Adrenocortical axis responses to adrenergic and glutamate stimulation are regulated by the amygdala.

We have examined the effect of lesions of the central and medial amygdala on the pituitary-adrenal responses to noradrenergic stimulation and to the injection of glutamate into the paraventricular nucleus. Bilateral lesions of the amygdalar nuclei inhibited adrenocorticotrophic hormone and corticosterone responses to electrical stimulation of the ventral noradrenergic bundle, and to the injection of the alpha1-adrenergic agonist phenylephrine or glutamate. These results suggest that the amygdala may facilitate the stimulatory roles of noradrenaline and glutamate on the adrenocortical axis. The data contribute to understanding the mechanisms by which the amygdala is involved in the function of this axis.

Involvement of endogeneous glutamate in the stimulatory effect of norepinephrine and serotonin on the hypothalamo-pituitary-adrenocortical axis.

The effects of ionotropic glutamate receptor antagonists on the pituitary adrenal responses following injections of norepinephrine (NE) and serotonin (5-HT) receptor agonists into the hypothalamic paraventricular nucleus (PVN) or electrical stimulation of central NE and 5-HT pathways were studied in anesthetized male rats. PVN injections of an alpha(1)-adrenergic receptor agonist or a serotonergic 5-HT(1A) receptor agonist markedly increased both adrenocorticotropin (ACTH) and corticosterone (CS) serum levels. These responses were significantly inhibited by separate pre-injection of the selective non-NMDA and NMDA glutamate receptor subtype antagonists into the PVN in a dose-dependent manner. Electrical stimulation of either the ventral noradrenergic bundle or the dorsal raphe nucleus markedly increased serum ACTH and CS. These responses were also significantly attenuated by pre-injection of the above glutamate ionotropic receptor antagonists in a dose-dependent manner. These results suggest that glutamatergic interneurons in the PVN, acting via non-NMDA and NMDA receptors, may act as an excitatory mechanism in the NE and 5-HT control of hypothalamic ACTH secretagogues.

Further evidence for the central effect of dexamethasone at the hypothalamic level in the negative feedback mechanism.

The site of action of glucocorticoids (GC) in exerting negative feedback upon the hypothalamo-pituitary-adrenocortical (HPA) axis is not yet clear. In the present study we have examined whether dexamethasone (Dex) can inhibit the HPA axis stress responses by acting locally at the hypothalamic level in freely moving male rats. Local micro-injection of Dex in the paraventricular nuclei (PVN; 1 microg) prevented a decrease of CRH-41 content in the median eminence. The PVN Dex injections (0.25-1 microg) also inhibited the rise in plasma ACTH and corticosterone (CS) following short photic stimulation in a dose dependent manner. In PVN Dex-injected rats, i.v. injection of CRH-41 increased serum ACTH and CS levels similar to that observed in rats injected with saline into the PVN indicating normal sensitivity of the pituitary gland to CRH-41. Local injection of [3H]Dex in the PVN showed that only a negligible amount of radioactivity was found in the pituitary. These data indicate that minute amounts of Dex in the PVN, which did not affect the pituitary, blocked the HPA axis responses to photic stimulation. It is suggested that Dex may exert its inhibitory effect on the HPA axis at least in part at the hypothalamic level.

The amygdala regulates the pituitary-adrenocortical response and release of hypothalamic serotonin following electrical stimulation of the dorsal raphe nucleus in the rat.

The amygdala is known to modulate the function of the hypothalamo-pituitary-adrenocortical (HPA) axis, but the mechanism of this effect is still not clear. In the present study we examined the specific role of the serotonin (5-HT) system in mediating the effect of the amygdala on the activity of the HPA axis. Bilateral lesions of the amygdala in rats reduced the adrenocorticotropin (ACTH) and corticosterone responses to electrical stimulation of the dorsal raphe nucleus, where the cell bodies of serotonergic neurons are located. Amygdala lesions had no effect on the ACTH and corticosterone responses to administration of a 5-HT(1A) receptor agonist directly into the paraventricular nucleus (PVN) of the hypothalamus, indicating that there was no impairment in the activity of postsynaptic 5-HT(1A) receptors in the hypothalamus. In vivo microdialysis showed that amygdala lesions markedly attenuated the effect of electrical stimulation of the dorsal raphe to increase extracellular secretion of 5-HT in the PVN. This is the first demonstration that the amygdala has a facilitatory effect on the function of dorsal raphe 5-HT neurons which project to the PVN, and suggests a mechanism by which the amygdala may modulate the function of the HPA axis.

Evidence for a mutual interaction between noradrenergic and serotonergic agonists in stimulation of ACTH and corticosterone secretion in the rat.

We investigated the mutual interactions between hypothalamic norepinephrine (NE) and serotonin (5-HT) in mediating the ACTH and corticosterone responses to direct stimulation of the paraventricular nucleus (PVN) with adrenergic and serotonergic agonists. The hormone responses to the intrahypothalamic injection of the alpha1-adrenergic agonist phenylephrine (20 nmol/2 microl) were significantly reduced by prior depletion of hypothalamic 5-HT with intra-PVN injection of the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), but not after depletion of hypothalamic NE by intra-PVN injection of the noradrenergic neurotoxin 6-hydroxydopamine (6-OHDA). The ACTH and corticosterone responses to intrahypothalamic injection of the 5-HT(1A) receptor agonist 8-OH-DPAT (20 n mol/2 microl) were significantly reduced by depletion of hypothalamic NE with 6-OHDA, but not after depletion of hypothalamic 5-HT with 5,7-DHT. These mutual interactions between the NE and 5-HT neuronal systems, which innervate the PVN, may explain previous findings of equivalent reductions in the hypothalamic-pituitary-adrenal axis responses to neural stimulation after neurotoxic lesioning of either the NE or 5-HT systems.