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

Abstract

Guinea-pig cerebral cortical slices preincubated with [ 3H]5-hydroxytryptamine ([ 3H]5-HT) were superfused with Mg 2+-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 Ca 2+ or presence of 1.2 mM Mg 2+, but only partly inhibited by tetrodotoxin. The 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.