Glutamate: A Major Excitatory Transmitter in Neuroendocrine Regulation

Abstract

Excitatory amino acids (EAAs), such as glutamate and aspartate, are found in large concentrations in presynaptic boutons of a variety of important hypothalamic nuclei, including the arcuate nucleus, supraoptic nucleus, suprachiasmatic nucleus, paraventricular nucleus, organum vasculosa of the lamina terminalis (OVLT) and preoptic area (POA). Likewise, the different ionotropic/metabotropic EAA receptor subtypes are found in the same regions of the hypothalamus although there are differences in their individual patterns of localization. Furthermore, there is evidence supporting the presence of ionotropic N-methyl-D-aspartate (NMDA) receptors and non-NMDA (kainate and AMPA) receptors in the anterior lobe, intermediate lobe and posterior lobe of the pituitary. The majority of work to date has focused on the role of EAAs in the control of LH secretion. Administration of glutamate, NMDA, kainate or AMPA leads to rapid LH release mediated through the stimulation of hypothalamic GnRH release. The major site of NMDA action appears to be the OVLT/preoptic area – where GnRH cell bodies reside, whereas AMPA and kainate have been suggested to act primarily at the arcuate nucleus/median eminence – the site of GnRH nerve terminals. There is evidence that some of the effects of glutamate on GnRH release may involve activation of the novel neurotransmitter nitric oxide and possibly catecholamines. The physiological importance of EAAs in the control of LH surge expression is evidenced by the findings that the steroid-induced LH surge in ovariectomized animals and the preovulatory LH surge in cycling animals and in PMSG-primed animals is blocked by treatment with specific NMDA receptor antagonists, or non-NMDA receptor antagonists. EAAs also appear to be important in regulating the normal pulsatile pattern of LH release as evidenced by the finding that both the NMDA antagonist, AP5, and the AMPA/kainate antagonist, DNQX, lower mean LH levels, LH pulse amplitude and LH pulse frequency in the adult ovariectomized rat. A role for NMDA receptors in the achievement of puberty has been suggested since activation of NMDA receptors has been shown to advance the time of vaginal opening in the immature female rat, while kainate and DNQX were without effect. Steroids have been reported not to affect NMDA receptor binding in the hypothalamus; however, steroids appear to up-regulate AMPA receptor GluRi subunit levels and non-NMDA receptor binding in the hypothalamus. Steroids also increase the release rates of glutamate and aspartate in the POA during the steroid-induced LH surge in the ovariectomized adult rat. Evidence also exists supporting a role for EAAs in the release of other pituitary hormones such as ACTH, growth hormones, prolactin, oxytocin and vasopressin which will also be discussed. Taken as a whole, the studies described herein provide extensive and convincing evidence that EAA transmitters play a pivotal role in the neuroendocrine regulation of a variety of hormonal systems.

Metabotropic Glutamate Receptor Subtype 7 Ablation Causes Dysregulation of the HPA Axis and Increases Hippocampal BDNF Protein Levels: Implications for Stress-Related Psychiatric Disorders

“…Glutamatergic neurotransmission has long been implicated as a critical regulator of the stress response (van den Pol et al, 1990;Brann, 1995). mGluRs in particular appear to play a crucial role in mediating neuroendocrine responses.…”

Premature elevation in serum insulin-like growth factor-I advances first ovulation in rhesus monkeys

“…Acute administration of NMDA provided data on the developmental increase in activity of LHRH neurons (Brann 1995). Indeed, the activation of glutamate receptors has been implicated as a possible mechanism regulating the development of LHRH release (Plant et al 1989, Urbanski & Ojeda 1990 and NMDA induces LH secretion in monkeys via activation of LHRH neurons and not through any direct action on the pituitary (Gay & Plant 1987, Plant et al 1989.…”

“…The working hypothesis was that a significant elevation in serum IGF-I concentrations would accelerate age at first ovulation and that this effect would be due to an augmentation of LH secretion and not necessarily to a change in ovarian responsiveness to gonadotropin stimulation induced by IGF-I (Giudice 1992). To define further how IGF-I may affect the activity of LHRH neurons and pituitary responsiveness, the response of LH release to the acute administration of the glutamate receptor agonist N-methyl-, -aspartic acid (NMDA ;Brann 1995) and to an LHRH agonist were evaluated. The results of the study suggest that the premature elevation in peripheral IGF-I concentrations accelerates the occurrence of first ovulation by increasing the responsiveness of LHRH neurons and by an augmentation of LH secretion.…”

Nitric oxide modulation of the hypothalamo-neurohypophyseal system

“…At these sites, the modular protein-protein motif or PDZ domain of NOS, implicated in the signal transduction mechanism, links the synthase to protein complexes (19). Significantly, NOS and glutamate receptors are widely distributed in the hypothalamo-neurohypophyseal system (20) and circumventricular organs (21). Additionally, GABAergic innervation of magnocellular neurons is abundant (22) and presynaptic activation of glutamate receptors modulates release of GABA in these neurons (23).…”