Changes in responsiveness of the hypothalamic-pituitary-adrenocortical axis to 2-deoxy-D-glucose in developing rats.

During the first 2-3 weeks of postnatal life, the hypothalamic-pituitary-adrenocortical axis in rats exists in a relatively dormant state, termed the stress-hyporesponsive period. The development of the hypothalamic-pituitary-adrenal axis in young rats was examined by testing the ability of the nonmetabolizable glucose analog 2-deoxy-D-glucose (2-DG) to stimulate CRF in vitro and ACTH in vivo. Intraperitoneal injection of 2-DG into rats 11-12 days of age or into adult rats resulted in significant hyperglycemia by 60 min that was greater in magnitude in the adults. This response was accompanied by a significant increase in plasma ACTH to levels more than 500% of the noninjected or saline-injected control values in adults. A much smaller (approximately 200%) but still significant ACTH response was observed 60 min after 2-DG injection in the neonates. The drug had no effect on the ACTH response to exogenous CRF in the neonates. The pattern of corticosterone secretion paralleled that of ACTH, with a very moderate rise (from less than 1 to 2 micrograms/dl) seen in the neonate. To test the hypothesis that CRF was driving the ACTH response to glucoprivation induced by 2-DG in the neonate and to determine the ontogeny of hypothalamic responsiveness to this stressor, complete hypothalami were existed from rats 10-35 days of age and incubated in a defined buffer containing 5.5 mM glucose with or without 22 mM 2-DG. There was no effect of the analog on CRF secretion until day 35, at which time the magnitude of the response resembled that previously reported to occur in adult tissue. To determine if the failure to observe a CRF response was due to heightened sensitivity to the negative feedback effects of glucocorticoids, 8- to 10-day-old pups were adrenalectomized and returned to their mothers for 3 days, at which time the hypothalami were removed and tested for CRF secretion. No difference was observed between basal CRF secretory rates in the control or adrenalectomized groups, and there was still no significant response to 2-DG. Moreover, adrenalectomy did not potentiate the ACTH response to injection of 2-DG in vivo. The results suggest that during neonatal life in the rat, the hypothalamic glucostat/CRF cell mechanism is incapable of promoting a normal secretory response to glucoprivation. This deficit is probably not related to the increased sensitivity to negative feedback that has been proposed to account in part for the attenuated ACTH responses to stress in the neonatal animal.(ABSTRACT TRUNCATED AT 400 WORDS)