DNQX

Abstract: The contributions of two subclasses of excitatory amino acid transmitter receptors to the induction and expression of long-term potentiation (LTP) were analyzed in hippocampal slices. The quisqualate/kainate receptor antagonist DNQX (6,7-dinitro-quinoxaline-2,3-dione) blocked 85% of the evoked field potential, leaving a small response that was sensitive to D-AP5 (D-2-amino-5-phosphonopentanoate), an N-methyl-D-aspartate (NMDA) receptor blocker. This residual D-AP5-sensitive response was of comparable size in control and previously potentiated inputs. High-frequency stimulation in the presence of DNQX did not result in the development of robust LTP. Washout of the drug, however, revealed the potentiation effect. Thus NMDA-mediated responses can induce, but are not greatly affected by, LTP; non-NMDA receptors, conversely, mediate responses that are not needed to elicit LTP but that are required for its expression.

Abstract: The effects of gonadal steroid hormones on dendritic spines were studied in hippocampal neurons that were dissociated and grown in culture for 2–3 weeks. Exposure to estradiol caused up to a twofold increase in dendritic spine density in these neurons. The effect of estradiol was stereospecific and blocked by the steroid antagonist tamoxifen. The estradiol-induced rise in spine density was blocked by the NMDA antagonist APV, but not by the AMPA/KA antagonist DNQX. The estradiol-induced rise in spine density was blocked by the serine/threonine kinase inhibitor H7, but not by the tyrosine kinase inhibitor genestein, and was partially mimicked by PMA, an activator of protein kinase C. Estradiol also caused an increase in the fluorescence intensity of synaptophysin-immunoreactive terminals, corresponding to presynaptic boutons. Finally, estradiol caused a rise in [Ca]i reactivity of the cultured neurons to topical application of glutamate. These studies are the first to examine receptor and second messenger regulation of dendritic spines, and they illustrate the viability of cultured neurons as a powerful test system to address issues related to the regulation of dendritic spine maturation.

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 GluR1 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.(ABSTRACT TRUNCATED AT 400 WORDS)