Neurosteroid-BZ combinations: Strategy for reducing abuse and sedation

描述(申请人提供)：苯二氮卓类药物(BZS)被广泛用作抗焦虑药、催眠药、肌肉松弛药和抗惊厥药。尽管BZS是现代医学中最安全的精神活性药物之一，但它们的用途往往受到滥用倾向和镇静-运动效应等有害副作用的限制。此应用程序的总体目标是 为了定量地确定BZ与另一种类型的GABAA调节剂(一种神经活性类固醇)联合在多大程度上能够产生增强的抗焦虑作用，但不会增加不良副作用。具体目标1将评估这样一个假设，即作用于GABAA受体的神经活性类固醇将以超加法方式增强BZ类药物的抗焦虑效果。传统的BZS在被厌恶刺激抑制的操作行为中产生特征性的增加，即诱导“反冲突”效应。使用恒河猴冲突程序，我们将评估传统BZS(例如，氯硝西潘)单独或与神经活性类固醇(例如，加纳松龙、孕酮)联合使用的抗焦虑效果。特定目标2将评估作用于GABAA受体的神经活性类固醇将以次加性方式改变BZ类药物自我给药的假设。这些研究将采用静脉注射药物的累进比率(PR)程序来检查BZS单独或与神经活性类固醇联合使用的增强效果。具体目标3将启动一项新的观察程序，研究神经活性类固醇和BZ类药物的联合作用，以区分不同水平的镇静和运动功能。我们将使用我们实验室最近开发的观察程序来分离共济失调样效应、睡眠/休息相关姿势、中度和深度镇静。在所有研究中，作用机制将通过测试受体亚型特异性GABAA化合物来评估。所有的组合数据都将通过等效学/剂量相加分析进行评估，以确定药物组合的效果是相加的、超相加的还是次相加的。最后，我们将开始对雌性猴子进行有针对性的研究 通过观察黄体期内源性神经活性类固醇水平随孕酮水平的升高，探讨月经周期在BZS镇静-运动作用中的作用。这项先导性研究应该为在未来的应用中评估性别作为BZ和神经活性类固醇药理学的一个因素提供一个跳板。这项研究计划的最终目标是为开发一种广泛有效、副作用改善的联合产品治疗焦虑症提供关键的临床前信息。

DESCRIPTION (provided by applicant): Benzodiazepines (BZs) are prescribed widely as anxiolytics, hypnotics, muscle relaxants, and anticonvulsants. Although BZs are among the safest psychoactive drugs in modern medicine, their utility is often limited by unwanted side effects such as abuse liability and sedative-motor effects. The overall goal of this application is to determine quantitatively the extent to which combining a BZ with another type of GABAA modulator, a neuroactive steroid, results in enhanced anxiolytic-like effects but not enhanced unwanted side-effects. Specific Aim 1 will evaluate the hypothesis that neuroactive steroids that act at GABAA receptors will enhance the anxiolytic-like effects of BZ-type drugs in a supra-additive manner. Conventional BZs produce characteristic increases in operant behavior that are suppressed by aversive stimuli, i.e., induce "anti-conflict" effects. Using a rhesus monkey conflict procedure, we will evaluate the anxiolytic-like effects of conventional BZs (e.g., clonazepam), alone or in combination with neuroactive steroids (e.g., ganaxolone, pregnanolone). Specific Aim 2 will evaluate the hypothesis that neuroactive steroids that act at GABAA receptors will alter the self-administration of BZ-type drugs in an infra-additive manner. These studies will employ a progressive-ratio (PR) schedule of intravenous drug injection to examine the reinforcing effectiveness of BZs, either alone or in combination with neuroactive steroids. Specific Aim 3 will initiate investigation of the combined effects of neuroactive steroid and BZ-type drugs in a novel observation procedure that distinguishes different levels of sedation and motor function. We will use observational procedures recently developed in our laboratory that dissociate ataxia-like effects, sleep/rest-associated postures, moderate and deep sedation. In all studies, mechanism of action will be assessed by testing receptor subtype-specific GABAA compounds. All combination data will be evaluated with isobolographic/dose-addition analysis in order to determine if effects of drug combinations are additive, supra-additive, or infra-additive. Finally, we will conduct targeted studies with female monkeys to begin to investigate the role of the menstrual cycle in mediating the sedative-motor effects of BZs, based on the observation that endogenous neuroactive steroid levels increase with the progesterone surge during the luteal phase. This pilot study should provide a springboard for evaluating sex as a factor in BZ and neuroactive steroid pharmacology in future applications. The ultimate goal for this research program is to provide critical preclinical information for development of a broadly effective combination product with an improved side effect profile for treating anxiety disorders.