Behavioral Effects of Neuroactive Steroids

描述（由申请人提供）：苯二氮卓类药物依赖可能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效应与苯二氮卓类药物不同;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。与苯二氮卓类药物一样，神经活性类固醇是阳性GABAA调节剂，当急性给药时，它们产生的作用在性质上与苯二氮卓类药物相似。然而，这项资助支持的研究已经证明了神经活性类固醇和苯二氮卓类药物在慢性治疗中的根本差异。在长期接受苯二氮卓类药物氟硝西泮的大鼠中，对氟硝西泮的敏感性降低（即，耐受性发展），而当大鼠长期接受神经活性类固醇孕烷醇酮时，对氟硝西泮的敏感性增加。虽然这一令人兴奋的观察可能是非常有益的临床，这一发现的一般性还没有得到研究。此外，这些意外的敏感性变化预测这些药物逆转戒断的效力的程度尚不清楚。目的1将检查长期治疗期间的效力变化，以了解发生这些差异的条件范围。将在目标2中评价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，以确定神经活性类固醇治疗（替代或补充苯二氮卓类药物治疗）是否降低耐受性并预防戒断的出现。总之，这两个具体的目标将探讨在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戒断的独特策略。因为这些策略在治疗酒精戒断中可能同样有用，最终的具体目标将是比较酒精和神经活性类固醇。目标3将建立在这些研究的另一个关键发现的基础上，该发现表明神经活性类固醇的区别性刺激作用与乙醇不同，尽管它们的作用机制重叠;该目标将在更广泛的条件下研究乙醇和神经活性类固醇之间的差异。 公共卫生相关性：苯二氮卓类药物依赖限制了这些药物的临床使用。该补助金评估苯二氮卓类药物和神经活性类固醇的慢性效应的差异，并研究使用神经活性类固醇减少苯二氮卓类药物耐受性和依赖性的发展或表达的可能性。

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.