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Science 319 (5869): 1536-1539

Copyright © 2008 by the American Association for the Advancement of Science

Neurokinin 1 Receptor Antagonism as a Possible Therapy for Alcoholism

David T. George,1* Jodi Gilman,1* Jacqueline Hersh,1* Annika Thorsell,1* David Herion,1 Christopher Geyer,2 Xiaomei Peng,3 William Kielbasa,3 Robert Rawlings,1 John E. Brandt,3 Donald R. Gehlert,3 Johannes T. Tauscher,3 Stephen P. Hunt,4 Daniel Hommer,1 Markus Heilig1{dagger}

Abstract: 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.

1 Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
2 Department of Nursing, Mark O. Hatfield Clinical Research Center, National Institutes of Health, Bethesda, MD 20892, USA.
3 Lilly Research Laboratories, Indianapolis, IN 46285, USA.
4 Department of Anatomy and Developmental Biology, University College London, London WC1E 6BT, UK.

* These authors contributed equally.

{dagger} To whom correspondence should be addressed. E-mail: markus.heilig{at}mail.nih.gov


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