Voltage-dependent block of NMDA responses by 5-HT agonists in ventral spinal cord neurones

1. Modulation by 5-hydroxytryptamine receptor agonists of the NMDA responses of ventral spinal cord neurones was studied by use of the whole-cell patch-clamp technique. 2. In a Mg-free solution containing tetrodotoxin and glycine, 5-hydroxytryptamine (5-HT, 10-100 microM) reduced the NMDA response, the block increasing with hyperpolarization. Kainate responses were little affected. 3. Some classical agonists of 5-HT receptors induced similar blocking effects. At 10 microM, both a selective agonist of 5-HT2 receptors, (+/-)-2,5-dimethoxy-4 iodo amphetamine (DOI), and a selective agonist of some 5-HT1 receptors, (+/-)-8-hydroxy-2(n-dipropyl amino) tetralin (8-OH-DPAT), induced pronounced blocking effects, of 48% and 33% respectively at -100 mV, whereas another 5-HT1 agonist, 5-carboxamidotryptamine (5-CT) was ineffective. At 100 microM, 5-methoxytryptamine (5-MeOT) induced a complete block of the NMDA responses recorded at -100 mV. The order of potency was: 5-MeOT congruent to DOI > 8-OH-DPAT > 5-HT > 5-CT. 4. Neither spiperone nor ketanserin (1 microM) prevented the blocking effect of 5-HT or DOI. 5. Prolonged preincubations with 5-HT did not block the response if NMDA was applied without 5-HT. When 5-HT agonists were applied both by preincubation and with NMDA, the degree of block increased during the NMDA application. 6. Lowering the NMDA concentration (from 100 to 20 microM) slightly decreased the blocking effect of 5-MeOT. 7. External Mg2+ ions (1 mM) also reduced the blocking effects of 5-HT and 5-MeOT. 8. The blocking effects described appear to be independent of classical 5-HT receptors. Their voltage-dependence suggests a mechanism of open channel block consistent with all the results obtained.