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

• 批准号: 9597007
• 负责人: ABRAHAM A PALMER
• 金额: $ 39.58万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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/9597007
• 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; Comorbidity; Complement; Data; Disease; Dose; Electrophysiology (science); Enzyme Inhibitor Drugs; Enzymes; Equilibrium; Ethanol; Ethanol dependence; Evaluation; GABA-A Receptor; GABA-B Receptor; Gated Ion Channel; 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; 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

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.

项目摘要 酒精使用障碍（AUD）给我们的社会带来了巨大的负担。除了他们 心理和社会损失，据估计，AUDS一年中损失了美国经济的2490亿美元 仅2010年。尽管已经有几种有效的行为和药理治疗，但 迫切需要通过新型机制起作用的新药物治疗。 我们最近表明，酶乙二醛酶1（GLO1）的抑制剂减少了自愿 小鼠乙醇饮用（McMurray等，2017a）。 GLO1是一种代谢的胞质酶 甲基甘氨酸（mg）。 Mg是糖酵解的非酶侧产物，因此存在于所有 细胞。因此，GLO1活性与Mg浓度成反比。我们以前已经表明 GLO1的转基因过表达增加了小鼠的焦虑样行为并降低Mg 大脑的浓度。相互表明，直接施用Mg，遗传 使用小分子抑制剂敲低glo1或抑制GLO1均可减少焦虑样 行为并增加大脑中的Mg浓度。我们发现产生的更高剂量的毫克 运动抑郁症，共济失调和体温过低；总共这些数据表明MG可能 通过GABA-A受体作用。确实，使用贴片夹程序，我们发现MG是一个 GABA-A受体的竞争性部分激动剂。我们还表明MG具有很高的选择性：它确实 不激活GABA-B受体，其他配体门控离子通道或电压门控离子通道。更多的 最近，我们表明GLO1抑制具有抗抑郁药样作用，表明GLO1 抑制剂可能会治疗焦虑和抑郁症，两者都与AUD合并。鉴于 GABA-A信号在乙醇的作用中的重要性，我们推测GLO1和MG可能 还调节与乙醇相关的行为，这使我们研究了GLO1对乙醇的影响 喝。这些研究表明，抑制GLO1降低了乙醇饮用，这是 本应用程序中提出的实验的理由。 我们提出的研究旨在了解为什么抑制GLO1会减少自愿 乙醇喝。在AIM 1中，我们将使用颅内自刺激（ICS）程序来检查 GLO1的遗传和药理学操纵对享乐和享乐的急性和慢性作用对享乐和 小鼠对乙醇的反反应。在AIM 2中，我们将使用条件的地方偏好（CPP） 和条件口味厌恶（CTA），以研究GLO1对偏好和厌恶的影响 小鼠乙醇。最后，在AIM 3中，我们将使用慢性间歇性乙醇（CIE）程序进行 检查GLO1抑制剂对急性乙醇戒断的影响，强迫性响应 乙醇和恢复大鼠节制持久性后寻求行为的恢复。