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

Abstract

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.