GHB Tolerance and Dependence

GHB 耐受性和依赖性

• 批准号: 6610213
• 负责人: Cynthia M Kuhn
• 金额: $ 26.95万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-20 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6610213
• 关键词: GABA receptor; barbiturates; behavior test; benzodiazepines; blood pressure; dosage; drug abuse; drug tolerance; drug withdrawal; electrophysiology; frontal lobe /cortex; gamma aminobutyrate; gamma hydroxybutyrate; heart rate; laboratory rat; sleep; steroids; synaptosomes

DESCRIPTION (provided by applicant): The purpose of this proposal is to investigate mechanisms of Gamma hydroxy butyrate (GHB) tolerance and dependence after chronic administration of low and high doses of GHB to rats. GHB is a novel sedative-hypnotic that is an emerging drug of abuse. GHB activates GHB, GABA-B and possibly GABA-A receptors, with a unique dose response relationship for each. When recreational users escalate use, tolerance develops and a withdrawal syndrome can occur that is characterized by insomnia, anxiety, and hallucinations. Tolerance and dependence to GHB are poorly characterized in animal models. We hypothesize that tolerance is related to dose and duration of exposure. We also hypothesize that the different receptor populations adapt at varying rates. We postulate that chronic treatment with lower doses or shorter regimens will cause tolerance at GHB and perhaps GABA-B receptors, while higher doses and longer treatments will lead to marked tolerance to GHB, GABA-A and GABA-B receptors. We will assess tolerance to GHB effects on sleep time, tilt plane and plus maze performance after chronic treatment with low or high doses for 7, 14 or 21 days. We will assess spontaneous and GHB (NCS-382) and GABA-B (CGP46381) antagonist-precipitated withdrawal by measuring sleep-wake cycle, locomotion as well as blood pressure and heart rate. Cross-tolerance to GABA-B (baclofen) and GABA-A (pentobarbital, diazepam) agonists will be assessed with the same behavioral measures. We will characterize inhibitory GHB mechanisms using electrophysiologic techniques in frontal cortex. GHB effects on spontaneous, evoked and mini GABA-A IPSCs and on postsynaptic potassium conductance will be determined. The effects of low and high GHB concentrations will be contrasted, and blockade by NCS-382 and CGP46381 on all parameters will be determined. Tolerance to specific GHB and GABA-B mechanisms will be studied by evaluating the same parameters in frontal cortex slices from animals treated chronically with low or high dose GHB. Finally, we will assess GHB effects on GABA-A receptors in naive and tolerant animals by measuring effects on GABA-mediated C1 uptake into synaptoneurosomes and its modulation by benzodiazepines, barbiturates and neurosteroids. These experiments should ultimately lead to the development of more effective pharmacotherapies for GHB dependence, which is an emerging drug abuse problem.

描述（由申请人提供）：该提案的目的是研究hydroxy丁酸酯（GHB）的耐受性和依赖性的机制，在长期对大鼠的低剂量和高剂量GHB施用后的依赖性。 GHB是一种新型的镇静催眠，是一种新兴的滥用药物。 GHB激活GHB，GABA-B和可能的GABA-A受体，每个受体都具有独特的剂量反应关系。当娱乐用户升级使用时，耐受性会发展，并且可能发生以失眠，焦虑和幻觉为特征的戒断综合症。 在动物模型中，对GHB的耐受性和依赖性的特征很差。我们假设公差与剂量和暴露时间有关。我们还假设不同的受体种群以不同的速度适应。我们假设，使用较低剂量或较短方案的慢性治疗会导致GHB和GABA-B受体的耐受性，而较高剂量和更长的处理将导致对GHB，GABA-A和GABA-B受体的明显耐受性。我们将评估对睡眠时间，倾斜平面和加上低剂量治疗后对GHB影响的耐受性，持续7、14或21天。我们将通过测量睡眠效果周期，运动以及血压和心率来评估自发性和GHB（NCS-382）和GABA-B（CGP46381）拮抗作用戒断。将通过相同的行为措施评估对GABA-B（Baclofen）和GABA-A（五体性，地西epa）激动剂的交叉耐受性。我们将使用额叶皮质中的电生理技术来表征抑制性GHB机制。将确定GHB对自发，诱发和迷你GABA-A IPSC以及突触后钾电导的影响。低GHB浓度的影响将与NCS-382和CGP46381进行对比，并确定所有参数。通过评估从慢性或高剂量GHB经过长期处理的动物中的额叶皮质切片中相同的参数来研究对特定GHB和GABA-B机制的耐受性。最后，我们将通过测量对GABA介导的C1摄取对突触型尿素的影响以及对苯二氮卓类药物，巴比妥类药物和神经类固醇的调节的影响，评估GHB对天真和耐受动物中GABA-A受体的影响。这些实验最终应导致开发用于GHB依赖性的更有效的药物治疗，这是一个新兴的药物滥用问题。