Behavioral Effects of Neuroactive Steroids

描述（由申请方提供）：拟定研究的目的是确定和表征积极调节γ-氨基丁酸A（GABAA）受体复合物的药物（包括苯二氮卓类、巴比妥类和神经活性类固醇）的行为效应差异。已经观察到神经活性类固醇和其他阳性GABAA调节剂的行为效应之间的一些差异，并表明神经活性类固醇可能提供独特的临床优势，例如显著降低滥用和依赖倾向。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醇酮的药理学，并将其效果与苯二氮卓类和巴比妥类药物进行比较。具体目标1将使用药物辨别程序来评价GABAA调节剂的作用的差异，所述GABAA调节剂对不同调节位点的选择性不同或在特定调节位点的功效不同。具体目标2将使用重复采集和性能程序检查孕烯醇酮和其他阳性GABAA调节剂之间的差异。对于将在前两项特定目的中进行的急性研究，将使用定量药理学分析比较GABAA调节剂之间和两种程序之间的药物联合研究结果。最后，具体目标3将使用时间表控制的行为，以确定是否耐受性和依赖性的长期治疗期间与阳性GABAA调节剂孕烷醇酮，氟硝西泮或戊巴比妥发展。此外，交叉耐受性和交叉依赖性的发展将被检查。总之，这些研究将提供神经活性类固醇孕烷醇酮的急性和慢性效应的广泛表征，以及孕烷醇酮与其他阳性GABAA调节剂的行为效应的彻底比较。这些信息最终可能导致改善对各种疾病的治疗，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.