VENTROMEDIAL HYPOTHALAMIC-LESIONS INHIBIT CORTICOSTEROID FEEDBACK-REGULATION OF BASAL ACTH DURING THE TROUGH OF THE CIRCADIAN-RHYTHM

We have determined the effects of bilateral electrolytic lesions of th e ventromedial hypothalamus (VMH) on activity in the hypothalamo-pitui tary-adrenal (HPA) system. Acutely, during the first 5 days, lesions o f the anterior-medial VMH caused loss of the diurnal rhythms in food i ntake and plasma corticosterone (B) levels. Plasma B concentrations we re elevated during the time of the normal trough of the basal diurnal rhythm in HPA axis activity and the diurnal rhythm in food intake was abolished, in agreement with the results of others. Consistent with hy peractivity in the HPA axis, lesioned rats had increased adrenal weigh t, decreased thymus and body weights and decreased plasma transcortin concentrations. To determine how lesions of the VMH provoke these incr eases in activity of the HPA system, the sensitivity of ACTH in adrena lectomized, lesioned rats to replacement with exogenous B was determin ed under basal conditions during the trough (morning - AM) and peak (e vening - PM) of the diurnal rhythm in HPA axis activity. ACTH in lesio ned rats in the AM was insensitive to feedback over the very low range of plasma B of 14 mu g/dl, whereas sham-lesioned controls exhibited t he normal, high sensitivity of ACTH to B at this time of day. There wa s no difference between the sensitivity of ACTH to this low range of B in the PM in VMH- and sham-lesioned rats. Two to 5 weeks after VMH le sions, as found by others, mean daily plasma B levels did not differ f rom sham-lesioned controls; however; plasma B during the AM was still mildly elevated in these rats. Inhibition of plasma B in the PM by dex amethasone was less effective in lesioned rats. Although HPA system re sponses to hypoglycemia, corticotropin-releasing factor and ACTH were normal, the lesioned rats exhibited obesity, hyperinsulinemia, hypergl ycemia, hypertension and tachycardia, all signs consistent with mild h yperactivity of the PHA axis. Occupancy of type I, high-affinity corti costeroid receptors is known to control basal activity of the HPA syst em during the trough of the diurnal rhythm and to interact with glucoc orticoid receptors to affect basal activity during the peak of the diu rnal rhythm and during AM stress. We conclude that VMH lesions disrupt transmission of inhibitory signals, mediated by occupancy of type I c orticosteroid receptors, that are initiated by a B feedback site.