Behavioral Effects of Neuroactive Steroids

描述（由申请人提供）：苯二氮卓类药物依赖会限制这类重要药物的临床使用，并导致其滥用。新出现的证据表明，神经活性类固醇的慢性作用不同于苯二氮卓类药物；这种差异可以用来提高我们对GABAA受体功能的理解，特别是在慢性治疗期间，并可能提供临床优势。像苯二氮卓类药物一样，神经活性类固醇是GABAA阳性调节剂，当急性给药时，它们产生的效果在质量上与苯二氮卓类药物相似。然而，该基金支持的研究表明，在慢性治疗中，神经活性类固醇和苯二氮卓类药物之间存在根本差异。长期接受苯二氮卓类药物氟硝西泮的大鼠对氟硝西泮的敏感性降低（即产生耐受性），而长期接受神经活性类固醇孕酮的大鼠对氟硝西泮的敏感性增加。虽然这一令人兴奋的观察结果可能在临床上特别有益，但这一发现的普遍性尚未得到调查。此外，这些意想不到的敏感性变化在多大程度上预测了这些药物逆转戒断的效力尚不清楚。目的1将检查慢性治疗期间的效力变化，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类药物耐受性、依赖性和戒断的能力将在Aim 2中进行评估，以确定用神经活性类固醇替代或加用苯二氮卓类药物治疗是否会降低耐受性并防止戒断的出现。总之，这两个特定的目的将探讨GABAA受体功能在慢性治疗期间发生的变化，并确定神经活性类固醇是否可以提供独特的策略来预防或逆转苯二氮卓类药物戒断。因为这些策略在治疗乙醇戒断方面可能同样有效，所以最后的具体目标是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，该发现表明，尽管它们的作用机制重叠，但神经活性类固醇的区别刺激作用与乙醇的区别刺激作用并不相同；本目的将在更广泛的条件下检查乙醇和神经活性类固醇之间的差异。

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.