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A Novel Pharmacotherapy for Alcoholism: Evaluation of Reward, Aversion, Compulsivity, Withdrawal & Reinstatement

一种治疗酒精中毒的新型药物疗法：奖励、厌恶、强迫、戒断的评估

基本信息

批准号：
9919481
负责人：
ABRAHAM A PALMER
金额：
$ 38.34万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-05 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9919481
关键词：
Abstinence Acute Agonist Alcohol consumption Alcohol withdrawal syndrome Alcoholism Animals Antidepressive Agents Anxiety Ataxia Attenuated Behavior Behavior Therapy Behavioral Biological Brain Cells Chronic Complement Data Disease Dose Electrophysiology (science)Enzyme Inhibitor Drugs Enzymes Equilibrium Ethanol Ethanol dependence Evaluation GABA-A Receptor GABA-B Receptor Genes Genetic Glycolysis Goals In Vitro Investigational Drugs Ion Channel Gating Lactoylglutathione Lyase Ligands Measures Mental Depression Modeling Mus Pharmacological Treatment Pharmacology Pharmacotherapy Physiological Procedures Property Pyruvaldehyde Quinine Rattus Reflex action Relapse Rewards Role Saccharin Sedation procedure Self Administration Self Stimulation Side Signal Transduction Societies Stress Taste aversion Testing Transgenic Organisms Withdrawal Withdrawal Symptom addiction alcohol behavior alcohol effect alcohol exposure alcohol response alcohol seeking behavior alcohol use disorder alcoholism pharmacotherapy anxiety-like behavior comorbidity conditioned place preference cost design drinking drinking water experimental study gamma-Aminobutyric Acid hedonic inhibitor/antagonist insight knock-down natural hypothermia novel overexpression patch clamp preference psychologic receptor small molecule inhibitor social voltage

项目摘要

Project Summary Alcohol use disorders (AUD) place an enormous burden on our society. In addition to their psychological and social toll, it is estimated that AUDs cost the US economy $249 billion in the year 2010 alone. Although there are already several effective behavioral and pharmacological treatments, there is an urgent need for new pharmacotherapies that act via novel mechanisms. We have recently shown that inhibitors of the enzyme Glyoxalase 1 (GLO1) reduce voluntary ethanol drinking in mice (McMurray, et al 2017a). GLO1 is a cytosolic enzyme that metabolizes methylglyoxal (MG). MG is a non-enzymatic side product of glycolysis and is therefore present in all cells. Thus, GLO1 activity is inversely related to MG concentration. We have previously shown that transgenic overexpression of GLO1 increases anxiety-like behavior in mice and decreases MG concentrations in the brain. Reciprocally, we showed that direct administration of MG, genetic knockdown of Glo1 or inhibition of GLO1 using a small molecule inhibitor all decrease anxiety-like behavior and increase MG concentrations in brain. We found that even higher doses of MG produced locomotor depression, ataxia and hypothermia; taken together these data suggested that MG might be acting through GABA-A receptors. Indeed, using a patch clamp procedure, we found that MG is a competitive partial agonist at GABA-A receptors. We also showed that MG is highly selective: it does not activate GABA-B receptors, other ligand gated ion channels or voltage gated ion channels. More recently, we have shown that GLO1 inhibition has antidepressant-like effects, suggesting that GLO1 inhibitors might treat anxiety and depression, both of which are comorbid with AUD. Given the importance of GABA-A signaling in the effects of ethanol, we speculated that GLO1 and MG might also modulate ethanol-related behaviors, which led us to study the effects of GLO1 on ethanol drinking. Those studies showed that inhibition of GLO1 decreased ethanol drinking, which is the rationale for the experiments proposed in this application. We are proposing studies aimed at understanding why inhibition of GLO1 reduces voluntary ethanol drinking. In Aim 1 we will use the intracranial self-stimulation (ICSS) procedure to examine the acute and chronic effects of genetic and pharmacological manipulations of GLO1 on hedonic and anhedonic responses to ethanol in mice. In Aim 2 we will use conditioned place preference (CPP) and conditioned taste aversion (CTA) to study the effects of GLO1 on preference and aversion for ethanol in mice. Finally, in Aim 3, we will use the chronic intermittent ethanol (CIE) procedure to examine the effects of Glo1 inhibitors on acute ethanol withdrawal, compulsive-like responding for ethanol and reinstatement of ethanol seeking behavior after protracted abstinence in rats.

项目总结