Behavioral Effects of Neuroactive Steroids

描述（由申请人提供）：拟议研究的目标是确定和表征正向调节γ -氨基丁酸（GABAA）受体复合物的药物的行为效应差异，包括苯二氮卓类药物、巴比妥类药物和神经活性类固醇。神经活性类固醇与其他阳性GABAA调节剂的行为效果存在一些差异，这表明神经活性类固醇可能具有明显的临床优势，例如显着减少滥用和依赖。这些研究将使用三种不同的操作程序进一步表征神经活性类固醇，以评估神经活性类固醇孕烷酮的药理学，并将其与苯二氮卓类药物和巴比妥类药物的作用进行比较。Specific Aim 1将使用药物鉴别程序来评估GABAA调节剂在不同调节位点的选择性不同或在特定调节位点的疗效不同的作用差异。具体目标2将使用重复获取和性能程序检查孕烷酮和其他阳性GABAA调节剂之间的差异。对于将在前两个特定目标中进行的急性研究，将使用定量药理学分析来比较GABAA调节剂之间以及两种程序之间的药物联合研究结果。最后，Specific Aim 3将使用时间表控制行为来确定在使用阳性GABAA调节剂妊娠烷酮、氟硝西泮或戊巴比妥进行慢性治疗期间是否会产生耐受性和依赖性。此外，还将探讨交叉耐受和交叉依赖的发展。总之，这些研究将提供神经活性类固醇孕酮的急性和慢性影响的广泛特征，以及孕酮与其他阳性GABAA调节剂的行为影响的彻底比较。这些信息最终可能导致改善各种疾病的治疗，包括酒精或苯二氮卓类药物依赖。

DESCRIPTION (provided by applicant): The goal of the proposed research is to identify and characterize differences in behavioral effects of drugs that positively modulate the gamma-aminobutyric acidA (GABAA) receptor complex, including benzodiazepines, barbiturates and neuroactive steroids. Some differences between the behavioral effects of neuroactive steroids and those of other positive GABAA modulators have been observed and suggest that neuroactive steroids might offer distinct clinical advantages, such as markedly reduced abuse and dependence liability. These studies will further characterize neuroactive steroids using three different operant procedures to evaluate the pharmacology of the neuroactive steroid pregnanolone and compare its effects to those of the benzodiazepines and barbiturates. Specific Aim 1 will use a drug discrimination procedure to evaluate differences in effects of GABAA modulators that vary in selectivity for different modulatory sites or that vary in efficacy at a particular modulatory site. Specific Aim 2 will examine differences between pregnanolone and other positive GABAA modulators using a repeated-acquisition and performance procedure. For the acute studies that will be conducted in the first two Specific Aims, quantitative pharmacological analyses will be used to compare the results of drug combination studies among GABAA modulators and between the two procedures. Finally, Specific Aim 3 will use schedule-controlled behavior to determine whether tolerance and dependence develop during chronic treatment with the positive GABAA modulators pregnanolone, flunitrazepam or pentobarbital. In addition, the development of cross tolerance and cross dependence will be examined. Together, 'these studies will provide an extensive characterization of the acute and chronic effects of the neuroactive steroid pregnanolone as well as a thorough comparison of the behavioral effects of pregnanolone to those of other positive GABAA modulators. Such information could ultimately lead to improved treatment of a variety of conditions, including alcohol or benzodiazepine dependence.