Neurosteroid-BZ combinations: Strategy for reducing abuse and sedation

性状（由申请方提供）：苯二氮卓类（BZ）广泛用作抗焦虑药、催眠药、肌肉松弛药和抗惊厥药。虽然BZ是现代医学中最安全的精神活性药物之一，但它们的效用往往受到不必要的副作用的限制，如滥用倾向和镇静运动效应。此应用程序的总体目标是 定量测定BZ与另一种类型的GABAA调节剂（神经活性类固醇）组合导致抗焦虑样作用增强但不增强不希望的副作用的程度。具体目标1将评估以下假设：作用于GABAA受体的神经活性类固醇将以超累加方式增强BZ型药物的抗焦虑样作用。传统的BZ在操作性行为中产生特征性的增加，这些增加被厌恶性刺激抑制，即，产生“反冲突”效果。使用恒河猴冲突程序，我们将评估常规BZ的抗焦虑样作用（例如，氯硝西泮），单独或与神经活性类固醇（例如，加奈索酮、孕烷醇酮）。具体目标2将评估以下假设：作用于GABAA受体的神经活性类固醇将以累加后的方式改变BZ型药物的自我给药。这些研究将采用静脉注射药物的渐进比（PR）时间表，以检查BZ单独或与神经活性类固醇联合使用的强化效果。具体目标3将在一种新的观察程序中开始研究神经活性类固醇和BZ型药物的联合作用，该程序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，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，将通过检测受体亚型特异性GABAA化合物来评估作用机制。将采用等效线/剂量相加分析评价所有组合数据，以确定药物组合的效应是相加、超相加还是相加内。最后，我们将对雌性猴子进行有针对性的研究，以开始 研究月经周期在介导BZ的镇静-运动效应中的作用，基于观察到内源性神经活性类固醇水平随着黄体期孕酮激增而增加。这项初步研究应提供一个跳板，评估性别作为一个因素，在BZ和神经活性类固醇药理学在未来的应用。该研究计划的最终目标是为开发广泛有效的组合产品提供关键的临床前信息，该产品具有改善的副作用特征，用于治疗焦虑症。

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.