ROLES OF TYPE-I AND TYPE-II CORTICOSTEROID RECEPTORS IN REGULATION OFBASAL ACTIVITY IN THE HYPOTHALAMO-PITUITARY-ADRENAL AXIS DURING THE DIURNAL TROUGH AND THE PEAK - EVIDENCE FOR A NONADDITIVE EFFECT OF COMBINED RECEPTOR OCCUPATION

Negative feedback regulation of basal activity in the hypothalamopitui tary-adrenal (HPA) axis requires less corticosterone (B) at the trough (morning) than at the peak (evening) of the diurnal rhythm. It has be en hypothesized that in the morning in rats, occupation of the high af finity, type I corticosteroid receptors is sufficient to inhibit adren alectomy (ADX)-induced increases in plasma ACTH secretion, whereas in the evening, regulation occurs through the occupation of the lower aff inity type II corticosteroid receptors. To examine this hypothesis, th e sensitivity of ACTH to inhibition by two different doses of B or of dexamethasone (DEX) were compared in ADX rats killed in the morning or the evening (B has a higher affinity for type I receptors in vitro an d in vivo; in vivo, DEX has a higher affinity for type IT receptors). The requirement for greater concentrations of corticosteroids to inhib it ACTH secretion in the evening was verified. The effect of these tre atments on the number of neurons immunoreactive for vasopressin (AVP) and on the expression of AVP messenger RNA (mRNA) in the parvocellular portion of the paraventricular nuclei was also examined. In the morni ng, plasma concentrations of B equivalent to the IC50 for the reductio n of plasma ACTH in the morning reduced the amount of AVP mRNA, but no t immunoreactive AVP cell number as compared with ADX rats. DEX reduce d plasma ACTH in the morning but did not prevent high levels of expres sion of AVP mRNA or protein. AVP mRNA was more sensitive to B in the m orning than in the evening. Antagonist to the type I receptor (spirono lactone) given chronically to ADX rats treated with B increased plasma ACTH secretion at both times of day, even though the plasma B concent rations suggested occupancy of a large proportion of the type II recep tors. To test the hypothesis that an interaction between the type I an d II receptor is necessary for the control of HPA activity at the peak of the diurnal rhythm, ADX rats were given B or DEX, alone or in comb ination. DEX reduced evening plasma ACTH only in the presence of very low concentrations of B, suggesting that for full potency, type II rec eptor occupation requires type I receptor occupation. In summary, thes e results demonstrate that occupation of type I corticosteroid recepto rs is capable of controlling basal activity in the HPA axis in the mor ning and that in the evening, type I receptor occupation potentiates t he inhibition of plasma ACTH by occupation of type II receptors.