GHB Tolerance and Dependence

描述（由申请人提供）：本提案的目的是研究大鼠长期给予低剂量和高剂量伽马-羟基丁酸（GHB）后的耐受性和依赖性机制。GHB是一种新型镇静催眠药，是一种新兴的滥用药物。GHB激活GHB、GABA-B和可能的GABA-A受体，每种受体都具有独特的剂量反应关系。当娱乐性使用者逐步增加使用时，耐受性发展，并且可能发生以失眠、焦虑和幻觉为特征的戒断综合征。 在动物模型中，对伽马-羟丁酸的耐受性和依赖性的特征很差。我们假设耐受性与暴露剂量和持续时间有关。我们还假设不同的受体群体以不同的速度适应。我们假设，长期治疗较低剂量或较短的方案将导致耐受GHB和可能GABA-B受体，而较高的剂量和较长的治疗将导致显着的耐受GHB，GABA-A和GABA-B受体。我们将评估长期低剂量或高剂量治疗7天、14天或21天后对GHB对睡眠时间、倾斜平面和十字迷宫性能影响的耐受性。我们将通过测量睡眠-觉醒周期、运动以及血压和心率来评估自发性和GHB（NCS-382）和GABA-B（CGP 46381）拮抗剂促进的戒断。将采用相同的行为测量评估对GABA-B（巴氯芬）和GABA-A（戊巴比妥、地西泮）激动剂的交叉耐受性。我们将在额叶皮层使用电生理技术的特点抑制GHB机制。将确定GHB对自发、诱发和微型GABA-A IPSC以及对突触后钾电导的影响。将对比低和高GHB浓度的影响，并确定NCS-382和CGP 46381对所有参数的阻断作用。对特定GHB和GABA-B机制的耐受性将通过评价长期接受低剂量或高剂量GHB治疗的动物的额叶皮层切片中的相同参数来研究。最后，我们将评估GHB对GABA-A受体在幼稚和耐受动物的影响，通过测量GABA介导的C1摄取到突触神经小体和其调制苯二氮卓类，巴比妥类药物和神经类固醇。这些实验最终应导致开发出更有效的伽马--羟丁酸依赖性药物疗法，这是一个新出现的药物滥用问题。

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.