Glutamate: A major excitatory transmitter in neuroendocrine regulation

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.