Neurosteroid-BZ combinations: Strategy for reducing abuse and sedation

神经类固醇-BZ 组合：减少滥用和镇静的策略

• 批准号: 8485568
• 负责人: JAMES K ROWLETT
• 金额: $ 5.73万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-15 至 2013-08-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8485568
• 关键词: Adverse drug effect; Adverse effects; Anti-Anxiety Agents; Anticonvulsants; Anxiety; Anxiety Disorders; Ataxia; Aversive Stimulus; Behavior; Benzodiazepines; Brain; Characteristics; Clinical; Clonazepam; Conflict (Psychology); Data; Development; Diazepam; Dose; Drug Combinations; Effectiveness; Female; Future; Goals; Gonadal Steroid Hormones; Injection of therapeutic agent; Intravenous; Investigation; Laboratories; Luteal Phase; Macaca mulatta; Measures; Mediating; Menstrual cycle; Modeling; Modern Medicine; Monkeys; Motor; Muscle relaxants; Nature; Pharmaceutical Preparations; Pharmacology; Pilot Projects; Posture; Pregnanolone; Procedures; Progesterone; Psychotropic Drugs; Research; Rest; Role; Schedule; Sedation procedure; Self Administration; Sleep; Sleep Disorders; Testing; Therapeutic Index; base; ganaxolone; hypnotic; improved; neurosteroids; novel; novel strategies; pre-clinical; programs; receptor; sedative; sex

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.

描述（由申请人提供）：苯二氮卓类药物（BZ）被广泛用作抗焦虑药、安眠药、肌肉松弛剂和抗惊厥药。尽管 BZ 是现代医学中最安全的精神活性药物之一，但其效用常常受到不良副作用的限制，例如滥用倾向和镇静运动效应。该应用程序的总体目标是 定量确定 BZ 与另一种类型的 GABAA 调节剂（一种神经活性类固醇）组合可在多大程度上增强抗焦虑样作用，但不会增强不良副作用。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加和方式增强 BZ 类药物的抗焦虑样作用。传统的 BZ 会产生被厌恶刺激抑制的操作行为的特征性增加，即诱导“反冲突”效应。使用恒河猴冲突程序，我们将评估传统 BZ（例如氯硝西泮）单独使用或与神经活性类固醇（例如加奈索酮、孕烯醇酮）联合使用的抗焦虑样作用。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亚加成方式改变 BZ 类药物的自我给药。这些研究将采用静脉注射药物的渐进比例 (PR) 方案来检查 BZ 的增强效果，无论是单独使用还是与神经活性类固醇联合使用。具体目标 3 将在一种区分不同程度的镇静和运动功能的新颖观察程序中启动对神经活性类固醇和 BZ 类药物的联合作用的研究。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/休息相关的姿势、中度和深度镇静。在所有研究中，将通过测试受体亚型特异性 GABAA 化合物来评估作用机制。所有组合数据将通过等辐射/剂量相加分析进行评估，以确定药物组合的效果是相加的、超相加的还是亚相加的。最后，我们将以雌性猴子为对象进行针对性研究，开始 基于黄体期内源性神经活性类固醇水平随着黄体酮激增而增加的观察，研究月经周期在介导 BZ 镇静运动作用中的作用。这项初步研究应该为未来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。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，并改善治疗焦虑症的副作用。