Separate and Combined Effects of Progesterone and Triazolam in Healthy Women

There is accumulating evidence from many directions indicating that gender plays a critical role in drug abuse. Biological factors, including gonadal sex hormones, contribute in a significant although incompletely understood manner, to gender differences in drug abuse. Female sex hormones have been shown to affect central nervous system function and modulate the effects of drugs of abuse. For example, GABAA receptor function is positively modulated by both progesterone and many sedative drugs, including the benzodiazepines. There is evidence from preclinical in vitro and in vivo studies as well as some clinical research suggesting that progesterone and its metabolites may enhance the behavioral effects of benzodiazepines. The first proposed study will utilize a within-subject design to examine the separate and combined effects of a range of doses of micronized sublingual progesterone (0, 50, 150 and 250) and oral triazolam (0.00, 0.12 and 0.25 mg/70 kg) on the subjective, psychomotor and physiological effects of healthy premenopausal women under conditions of low circulating sex hormones. The second study, also a withinsubject design, will examine the effect of progesterone pretreatment on the discriminative stimulus effects of triazolam (0.00,0.06,0.12 and 0.25 mg/70 kg) in healthy, premenopausal women, also under conditions of low circulating sex hormones. The progesterone dose to be tested will be determined based on the results of the initial study (i.e., the dose, inactive in isolation, that engenders the most robust potentiation of triazolam effects). The proposed studies will help to clarify the manner in which the ovarian hormone progesterone modulates the behavioral effects of the sedative drug triazolam. In addition, these studies will establish a foundation for additional studies designed to further elucidate mechanisms associated with progesterone modulation of benzodiazepine effects, thereby further informing gender differences in health and behavior. As such, these studies will contribute towards the development of gender-specific intervention and/or prevention strategies and health management approaches.