Abstract
BACKGROUND: Alcohol use disorder (AUD) is characterized by compulsive alcohol consumption and negative emotional states during withdrawal, often perpetuating a cycle of addiction through arousal dysfunction. The hypocretin/orexin (HCRT) neuropeptide system is a key regulator of arousal that is implicated in these processes, particularly in its interactions with corticotropin-releasing factor (CRF) neurons within the bed nucleus of the stria terminalis (BNST). METHODS: Using CRF-specific genetic deletion of Hcrt r 1 and/or Hcrt r 2 receptors in mice combined with behavioral and electrophysiological approaches, we investigated the role of HCRT receptor signaling in CRF neurons in modulating alcohol intake, anxiety behaviors, and BNST excitability, with a focus on sex-specific differences. RESULTS: We found that deletion of Hcrt r 1 significantly reduced alcohol intake, with sex-specific effects on BNST excitability and synaptic drive. CRF-specific Hcrt r 2 deletion, while not affecting alcohol consumption, decreased baseline anxiety-like behaviors in males relative to females. Moreover, the double deletion of both HCRT receptors from CRF neurons led to reduced alcohol drinking in males (while tending to increase alcohol drinking in females) and dampened anxiety behaviors and BNST excitability in both sexes during protracted withdrawal. CONCLUSIONS: These findings suggest that HCRT signaling in CRF neurons plays a critical role in the persistence of excessive alcohol consumption and the development of negative affective states, with distinct contributions from HcrtR1 and HcrtR2. The observed sex-specific differences underscore the need for tailored therapeutic approaches targeting the HCRT system in the treatment of AUD. In this study, we explored how 2 brain systems - one controlling stress (CRF) and another regulating arousal and wakefulness (hypocretin), work together to influence alcohol drinking and anxiety. By turning off specific hypocretin receptors in stress-sensitive neurons in mice, we found reduced alcohol drinking and anxiety-related behaviors, with some differences between females and males. These effects were also linked to changes in brain activity in a region called the BNST, part of the extended amygdala emotional network. Our findings suggest that targeting these systems could lead to better, more personalized treatments for alcohol use disorder.