Impact of DHEA on GABA-agonist Challenge in Healthy Young and Older adults

摘要

The primary goal of this dissertation research was to investigate the effect of dehydroepiandrosterone (DHEA) administration on recovery from a GABA-agonist challenge in healthy young and older adults. DHEA and its sulfate metabolite DHEA-S are natural steroid hormones that are produced primarily in the adrenal glands and act as precursors to other hormones (e.g., testosterone and estrogen) in the body. Animal studies have demonstrated antagonistic effects of DHEA and DHEA-S at the GABA receptor complex. When compared to young adults, the elderly have lower concentrations of DHEA and DHEA-S and recover more slowly from the CNS effects of benzodiazepines, the most commonly prescribed class of GABA-agonists. To investigate the role of DHEA and/or DHEA-S as excitatory steroids in the human brain, a GABA-agonist challenge study was proposed. Secondary goals included evaluations of SEM variability over repeated same-day testing and assessing the influence of age and endogenous concentrations of DHEA and DHEA-S on SEMs.Both young (20 to 30 years) and older (60 to 79 years) men and women participated in this four-way crossover of placebo, DHEA, alprazolam plus placebo and alprazolam plus DHEA. For the 12.5 hours after the drug or placebo was administered, responses mediated via the GABA-A receptor complex (saccadic eye movements (SEMs), sedation, memory, and psychomotor performance) were assessed and blood samples were collected for the purpose of determining DHEA, DHEA-S, and alprazolam concentrations. These data demonstrate that DHEA administration enhanced impairment in older men and women and did not alter impairment in young men and women. DHEA administration did not accelerate recovery from GABA-agonist challenge in the older subjects. In fact, the opposite effect was seen with the older men and women who demonstrated saccades with slower velocities and longer durations during the recovery phase of the DHEA/Alp treatment. A surprising outcome of this report is the number of older subjects who experienced impairment at a level where they were unable to complete the SEM tasks in both treatments. The number of older subjects unable to perform the SEM tasks during the DHEA/Alp treatment was significantly greater than during the PL/Alp treatment.