Neurokinin 1 receptor antagonism as a possible therapy for alcoholism.
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.
George
David T
DT
Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
Gilman
Jodi
J
Hersh
Jacqueline
J
Thorsell
Annika
A
Herion
David
D
Geyer
Christopher
C
Peng
Xiaomei
X
Kielbasa
William
W
Rawlings
Robert
R
Brandt
John E
JE
Gehlert
Donald R
DR
Tauscher
Johannes T
JT
Hunt
Stephen P
SP
Hommer
Daniel
D
Heilig
Markus
M
D000328:Adult; D000368:Aged; D000428:Alcohol Drinking / Q000188:drug therapy; D000437:Alcoholism / Q000188:drug therapy*; D000818:Animals; D016739:Behavior, Addictive / Q000188:drug therapy; D001921:Brain / Q000187:drug effects / Q000502:physiology; D004644:Emotions / Q000187:drug effects; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D064729:Neurokinin-1 Receptor Antagonists; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D018040:Receptors, Neurokinin-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
C527551:LY686017; D064729:Neurokinin-1 Receptor Antagonists; D011725:Pyridines; D018040:Receptors, Neurokinin-1; D014230:Triazoles; D000431:Ethanol; D006854:Hydrocortisone