Presynaptic 5-HT autoreceptors modulate N-methyl-D-aspartate-evoked 5-hydroxytryptamine release in the guinea-pig brain cortex

Guinea-pig cerebral cortical slices preincubated with [H-3]S-hydroxytryptamine ([H-3]5-HT) were superfused with Mg2+-free Krebs' solution. N-Methyl-D-aspartate (NMDA) stimulated tritium overflow in a concentration-dependent manner. The NMDA-evoked overflow was abolished by omission of Ca2+ or presence of 1.2 mM Mg2+, but only partly inhibited by tetrodotoxin. ?he competitive and noncompetitive NMDA receptor antagonists, DL-(E)-2-amino-4-methyl-5-phosphono-3-pentanoic acid (CGP 37849) and dizocilpine, respectively, also blocked the stimulatory effect of NMDA. Furthermore, the NMDA-evoked tritium overflow was inhibited by 5-carboxamidotryptamine in a manner susceptible to blockade by methiothepin, which given alone facilitated overflow. This facilitatory effect was increased in the presence of 6-nitroquipazine, a selective 5-HT reuptake inhibitor. it is concluded that the release of 5-HT in the guinea-pig cerebral cortex is stimulated via NMDA receptors, which are in part located on the serotoninergic axon terminals, and that the NMDA-evoked 5-HT release is modulated via inhibitory 5-HT autoreceptors.