Year of Publication

2010

Degree Name

Doctor of Philosophy (PhD)

Document Type

Dissertation

College

Arts and Sciences

Department

Psychology

First Advisor

Thomas H. Kelly, Ph.D.

Abstract

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 progesterone. 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, which also serve as positive modulators of GABAA receptors.

The three studies presented here utilize within subject designs to assess the role of progesterone on the discriminative stimulus, subjective, performance and cardiovascular effects of triazolam, a short-acting benzodiazepine, in healthy, premenopausal women. The first study examined the effect of menstrual cycle phase on the discriminative stimulus effects of triazolam (0.00, 0.06, 0.12 and 0.25 mg/70 kg). The results of this study indicated that when progesterone levels peak (mid luteal phase), the discriminative stimulus effects of triazolam (0.12 mg/70 kg) are enhanced. The second study examined the separate and combined effects of a range of acute doses of oral micronized progesterone (0, 100 and 200 mg) and oral triazolam (0.00, 0.12 and 0.25 mg/70 kg) on the subjective, psychomotor and physiological effects of these medications, tested under conditions of low circulating sex hormones. The results of this study indicated that progesterone alone has some short-acting, sedative-like effects and enhances the subjective and performance effects of triazolam. The final study examined the effects of progesterone (0 and 100 mg) on the discriminative stimulus effects of triazolam (0.00, 0.06, 0.12 and 0.25 mg/70 kg), also under conditions of low circulating sex hormones. The results of this study indicated that the parent hormone progesterone does not appear to alter sensitivity to the discriminative stimulus effects of triazolam. Increases in sensitivity to triazolam in studies 1 and 2 may have been the result of neuroactive progesterone metabolites (e.g., allopregnanolone, TH-DOC), although future studies will be required to further examine this possibility. Taken together, these studies help clarify the manner in which the ovarian hormone progesterone and its metabolites modulate the behavioral effects of the benzodiazepines.

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