Neurosteroids, which are synthesized in the brains of humans and other mammals, are under investigation for use in a range of human health conditions (e.g., anxiety, memory, immune function, problems associated with aging). One of these compounds, dehydroepiandrosterone (DHEA), is a powerful inhibitor of aggression in murine models when given for fifteen days and potentially may be useful in the management of inappropriate human aggression. Although the biosynthesis and metabolism of DHEA have been described, a significant gap exists concerning the mechanism(s) of this anti-aggressive effect. We know that 15 days of DHEA treatment reduces whole brain levels of pregnenolone sulfate (PREG-S), a GABAA receptor antagonist that works directly at the membrane level, and we recently discovered that DHEA also up-regulates androgen receptor (AR) in the limbic system, demonstrating a genomic effect. Both events can contribute to enhanced GABA activity, an inhibitory neurotransmitter known to reduce aggression. The major goal of the proposed research, therefore, will be to identify and/or quantitate the metabolic, membrane level, and genomic effects of extended DHEA treatment and then determine the contributions of each to the aggression- inhibiting effect of this neurosteroid. Experiments will be undertaken to localize the specific brain regions where DHEA treatment causes a significant decline in PREG-S, characterize the regional changes in GABAA receptor binding that occur over the course of DHEA exposure, define effects of the androgenic metabolites of DHEA on AR regulation that may be linked to the anti-aggressive action of this neurosteroid and, finally, perform functional biobehavioral and in vivo microinfusion studies involving pharmacological manipulations to begin defining underlying neural regulatory mechanisms. The results should achieve two objectives. One is that critical mechanisms and sites of action for the inhibition of aggression by DHEA will be defined, advancing models of the neurobiology of this behavior. The other is that with the characterization of both membrane-level and genomic actions linked to the anti- aggressive effect of DHEA, a """"""""cross-talk"""""""" cellular signaling system associated with extended neurosteroid treatment would be established. This finding would significantly advance our understanding of the mechanism of action of DHEA, an important consideration given proposed clinical uses.
