A Novel Delta Opioid Receptor Antagonist, SoRI-9409, Produces a Selective and Long-Lasting Decrease in Ethanol Consumption in Heavy-Drinking Rats

• Published in: Biological psychiatry (1969) Vol. 64; no. 11; pp. 974 - 981
• Main Authors: Nielsen, Carsten K, Simms, Jeffrey A, Pierson, Haley B, Li, Rui, Saini, Surendra K, Ananthan, Subramaniam, Bartlett, Selena E
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-12-2008; Elsevier
• Subjects: Addictive behaviors; Adult and adolescent clinical studies; Alcohol Drinking - drug therapy; Alcohol Drinking - psychology; Alcoholism; Alcoholism - drug therapy; Alcoholism - physiopathology; Alcoholism and acute alcohol poisoning; Animals; Behavior, Animal - drug effects; Biological and medical sciences; Brain - drug effects; Brain - ultrastructure; Choice Behavior - drug effects; Disease Models, Animal; Dose-Response Relationship, Drug; ethanol; Ethanol - administration & dosage; Food Preferences - drug effects; Guanosine 5'-O-(3-Thiotriphosphate) - pharmacology; Male; Medical sciences; Morphine Derivatives - therapeutic use; Naloxone - therapeutic use; naltrexone; Narcotic Antagonists - therapeutic use; Narcotics - pharmacology; opioid receptor antagonist; Protein Binding - drug effects; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Rats; Rats, Long-Evans; Receptors, Opioid, delta - antagonists & inhibitors; SoRI-9409; Sucrose - administration & dosage; Toxicology; opioid receptor antagonist; naltrexone; rats; ethanol; Alcoholism; SoRI-9409; Morphinan derivatives; Narcotic antagonist; Ethanol; Rat; Opioid receptor; Rodentia; Naltrexone; δ Opioid receptor; Alcoholic beverage; Vertebrata; Mammalia; Animal
• DOI: 10.1016/j.biopsych.2008.07.018
• EISSN: 1873-2402
• ISSN: 0006-3223

Background Naltrexone, a compound with high affinity for the μ opioid receptor (MOP-R) reduces alcohol consumption. SoRI-9409 is a derivative of naltrexone that has highest affinity at δ opioid receptors (DOP-Rs). We have investigated the effects of SoRI-9409 on ethanol consumption to determine the consequences of altering the naltrexone compound to a form with increased efficacy at DOP-Rs. Methods Effects of the opioid receptor antagonists, SoRI-9409 (0–30 mg/kg, IP), naltrexone (0–30 mg/kg, IP), or naltrindole (0–10 mg/kg, IP) on ethanol consumption was measured in high- and low-ethanol–consuming rats with two different drinking paradigms. SoRI-9409-, naltrexone-, and naltrindole-mediated inhibition of DOP-R–stimulated [35 S]GTPγS binding was measured in brain membranes prepared from high-ethanol–consuming rats. The effects of SoRI-9409 on morphine-mediated analgesia, conditioned place preference, and anxiety were also examined. Results In high- but not low-ethanol–consuming animals, SoRI-9409 is threefold more effective and selective at reducing ethanol consumption when compared with naltrexone or naltrindole for up to 24 hours. SoRI-9409 administered daily for 28 days continuously reduced ethanol consumption, and when the administration of SoRI-9409 was terminated, the amount of ethanol consumed remained lower compared with vehicle-treated animals. Furthermore, SoRI-9409 inhibits DOP-R–stimulated [35 S]GTPγS binding in brain membranes of high-ethanol–consuming rats. Conclusions SoRI-9409 causes selective and long-lasting reductions of ethanol consumption. This suggests that compounds that have high affinity for DOP-Rs such as SoRI-9409 might be promising candidates for development as a novel therapeutic for the treatment of alcoholism.