GLUTAMATE - A MAJOR EXCITATORY TRANSMITTER IN NEUROENDOCRINE REGULATION

Excitatory amino acids (EAAs), such as glutamate and aspartate, are fo und in large concentrations in presynaptic boutons of a variety of imp ortant hypothalamic nuclei, including the arcuate nucleus, supraoptic nucleus, suprachiasmatic nucleus, paraventricular nucleus, organum vas culosa of the lamina terminalis (OVLT) and preoptic area (POA). Likewi se, the different ionotropic/metabotropic EAA receptor subtypes are fo und in the same regions of the hypothalamus although there are differe nces 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 ant erior lobe, intermediate lobe and posterior lobe of the pituitary. The majority of work to date has focused on the role of EAAs in the contr ol of LH secretion. Administration of glutamate, NMDA, kainate or AMPA leads to rapid LH release mediated through the stimulation of hypotha lamic GnRH release. The major site of NMDA action appears to be the OV LT/preoptic area - where GnRH cell bodies reside, whereas AMPA and kai nate have been suggested to act primarily at the arcuate nucleus/media n eminence - the site of GnRH nerve terminals. There is evidence that some of the effects of glutamate on GnRH release may involve activatio n of the novel neurotransmitter nitric oxide and possibly catecholamin es. The physiological importance of EAAs in the control of LH surge ex pression is evidenced by the findings that the steroid-induced LH surg e in ovariectomized animals and the preovulatory LH surge in cycling a nimals and in PMSG-primed animals is blocked by treatment with specifi c NMDA receptor antagonists, or non-NMDA receptor antagonists. EAAs al so appear to be important in regulating the normal pulsatile pattern o f 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 ra t. A role for NMDA receptors in the achievement of puberty has been su ggested since activation of NMDA receptors has been shown to advance t he time of vaginal opening in the immature female rat, while kainate a nd DNQX were without effect. Steroids have been reported not to affect NMDA receptor binding in the hypothalamus; however, steroids appear t o up-regulate AMPA receptor GluR(1) subunit levels and non-NMDA recept or binding in the hypothalamus. Steroids also increase the release rat es of glutamate and aspartate in the POA during the steroid-induced LH surge in the ovariectomized adult rat. Evidence also exists supportin g a role for EAAs in the release of other pituitary hormones such as A CTH, growth hormones, prolactin, oxytocin and vasopressin which will a lso be discussed. Taken as a whole, the studies described herein provi de extensive and convincing evidence that EAA transmitters play a pivo tal role in the neuroendocrine regulation of a variety of hormonal sys tems.