Hypothalamic mechanisms mediating glutamate effects on the hypothalamo-pituitary-adrenocortical axis.

The effect of local administration of glutamate into the hypothalamic paraventricular nucleus (PVN) on the hypothalamo-pituitary adrenocortical (HPA) axis was studied in male rats. Glutamate caused CRH-41 depletion from the median eminence (ME) and a consequent rise in ACTH and corticosterone (CS) serum levels. In rats pretreated with systemic dexamethasone (dex) these effects were completely inhibited. The administration of the glucocorticoid receptor antagonist RU-38486 abolished the inhibitory effect of dex on the adrenocortical discharge. In addition, the depletion of hypothalamic norepinephrine (NE) and serotonin (5-HT) by specific neurotoxins administered into the ventral noradrenergic blundle or into the raphe nuclei respectively, inhibited the response of serum ACTH and CS following PVN glutamate administration. These data indicate that glutamate stimulated the HPA axis via the release of ME CRH-41 into the portal circulation. This response is steroid sensitive involving type II glucocorticoid receptors. Hypothalamic NE and 5-HT participate in the glutamate induced HPA axis activation.