Behavioral Effects of Neuroactive Steroids

神经活性类固醇的行为影响

• 批准号: 8212441
• 负责人: LISA R GERAK
• 金额: $ 21.61万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212441
• 关键词: Acute; Alcohol withdrawal syndrome; Anxiety; Behavioral; Benzodiazepines; Chronic; Clinical; Dependence; Development; Disease; Dose; Drug Interactions; Drug usage; Effectiveness; Ethanol; Flunitrazepam; Food; Grant; Laboratories; Laboratory Finding; Measures; Pentylenetetrazole; Pharmaceutical Preparations; Pregnanolone; Procedures; Rattus; Seizures; Site; Sleeplessness; Stimulus; System; Testing; Training; Withdrawal; alcohol pharmacology; drug discrimination; improved; insight; neurosteroids; prevent; public health relevance; receptor; receptor function; treatment duration

DESCRIPTION (provided by applicant): Benzodiazepine dependence can limit the clinical use of this important class of drugs and contribute to their abuse. Emerging evidence suggests that the chronic effects of neuroactive steroids are different from those of benzodiazepines; such differences can be exploited to improve our understanding of GABAA receptor function, particularly during chronic treatment, and might offer clinical advantages. Like benzodiazepines, neuroactive steroids are positive GABAA modulators, and when administered acutely, they produce effects that are qualitatively similar to those of benzodiazepines. However, studies supported by this grant have demonstrated fundamental differences between neuroactive steroids and benzodiazepines during chronic treatment. In rats receiving the benzodiazepine flunitrazepam chronically, sensitivity to flunitrazepam decreases (i.e., tolerance develops), whereas when rats receive the neuroactive steroid pregnanolone chronically, sensitivity to flunitrazepam increases. Although this exciting observation could be exceptionally beneficial clinically, the generality of this finding has not been investigated. Moreover, the extent to which these unexpected changes in sensitivity predict the potency of these drugs to reverse withdrawal is not known. Aim 1 will examine potency changes during chronic treatment to understand the range of conditions under which these differences occur. The ability of neuroactive steroids to modulate benzodiazepine tolerance, dependence and withdrawal will be evaluated in Aim 2 to determine whether treatment with neuroactive steroids, either instead of or in addition to, benzodiazepine treatment reduces tolerance and prevents the emergence of withdrawal. Together, these two specific aims will explore changes in GABAA receptor function that occur during chronic treatment and determine whether neuroactive steroids could provide unique strategies for preventing or reversing benzodiazepine withdrawal. Because such strategies might be equally useful in treating ethanol withdrawal, the final specific aim will compare ethanol to neuroactive steroids. Aim 3 will build upon another key finding of these studies which indicates that the discriminative stimulus effects of neuroactive steroids are not identical to those of ethanol, despite their overlapping mechanisms of action; this Aim will examine differences between ethanol and neuroactive steroids under a broader range of conditions. PUBLIC HEALTH RELEVANCE: Benzodiazepine dependence limits the clinical use of these drugs. This grant evaluates differences in the chronic effects of benzodiazepines and neuroactive steroids and investigates the possibility of using neuroactive steroids to reduce the development or expression of benzodiazepine tolerance and dependence.

描述（由申请人提供）：苯二氮卓类药物的依赖性可以限制这种重要的药物的临床使用，并促进其滥用。新兴的证据表明，神经活性类固醇的慢性作用与苯二氮卓类药物的慢性作用不同。可以利用这种差异来提高我们对GABAA受体功能的理解，尤其是在慢性治疗期间，并且可能具有临床优势。像苯二氮卓类药物一样，神经活性类固醇是阳性GABAA调节剂，当急性施用时，它们产生的作用在质量上与苯二氮卓类药物的作用相似。但是，该赠款支持的研究表明，在慢性治疗过程中，神经活性类固醇和苯二氮卓类药物之间存在基本差异。在长期接受苯二氮卓氟尼氏酶的大鼠中，对氟硝西zepam的敏感性降低（即耐受性发展），而当大鼠长期接受神经活性类固醇妊娠时，对氟尼替朗西m的敏感性增加。尽管这种令人兴奋的观察在临床上可能非常有益，但尚未研究该发现的一般性。此外，尚不清楚这些敏感性的这些意外变化预测这些药物逆转戒断的效力的程度。 AIM 1将检查慢性治疗过程中的效力变化，以了解这些差异发生的条件范围。神经活性类固醇调节苯二氮卓的耐受性，依赖性和戒断的能力将在AIM 2中进行评估，以确定使用神经活性类固醇的治疗是苯并二氮卓类药物的治疗是否会降低耐受性，并降低耐受性并阻止戒断的出现。总之，这两个特定的目标将探索慢性治疗过程中发生的GABAA受体功能的变化，并确定神经活性类固醇是否可以提供预防或逆转苯二氮卓类药物的独特策略。由于此类策略在治疗乙醇戒断方面可能同样有用，因此最终的特定目的将将乙醇与神经活性类固醇进行比较。 AIM 3将建立在这些研究的另一个关键发现的基础上，表明神经活性类固醇的歧视性刺激作用与乙醇的作用机制重叠，但与乙醇的效果并不相同。该目标将检查乙醇和神经活性类固醇之间的差异。 公共卫生相关性：苯二氮卓类依赖性限制了这些药物的临床使用。该赠款评估了苯二氮卓类药物和神经活性类固醇的慢性作用的差异，并研究了使用神经活性类固醇来降低苯二氮卓耐受性和依赖性的发育或表达的可能性。