Alprazolam and DHEA in healthy men and wome

This research explored the effects of alprazolam on endogenous and exogenous dehydroepiandrosterone (DHEA). The GABA-agonist, alprazolam, is known to decrease adrenocorticotrophin (ACTH) and cortisol concentrations. The major objective of this research was to determine whether alprazolam affects concentrations of DHEA and its sulfated metabolite, DHEA-S and to establish the foundation for future investigations into the in vivo role of DHEA. In vitro studies have demonstrated that DHEA-S, and perhaps DHEA, have GABA-antagonist activity. A second objective was to determine whether DHEA-S and/or DHEA concentrations are related to psychomotor impairment after alprazolam. Thirty-eight young and elderly men received a single intravenous dose of alprazolam 2 mg/2 min (part 1). Twenty-eight of these subjects responded to alprazolam and agreed to participate in part 2, which was a crossover of placebo and alprazolam infusion to plateau for 9 h. Alprazolam produced (1) significant increases in DBEA concentrations at 7 h in both young and elderly men; (2) significant decreases in cortisol concentrations; (3) no change in DHEA-S concentrations. The relationship between psychomotor decrement and DHEA concentrations at 7 h after alprazolam 2 mg/2 min in young men was described by a u-shaped curve (p = 0.0047). These results suggest that alprazolam modulates peripheral concentrations of DHEA and that DHEA and/or DHEA-S may have an in vivo role in modulating GABA-receptor mediated responses.;To identify the in vivo role of exogenously administered DHEA, the appropriate DHEA dose and the time of administration in order to achieve target plasma concentrations needed to be determined. Two sequential studies were designed. A total of 11 elderly men and women (ages 65--79) participated in these studies. Both studies were randomized, double-blind, placebo-controlled, two-way crossovers of alprazolam and DHEA, differing in dose and timing of DHEA relative to alprazolam.;On each of the two treatment days, psychomotor performance, memory, and sedation were assessed serially. Plasma samples were assayed for DHEA, DHEA-S, cortisol, and alprazolam concentrations. Plasma DHEA and DHEA-S concentrations in the desired range were achieved. Variability in alprazolam concentrations and in DHEA between the two treatments precluded ability to assess impact of DHEA on alprazolam-induced psychomotor impairment. Future studies of DHEA administration will allow for individualization of DHEA dose and timing of the dose.