EXCITATORY AMINO-ACIDS - FUNCTION AND SIGNIFICANCE IN REPRODUCTION AND NEUROENDOCRINE REGULATION

Excitatory amino acid neurotransmission is an essential component of t he neuroendocrine transmission line that regulates anterior pituitary luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secret ion. Excitatory amino acids (EAAs), such as glutamate and aspartate, a re found in large concentrations in presynaptic boutons of a variety o f important hypothalamic nuclei, including the arcuate nucleus, the su prachiasmatic nucleus, the supraoptic nucleus, the paraventricular nuc leus, and the preoptic area. EAA receptors can be divided into two bro ad groups, namely, ionotropic and metabotropic receptors. Ionotropic r eceptors are subdivided into NMDA (N-methyl-D-aspartate), kainate, and AMPA (DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) r eceptors. Their main mode of action is by the modulation of Na+, K+, a nd Ca2+ ion channels. Metabotropic receptors, on the other hand, act b y a G-protein-stimulated release of intracellular Ca2+ or modulation o f adenylate cyclase activity. The different EAA receptor subtypes are found in a variety of areas of the hypothalamus and the brain. In a va riety of species, the administration of glutamate, NMDA, or kainate le ads to LH release mediated through the stimulation of hypothalamic gon adotropin hormone-releasing hormone (GnRH) release. The major site of NMDA action appears to be the preoptic area-where GnRH cell bodies res ide. AMPA and kainate appear to act primarily at the arcuate nucleus/m edian eminence, the site of GnRH nerve terminals. NMDA may also act up on noradrenergic neurons in the locus coeruleus to influence hypothala mic GnRH release. The steroid-induced LH surge in ovariectomized anima ls and the preovulatory surge of LH in cycling animals and in pregnant mare's serum gonadotropic-primed animals are blocked by the NMDA anta gonist MK801 and the AMPA/kainate antagonist DNQX. MK801 also suppress ed FSH surges in most instances, whereas DNQX had no effect on FSH sur ges. In the ovariectomized female rat, both the NMDA antagonist AP5 an d the AMPA/kainate antagonist DNQX, lowered mean LH levels, LH pulse a mplitude, and LH pulse frequency. Activation of NMDA receptors advance d the time of vaginal opening in the immature female rat, while kainat e and DNQX were without effect. Gonadal steroid removal (castration) d id not alter NMDA receptor levels or affinity in the hypothalamus of f emale or male rats. Likewise, steroid replacement to castrate rats did not affect hypothalamic NMDA receptor levels or NMDA R(1) mRNA levels . Similarly, NMDA and kainate receptor levels in the hypothalamus did not change during the time of puberty in the female rat. In contrast, AMPA receptor (GluR(1)) immunoreactive levels in the magnocellular pre optic area (mPOA), the arcuate nucleus (ARC), and the suprachiasmatic nucleus (SCN) were found to be markedly elevated during the time of th e LH surge in estradiol-progesterone-treated castrate rats compared to those of the vehicle-only-treated castrate rat. The release rates of glutamate and aspartate in the POA were found to be significantly elev ated during the steroid-induced LH surge in the ovariectomized adult r at. Hence, the induction of the LH surge by steroids may involve enhan ced EAA neurotransmission mediated by steroid-induced elevations in th e release of glutamate and aspartate in the POA and AMPA receptors in the POA, the ARC, and the SCN. Evidence also exists supporting a role of EAAs in the release of other pituitary hormones, such as prolactin, ACTH, growth hormone, oxytocin, and vasopressin, as well as circadian rhythm induction and regulation. The above evidence points to a pivot al role of EAAs acting at the level of the hypothalamus in the neuroen docrine regulation of a variety of hormonal systems with the largest a mount of data available on the control of gonadotropin secretion. (C) 1994 Academic Press, Inc.