intake (bottle weights for ethanol, water, and sucrose) were successfully recorded across the duration of the paradigms, alongside corresponding BECs collected during the testing weeks. Results indicate that NPY over-expression significantly increased continuous, long-term ethanol consumption, specifically emerging on days 5 through 9 of the 2-Bottle Choice (2BC) test. Importantly, this effect was highly specific to ethanol, as NPY over-expression did not change concurrent water intake during the same testing period. Furthermore, the over-expression had no significant impact on short-term, binge-like ethanol consumption or natural reward intake, as measured by the limited-access Drinking in the Dark (DID) paradigms for both ethanol and sucrose. These findings reveal a paradigm-specific dissociation, demonstrating that NPY signaling regulates alcohol intake through access-dependent mechanisms, driving increases in chronic drinking models (2BC) but not in short-term binge models (DID). By pinpointing a brain pathway that specifically increases the drive to drink alcohol without affecting normal hydration or sugar cravings, these results identify a highly promising target for the future development of targeted medications to treat alcohol addiction.