ly686017 and 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.

Topics: Adult; Aged; Alcohol Drinking; Alcoholism; Animals; Behavior, Addictive; Brain; Emotions; Ethanol; Female; Humans; Hydrocortisone; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Middle Aged; Neurokinin-1 Receptor Antagonists; Pyridines; Receptors, Neurokinin-1; Triazoles

Topics: Alcoholism; Animals; Benzazepines; Humans; Naltrexone; Narcotic Antagonists; Neurokinin-1 Receptor Antagonists; Nicotinic Agonists; Pharmacogenetics; Pyridines; Quinoxalines; Receptors, Corticotropin-Releasing Hormone; Receptors, Opioid, mu; Stress, Psychological; Triazoles; Varenicline

Today solid evidence is available that pharmacological treatments can prevent relapse and improve clinically relevant outcomes in alcoholism. In a preclinical and experimental-clinical study George and colleagues first investigated the role of Substance P and its receptor (NK1R) in the context of alcoholism. They could demonstrate that either the blockade of the receptor, or the lack of the receptors leds to a decreased alcohol intake as well as reduced alcohol tolerance and craving concomitantly accompanied by improved general well-beeing.

Topics: Adult; Alcohol Deterrents; Alcoholism; Animals; Double-Blind Method; Female; Humans; Male; Mice; Mice, Knockout; Middle Aged; Neurokinin-1 Receptor Antagonists; Pyridines; Randomized Controlled Trials as Topic; Receptors, Neurokinin-1; Recurrence; Research; Substance P; Triazoles; Young Adult

Topics: Alcohol Deterrents; Alcoholism; Animals; Controlled Clinical Trials as Topic; Emotions; Humans; Neurokinin-1 Receptor Antagonists; Pyridines; Receptors, Corticotropin-Releasing Hormone; Reward; Stress, Psychological; Triazoles