GHB Tolerance and Dependence

描述(申请人提供)：这项建议的目的是研究长期给予大鼠低剂量和高剂量羟丁酸(GHB)后对GHB耐受和依赖的机制。GHB是一种新型的镇静催眠药，是一种新兴的滥用药物。GHB激活GHB、GABA-B和可能的GABA-A受体，每种受体都有独特的剂量反应关系。当娱乐性使用者增加使用时，会产生耐受性，并可能发生以失眠、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。我们推测，低剂量或短疗程的慢性治疗将导致对GHB受体和GABA-B受体的耐受，而较高剂量和较长时间的治疗将导致对GHB、GABA-A和GABA-B受体的明显耐受。我们将评估对GHB的耐受性在长期低剂量或高剂量治疗7、14或21天后对睡眠时间、倾斜平面和迷宫表现的影响。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和GHB(NCS-382)和GABA-B(CGP46381)拮抗剂催促的戒断。对GABA-B(巴氯芬)和GABA-A(戊巴比妥、安定)激动剂的交叉耐受性将通过相同的行为测量进行评估。我们将使用电生理学技术在额叶皮质表征抑制GHB的机制。GHB对自发的、诱发的和微小的GABA-A iPSCs和突触后钾电导的影响将被确定。将对比低浓度和高浓度GHB的影响，并确定NCS-382和CGP46381对所有参数的封锁。对特定的GHB和GABA-B机制的耐受性将通过评估长期服用低剂量或高剂量GHB的动物的额叶皮质切片中的相同参数来研究。最后，我们将通过测量对GABA介导的C1摄取到突触神经体的影响以及苯二氮卓类药物、巴比妥酸盐和神经类固醇对其调节来评估GHB对幼稚和耐受动物的GABA-A受体的影响。这些实验最终将导致开发出更有效的治疗GHB依赖的药物疗法，GHB依赖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.