Research reportGlutamate agonists activate the hypothalamic–pituitary–adrenal axis through hypothalamic paraventricular nucleus but not through vasopressinerg neurons
Introduction
In the hypothalamic stress response, the corticotropin-releasing hormone (CRH [50])- and arginine vasopressin (AVP [3])-containing nucleus paraventricularis hypothalami (PVN) plays a crucial role [36]. These neurons project to the median eminence and the CRH and AVP through portal blood activate the adrenocorticotropin (ACTH) secretion [43], which stimulate the adrenal gland glucocorticoid secretion through systemic blood circulation. Theoretically, lesioning the PVN would lead to total disruption of the hypothalamic–pituitary–adrenal (HPA) axis activation, although there are some contradictory data in the literarure (for details, see Ref. [58]). The partial conservation of the ACTH and corticosterone (CS) release after PVN lesion suggest that other brain regions may also have some measurable influence on the activation of the HPA, at least during some kind of stresses.
Glutamate is a well-known excitatory neurotransmitter and exerts its action at distinct receptor subtypes. These subtypes are the voltage-gated N-methyl-d-aspartate (NMDA)-preferring ionotropic group, the non-NMDA-preferring ionotropic excitatory amino acid (EAA) receptor family that includes several subtypes as the R,S-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate coreceptors and kainate-preferring EAA receptors and several metabotropic subtypes working by generation of second messengers [18], [38]. These receptors are present both in the hypothalamus [19] and pituitary [31], [32], suggesting their role in neuroendocrine regulation [34], [52].
EAAs play an important role in activation of the HPA axis, which is a key component of the stress adaptation. In rats, the first evidence was that glutamate injection into the third ventricle elevated plasma ACTH level [35]. Agonists of all subtypes had similar effects in later studies [12], [15], [21], [44], [25]. The role of endogenous glutamate was also demonstrated in stress-induced HPA activation using different antagonist in rats [23], [49], [57] as well as in humans [29].
The primary site of action of glutamate has been suggested to be at the level of the hypothalamus via the control of hypothalamic releasing factors. According to this suggestion in in vitro studies, EAA could influence CRH and AVP secretion from hypothalamic slides [13], [24], [41]. However, ACTH release could be evoked with EAA injection into other brain regions as well (dorsomedial hypothalamus in rat [5], locus coeruleus and dorsal rostral pons of cat [10], [11], nucleus trigeminus caudalis in cat [6]). There are several data demonstrating that glutamate can exert its action directly upon anterior pituitary cells, too. NMDA R1 receptor subunit immunoreactivity and mRNA is present on immature and adult male and female pituitary [7], [42]. Non-NMDA receptor subunits are also present on all three lobes of the pituitary [20], [27]. EAAs, applied in vitro directly to the pituitary, were able to induce ACTH and other hormone releases [31], [32], [39], [47], [55]. Moreover, EAAs can increase the intracellular Ca level in pituitary cells, which support their physiological role in the neuroendocrine regulation at the level of pituitary [53]. The adrenal gland also has stress-inducible glutamatergic receptors [20], [46].
There is a vast body of information that is available on the role of AVP in stress response [1], [2]; however, the role of AVP in the EAA–HPA interaction is controversial. Passive immunoneutralisation with anti-CRH but not anti-AVP antiserum effectively blocked the N-methyl-aspartate (NMA; the mixture of l and d isoforms) and kainate-induced ACTH release during stress hyporesponsive period [12]; however, in vitro AVP but not CRH release was inducible from hypothalamic slides by EAA agonists [13]. NMDA was also reported to have modulatory effect on central vasopressinerg system measured by V1a receptor binding [48] or hippocampal vasopressin release [40].
Although the glutamatergic innervation of the PVN seems to play a prominent role in the HPA activation, the role of the extended presence of glutamate and its receptors in the brain and also in the pituitary and adrenal gland has remained obscure. Our goal was to study the effect of PVN lesion on NMDA- and kainate-induced HPA axis activation to see whether there are some other EAA-driven brain regions outside the PVN or on other level of the HPA axis (hypophysis, adrenal gland) being involved in the hormonal stress reaction. The role of AVP was further studied using naturally AVP-deficient Brattleboro strain.
Section snippets
Materials and methods
Male rats (220–400 g) of Wistar strain were obtained from Charles River, Budapest, Hungary. Brattleboro rats were maintained in our Institute in a colony started from breeder rats from Harlan, Indianapolis, IN, USA. Prior to surgery, the animals were housed five per cage at 23–24 °C and 50–60% humidity with 12/12 h light–dark cycle (light on 06:00, off 18:00). After surgery, the animals were caged individually. Animals were given rat chow and tap water ad libitum. Sham-operated rats served as
Results
In Wistar rats, the i.v. injection of 5 mg/kg NMDA induced remarkable elevation of ACTH and corticosterone plasma levels already at 5 min, but this effect was quite short, and ACTH levels almost returned to normal 15 min after the injection (Fig. 1). The PVN lesion did not modify the basal levels but significantly diminished the NMDA-induced ACTH (Fig. 1A) and corticosterone (Fig. 1B) rise. Some elevation was still visible after PVN lesion in both hormones; however, this elevation did not reach
Discussion
The results of our study show that ionotrop glutamatergic agonist injected systemically can activate the HPA axis predominantly centrally (through PVN) and not at the pituitary or adrenal gland level [14], [16]. While the HPA axis activation was unchanged in AVP-deficient Brattleboro animals, the CRH-containing neurons of the PVN seem to be the principal site of activation.
The HPA stimulatory action of the EAA is well documented [8], [9], [15]. Different authors used different doses, and we
Acknowledgment
These studies were supported by an OTKA grant T 025845 to GBM.
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