Involvement of Endogeneous Glutamate in the Stimulatory Effect of Norepinephrine and Serotonin on the Hypothalamo-Pituitary-Adrenocortical Axis

Abstract

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 α₁-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.

Children under stress – COMT genotype and stressful life events predict cortisol increase in an acute social stress paradigm

“…However, it should be noted that COMT also metabolizes norepinephrine, which is an additional potential regulator of stress reactivity (Feldman & Weidenfeld, 2004). The PFC, in turn, has been implicated to be involved in the processing of psychological stressors (Dedovic et al 2009b), thus suggesting a mechanism through which COMT might exert an influence on peripheral stress parameters.…”

“…Dopamine and norepinephrine are among those regulators of the stress response (Feldman & Weidenfeld, 2004 ;Sullivan & Dufresne, 2006). In turn, stress has also been found to impact dopaminergic function (Arnsten & Goldman-Rakic, 1998 ;Murphy et al 1996).…”

Stress-related synaptic plasticity in the hypothalamus

“…For example, noradrenaline, which potently activates the HPA axis during stress 72,73 , acts on α1adrenergic receptors to robustly increase the frequency of spontaneous glutamatergic synaptic cur rents in PNCs 74 . Moreover, in vivo demonstrations that increases in circulating ACTH and CORT -induced by electrical stimulation of noradrenergic afferents to the PVN or by intraPVN administration of an α1adrenergic receptor agonist -are blocked by intra PVN microinjections of glutamate receptor antagonists (both NMDAR and nonNMDAR antagonists) provide additional evidence for a pivotal role of glutamate in noradrenalininduced HPAaxis activation 75 .…”

The Role of the Amygdala in Regulating the Hypothalamic-Pituitary-Adrenal Axis

“…For example, the efect of hypothalamic NE on CRH release is mediated by intrahypothalamic glutamatergic interneurons [36]. Also, the activation of the HPA axis by electrical stimulation of the VNAB, or by direct PVN injection of, phenylephrine (an agonist with high ainity to α1-adrenergic receptors) was markedly inhibited by PVN administration of selective ionotropic glutamate receptor antagonists [37].…”