The Site of the Suppressive Action of Dexamethasone on Pituitary-Adrenal Activity

Administration of 3H-dexamethasone with carrier to rats either into the third brain ventricle (ic) in doses ranging from 0.01 to 10 Wg, or intravenously in a dose of 10 μg was used to explore the site of the suppressive action of this steroid on pituitary-adrenal activity. Almost all of the radioactivity in the brain was shown to be unmodified dexamethasone. Following iv injection the uptake and disappearance patterns of dexamethasone in the brain were clearly distinct from that of the other tissues. Regional differences in concentration and uptake o:f dexamethasone could however be observed within the brain. In limbic and mesencephalic structures a rise in concentration was found up to 4 hr, yielding a maximum of approximately 0.025% of the injected dose per gram tissue. Four hr following ic injection, the dexamethasone concentration in the hypothalamus appeared to be much higher than after iv injection. This higher concentration was not associated with a proportionally greater suppression of the pituitary- adrenal system as determined by the corticosterone concentration in plasma. Further studies indicated that in spite of minor differences in localization of dexamethasone following both routes of injection, no relationship between the concentration of dexamethasone in hypothalamic fractions and the suppressing effect on pituitaryadrenal activation was found. However, such a concentration-effect relationship could be clearly demonstrated for the anterior pituitary particularly in the cell nuclear fraction. Four hr following iv and ic injection, the dexamethasone concentrations in plasma were not significantly different. At this time, the effect appeared to be dependent on the dose rather than on the route of administration. Hence, it seems that dexamethasone in the third brain ventricle is transported to its site of action by the general circulation. The results obtained in the present study favor a pituitary site of action of dexamethasone, while the presence of dexamethasone in the hypothalamus appears to be of little importance in the suppression of stress-induced pituitary-adrenal activity. (Endocrinology94: 61, 1974)