| Summary: | Cocaine and oxycodone use disorders represent urgent public health burdens, with limited treatment options for opioid dependence and no approved pharmacotherapies for cocaine-related disorders, highlighting the critical need to uncover novel molecular targets in the addiction neurocircuitry. The basolateral amygdala (BLA) modulates withdrawal and drug-seeking behaviors in substance use disorders (SUDs), but the molecular drivers of these effects are poorly understood. Here, we investigated the role of corticotrophin-releasing hormone binding protein (CRHBP) in the BLA using viral-mediated knockdown, single-nucleus RNA sequencing (snRNA-seq), and operant self-administration in rats. snRNA-seq revealed Crhbp expression in BLA somatostatin-positive interneurons, with minimal presence in the central amygdala. Crhbp knockdown in the BLA decreased cocaine self-administration and cue-induced reinstatement, suggesting a role in sustaining stimulant addiction. Conversely, it increased oxycodone intake and progressive ratio breakpoints, indicating heightened opioid reinforcement, while also elevating cue-induced reinstatement after 24 h of abstinence, reflecting enhanced opioid-seeking. These opposing effects highlight Crhbp’s substance-specific influence on addiction-related behaviors in the BLA. Our findings position Crhbp as a potential therapeutic target gene for tailored interventions in cocaine and opioid SUDs.
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