Feedback sensitivity of the rat hypothalamo-pituitary-adrenal axis and its capacity to adjust to exogenous corticosterone

Abstract

Chronic stress causing elevated morning (AM) corticosterone (B) concentrations of 2-8 micrograms B/dl does not appear to inhibit subsequent activity in the hypothalamic-pituitary-adrenal (HPA) axis, a surprising finding in view of the known depression in AM basal ACTH by only 3 micrograms B/dl in adrenalectomized rats. To distinguish between the possibilities that either intact rats are less sensitive to B feedback than adrenalectomized rats, or that chronic stress facilitates responses in the HPA axis, we elevated basal B levels in young male rats with slow-release B pellets in the absence of stress. Between 4-6 days after implantation of B pellets at three doses that elevated basal AM (diurnal trough) plasma B to approximately 1.2, 4, and 10 micrograms/dl, we studied basal ACTH and B at trough (AM) and peak evening (PM) times of the diurnal cycle, as well as the responses to the stress of restraint and blood collection from the tail at each time of day. We also determined mean daily plasma B, insulin, and glucose from samples collected at six intervals during the day. Adrenal, thymus, and body wts were measured as were transcortin (CBG) and adrenal phenylethanolamine-N-methyl transferase activity. Compared to controls implanted with wax pellets, all doses of B inhibited adrenal wt and AM stress responses and tended to inhibit pituitary ACTH content and adrenal phenylethanolamine-N-methyl transferase activity. Inhibition with the middle dose B pellet was close to maximally effective for these endpoints. Plasma glucose and thymus wt were significantly decreased and insulin was significantly increased in the middle and highest B pellet groups, with significantly greater effects at the highest dose. The gain in body wt and transcortin concentrations were significantly decreased only in the highest dose groups, in which mean daily plasma B was approximately 10 micrograms/dl, a level that clearly overwhelmed the capacity of the adrenocortical system to respond to any stimulus tested. By contrast, rats with low and middle dose B pellets appeared to adjust HPA axis function by decreasing the peak diurnal increase in B, so that 24-h mean B levels did not differ from control, and were maintained at approximately 5 micrograms/dl. Both of these groups also had inhibited ACTH responses to stress applied during the diurnal trough (AM). By contrast, neither group had inhibited ACTH responses to stress applied during the diurnal peak (PM). We conclude that: 1) The HPA axis of intact rats is extremely sensitive to exogenous B.(ABSTRACT TRUNCATED AT 400 WORDS)