Neurokinin 1 Receptor Antagonism as a Possible Therapy for Alcoholism

• Published in: Science (American Association for the Advancement of Science) Vol. 319; no. 5869; pp. 1536 - 1539
• Main Authors: George, David T, Gilman, Jodi, Hersh, Jacqueline, Thorsell, Annika, Herion, David, Geyer, Christopher, Peng, Xiaomei, Kielbasa, William, Rawlings, Robert, Brandt, John E, Gehlert, Donald R, Tauscher, Johannes T, Hunt, Stephen P, Hommer, Daniel, Heilig, Markus
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 14.03.2008; The American Association for the Advancement of Science
• Subjects: Addictive behaviors; Adult; Adult and adolescent clinical studies; Aged; alcohol abuse; Alcohol drinking; Alcohol Drinking - drug therapy; Alcohol Education; Alcohol related disorders; Alcoholic beverages; Alcoholism; Alcoholism - drug therapy; Alcoholism and acute alcohol poisoning; Alcohols; Animals; antagonists; Behavior, Addictive - drug therapy; Biological and medical sciences; brain; Brain - drug effects; Brain - physiology; cortisol; Craving; Drug therapy; Emotions - drug effects; Ethanol - administration & dosage; Ethanol - pharmacology; Female; Hormones; Humans; Hydrocortisone - blood; Magnetic Resonance Imaging; Male; Medical sciences; Mice; Mice, Inbred C57BL; Middle Aged; Neurokinin-1 Receptor Antagonists; Neurology; Neurotransmitters; patients; Placebos; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Public health; Pyridines - administration & dosage; Pyridines - pharmacology; Pyridines - therapeutic use; Receptors; Receptors, Neurokinin-1 - deficiency; Receptors, Neurokinin-1 - genetics; Receptors, Neurokinin-1 - physiology; Relapse; sedatives; stress response; therapeutics; Toxicology; Triazoles - administration & dosage; Triazoles - pharmacology; Triazoles - therapeutic use; NK1 Tachykinin receptor; Alcoholism; Rodentia; Central nervous system; Encephalon; Vertebrata; Mammalia; Treatment; Mouse; Animal; Dependence; Antagonist; Mechanism of action; Biological receptor
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.1153813

Alcohol dependence is a major public health challenge in need of new treatments. As alcoholism evolves, stress systems in the brain play an increasing role in motivating continued alcohol use and relapse. We investigated the role of the neurokinin 1 receptor (NK1R), a mediator of behavioral stress responses, in alcohol dependence and treatment. In preclinical studies, mice genetically deficient in NK1R showed a marked decrease in voluntary alcohol consumption and had an increased sensitivity to the sedative effects of alcohol. In a randomized controlled experimental study, we treated recently detoxified alcoholic inpatients with an NK1R antagonist (LY686017; n = 25) or placebo (n = 25). LY686017 suppressed spontaneous alcohol cravings, improved overall well-being, blunted cravings induced by a challenge procedure, and attenuated concomitant cortisol responses. Brain functional magnetic resonance imaging responses to affective stimuli likewise suggested beneficial LY686017 effects. Thus, as assessed by these surrogate markers of efficacy, NK1R antagonism warrants further investigation as a treatment in alcoholism.