GENOMIC & NONGENOMIC EFFECTS OF STEROIDS ON SALT INTAKE

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DESCRIPTION: The PI was among the first to demonstrate that sodium appetite is normally caused by a synergistic action of the peptide, angiotensin-II (A-II) and the steroid, aldosterone (ALDO), and he has also been instrumental in beginning to elucidate the receptor mechanisms involved. Because of the rapid elicitation of sodium appetite that can be observed by ALDO in some situations, the PI now proposes several experiments to examine both the genomic and the non-genomic effects of ALDO, to determine specific brain sites where adrenal steroids work to cause sodium appetite, and to interfere with the expression of endogenous steroid receptors in the brain by use of molecular biological techniques and determine the effect upon sodium appetite. In addition to a large behavioral and physiological base, the present research is based on the observation that many brain regions which contain corticosteroid receptors also contain enzymes that reduce the A- ring of steroids, thereby creating molecules which are thought to interact with membrane-bound receptors (possibly the GABAa- benzodiazepine receptor) and hence elicit rapid responses. These are called the non-genomic effects because they do not require the formation of new gene products in order to work. In pilot work, the PI has found that A-ring-reduced metabolites of both ALDO and deoxycorticosterone (DOC, another mineralocorticoid) both elicit rapid sodium appetite in rats. In proposed work, the PI will identify specific brain areas where these metabolites are active, compare their activity to that caused by the parent hormone, and correlate the findings with measurements of activity of the enzymes in the same areas. Although several areas will be investigated, the amygdala is hypothesized to be particularly important since ablation there decreases mineralocorticoid-elicited sodium appetite. Other areas include the medial preoptic area and the paraventricular nuclei. The other series of proposed experiments will investigate genomic control over salt appetite by corticosteroids by using intracranially applied antisense oligomers to the mineralocorticoid (Type I) and glucocorticoid (Type II) receptors. An additional series of experiments will relate the genomic and the non-genomic effects of ALDO. Several models of eliciting sodium appetite will be used in these experiments, and extensive controls are proposed.