A novel, potent, orally‐bioavailable nociceptin‐1 receptor antagonist reduces ethanol self‐administration and ethanol‐seeking in animal models of alcohol addiction (656.2)

Background: The receptor for nociceptin/orphanin-FQ (NOP) is localized in the mesolimbic reward pathway and has been suggested to play a role in addiction and motivated behavior. We characterize here a novel, potent, orally-bioavailable NOP antagonist in several ethanol self-administration models. Methods: Compound 1 was evaluated in homecage ethanol self-administration models, progressive ratio operant self-administration, stress-induced reinstatement to ethanol-seeking, and in vivo microdialysis. Results: Compound 1 dose-dependently reduced homecage ethanol self-administration in both P and msP rats, without affecting food or water intake. Compound 1 also attenuated progressive ratio operant responding and breakpoints in P rats. Stress-induced reinstatement of ethanol-seeking in msP rats was completely blocked by compound 1. Furthermore, compound 1 blocked ethanol-induced dopamine release in the nucleus accumbens. Conclusions: Compound 1 demonstrates efficacy in attenuating ethanol self-administration and stress-induced ethanol-seeking in two different lines of rats that exhibit excessive ethanol consumption. Compound 1 also blocks the motivation to consume ethanol and ethanol-stimulated increases in extracellular dopamine levels in the nucleus accumbens, suggesting potential therapeutic utility of NOP receptor antagonists in treating alcohol addiction.