Excitatory amino acids: Function and significance in reproduction and neuroendocrine regulation

Excitatory amino acid neurotransmission is an essential component of the neuroendocrine transmission line that regulates anterior pituitary luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. 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, the suprachiasmatic nucleus, the supraoptic nucleus, the paraventricular nucleus, and the preoptic area. EAA receptors can be divided into two broad groups, namely, ionotropic and metabotropic receptors. Ionotropic receptors are subdivided into NMDA (N-methyl-D-aspartate), kainate, and AMPA (DL-α-amino-3-hydroxy- 5-methyl-4-isoxazole propionic acid) receptors. Their main mode of action is by the modulation of Na⁺, K⁺, and Ca²⁺ ion channels. Metabotropic receptors, on the other hand, act by a G-protein-stimulated release of intracellular Ca²⁺ or modulation of adenylate cyclase activity. The different EAA receptor subtypes are found in a variety of areas of the hypothalamus and the brain. In a variety of species, the administration of glutamate, NMDA, or kainate leads to LH release mediated through the stimulation of hypothalamic gonadotropin hormone-releasing hormone (GnRH) release. The major site of NMDA action appears to be the preoptic area-where GnRH cell bodies reside. AMPA and kainate appear to act primarily at the arcuate nucleus/median eminence, the site of GnRH nerve terminals. NMDA may also act upon noradrenergic neurons in the locus coeruleus to influence hypothalamic GnRH release. The steroid-induced LH surge in ovariectomized animals and the preovulatory surge of LH in cycling animals and in pregnant mare's serum gonadotropic-primed animals are blocked by the NMDA antagonist MK801 and the AMPA/kainate antagonist DNQX. MK801 also suppressed FSH surges in most instances, whereas DNQX had no effect on FSH surges. In the ovariectomized female rat, both the NMDA antagonist AP5 and the AMPA/kainate antagonist DNQX, lowered mean LH levels, LH pulse amplitude, and LH pulse frequency. Activation of NMDA receptors advanced the time of vaginal opening in the immature female rat, while kainate and DNQX were without effect. Gonadal steroid removal (castration) did not alter NMDA receptor levels or affinity in the hypothalamus of female or male rats. Likewise, steroid replacement to castrate rats did not affect hypothalamic NMDA receptor levels or NMDA R₁ 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 (GluR₁) immunoreactive levels in the magnocellular preoptic area (mPOA), the arcuate nucleus (ARC), and the suprachiasmatic nucleus (SCN) were found to be markedly elevated during the time of the 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 elevated during the steroid-induced LH surge in the ovariectomized adult rat. Hence, the induction of the LH surge by steroids may involve enhanced EAA neurotransmission mediated by steroid-induced elevations in the 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 pivotal role of EAAs acting at the level of the hypothalamus in the neuroendocrine regulation of a variety of hormonal systems with the largest amount of data available on the control of gonadotropin secretion.