Voltage‐dependent inhibition of recombinant NMDA receptor‐mediated currents by 5‐hydroxytryptamine

1 The effect of 5‐HT and related indolealkylamines on heteromeric recombinant NMDA receptors expressed in Xenopus oocytes was investigated using the two‐electrode voltage‐clamp recording technique. 2 In the absence of external Mg 2+ ions, 5‐HT inhibited NMDA receptor‐mediated currents in a concentration‐dependent manner. The inhibitory effect of 5‐HT was independent of the NR1a and NR2 subunit combination. 3 The inhibition of glutamate‐evoked currents by 5‐HT was use‐ and voltage‐dependent. The voltage sensitivity of inhibition for NR1a+NR2 subunit combinations by 5‐HT was similar, exhibiting an e‐fold change per ∼20 mV, indicating that 5‐HT binds to a site deep within the membrane electric field. 4 The inhibition of the open NMDA receptor by external Mg 2+ and 5‐HT was not additive, suggesting competition between Mg 2+ and 5‐HT for a binding site in the NMDA receptor channel. The concentration‐dependence curves for 5‐HT and 5‐methoxytryptamine (5‐MeOT) inhibition of NMDA receptor‐mediated currents are shifted to the right in the presence of external Mg 2+ . 5 The related indolealkylamines inhibited glutamate‐evoked currents with the following order of inhibitory potency: 5‐MeOT=5‐methyltryptamine>tryptamine>7‐methyltryptamine>5‐HT≫tryptophan=melatonin. 6 Taken together, these data suggest that 5‐HT and related compounds can attenuate glutamate‐mediated excitatory synaptic responses and may provide a basis for drug treatment of excitoxic neurodegeneration.British Journal of Pharmacology (2005) 144 , 323–330. doi: 10.1038/sj.bjp.0706049