N‐Methyl‐d‐Aspartic Acid/Glycine Interactions on the Control of 5‐Hydroxytryptamine Release in Raphe Primary Cultures

Abstract

Glutamic acid and glycine were quantified in cells and medium of cultured rostral rhombencephalic neurons derived from fetal rats. In the presence of 1 mM Mg2+, NMDA (50 microM) significantly stimulated (by 69%) release of newly synthesized 5-[3H]hydroxytryptamine ([3H]5-HT). D-2-Amino-5-phosphonopentanoate (AP-5; 50 microM) blocked the stimulatory effect of NMDA. AP-5 by itself inhibited [3H]5-HT release (by 25%), suggesting a tonic control of 5-HT by glutamate. In the absence of Mg2+, basal [3H]5-HT release was 60% higher as compared with release with Mg2+. AP-5 blocked the increased [3H]5-HT release observed without Mg2+, suggesting that this effect was due to the stimulation of NMDA receptors by endogenous glutamate. Glycine (100 microM) inhibited [3H]5-HT release in the absence of Mg2+. Strychnine (50 microM) blocked the inhibitory effect of glycine, indicating an action through strychnine-sensitive inhibitory glycine receptors. The [3H]5-HT release stimulated by NMDA was unaffected by glycine. In contrast, when tested in the presence of strychnine, glycine increased NMDA-evoked [3H]5-HT release (by 22%), and this effect was prevented by a selective antagonist of the NMDA-associated glycine receptor, 7-chlorokynurenate (100 microM). 7-Chlorokynurenate by itself induced a drastic decrease in [3H]5-HT release, indicating that under basal conditions these sites were stimulated by endogenous glycine. These results indicate that NMDA stimulated [3H]5-HT release in both the presence or absence of Mg2+. Use of selective antagonists allowed differentiation of a strychnine-sensitive glycine response (inhibition of [3H]5-HT release) from a 7-chlorokynurenate-sensitive response (potentiation of NMDA-evoked [3H]5-HT release).

MK-801 interaction with the 5-HT transporter: a real-time study in brain slices using fast cyclic voltammetry

“…First, the selective NMDA receptor antagonist CPP (Davies et al, 1986) at 20 µM had no effect on the electrically evoked 5-HT release and, second, NMDA, even at a concentration of up to 100 µM, did not inhibit the electrically evoked 5-HT release. When 10 mM NMDA was pressure-ejected into the nigral slices it released 5-HT (results not shown), which is in agreement with previously reported findings in the DRN (Becquet et al, 1993;Tao and Auerbach, 1996), but is in contrast to the early results in the SN (Reisine et al, 1982). Therefore, the MK-801-mediated potentiation of electrically stimulated 5-HT must involve other mechanism(s).…”

“…Where the role of NMDA on 5-HT transmission has been investigated (for example, in the DRN), application of glutamate resulted in the increase of neuronal discharge (Vandermaelan and Aghajanian, 1983;Vandermaelan et al, 1986;Levine and Jacobs, 1992) and an increase in 5-HT release in vitro (Becquet et al, 1993) or in vivo (Tao and Auerbach, 1996).…”

“…It is noteworthy that the DRN also receives a very dense glutamatergic input (Kalén et al, 1985;Nicholas et al, 1992), and activation of NMDA receptors in this nucleus results in release of 5-HT (Becquet et al, 1993;Tao and Auerbach, 1996). In the SNr, 5-HT is densely and uniformly distributed in fine varicose fibres, the majority of which are in close apposition to peridendritic axon terminals, dendrites, and soma (Mori et al, 1987).…”

Serotonin 5-HT1A receptor activation prevents phosphorylation of NMDA receptor NR1 subunit in cerebral ischemia

“…Although the cellular mechanisms underlying the neuroprotective effect of 5-HT 1A receptor activation remain unclear, a proposed mechanisms is the hyperpolarization of pyramidal neurons that inhibits the excitotoxicity by glutamate after cerebral ischemia (45). Previous studies have shown that 5-HT 1A receptor stimulation can modulate NMDA receptor-induced Ca 2+ influx (22,41), and other reports have provided evidence for functional interactions between NMDA channels and 5-HT 1A receptors (1,36), suggesting that 5-HT 1A receptors may serve as mediators of autoprotective mechanisms of the brain against the effects of excitatory amino acid overstimulation (28). Also it is known that one of the regulatory sites of NMDA receptor is the Ser897 of NR1 subunit and that PP1 is one of the enzymes that regulate the function of this receptor mediating its dephosphorylation (17,20,44,47).…”

The Role of Nitric Oxide and Nitrosative Stress in Schizophrenia

“…Serotonergic 5-HT receptor activation may be responsible for the weakening of signal transduction dependent on NO and cGMP released by NMDA receptor activation as well as on arachidonic acid. Becquet et al observed that NMDA receptor activation stimulates the release of serotonin, and this effect is modulated by glycine (Becquet et al 1993 ). Serotonin via the 5-HT2 receptor reduces the cholinergic receptor-dependent increase in the release of IPs and the mobilization of intracellular calcium (Samochocki and Strosznajder 1995 ).…”