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 mu M) 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 mu M, 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 mu M, 5-methoxytryptamine (5-MeOT) induced a complete block of the NMDA responses recorded at -100 mV. The order of potency was: 5-MeOT similar or equal to DOI> 8-OH-DPAT > 5-HT > 5-CT. 4 Neither spiperone nor ketanserin (1 mu M) 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 mu M) 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.