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.
