Serotonin inhibition of the NMDA receptor/nitric oxide/cyclic GMP pathway in human neocortex slices: involvement of 5‐HT2Cand 5‐HT1Areceptors

The NMDA receptor/nitric oxide (NO)/cyclic GMP pathway and its modulation by 5‐hydroxytryptamine (5‐HT) was studied in slices of neocortical samples obtained from patients undergoing neurosurgery.The cyclic GMP elevation produced by 100 μMNMDA was blocked by 100 μMof the NO synthase inhibitor NG‐nitro‐L‐arginine (L‐NOARG) or by 10 μMof the soluble guanylate cyclase inhibitor 1H‐[1,2,4]oxadiazolo[4,3,‐α] quinoxaline‐1‐one (ODQ).The NMDA effect was prevented by 5‐HT or by the 5‐HT2agonist (±)‐1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane ((±)‐DOI; EC50=22 nM). The (±)‐DOI inhibition was insensitive to the 5‐HT2Areceptor antagonist MDL 100907 or the 5‐HT2Bantagonist rauwolscine; it was largely prevented by 1 μMof the non‐selective 5‐HT2Cantagonists mesulergine (5‐HT2A,B,C), ketanserin (5‐HT2A,C) or SB 200646A (5‐HT2B,C); it was completely abolished by 0.1 μMof the selective 5‐HT2Creceptor antagonist SB 242084.The NMDA‐induced cyclic GMP elevation also was potently inhibited by the selective 5‐HT2Cagonist RO 60‐0175 and by the antidepressant trazodone, both added at 1 μM, in an SB 242084‐sensitive manner.Finally, the 5‐HT1Aagonist 8‐hydroxy‐2‐(di‐n‐propylamino) tetralin (8‐OH‐DPAT; 1 μM) inhibited the NMDA‐evoked cyclic GMP response, an effect blocked by the selective 5‐HT1Areceptor antagonist WAY 100635.In conclusion, the NMDA receptor/NO/cyclic GMP pathway in human neocortex slices can be potently inhibited by activation of 5‐HT2Cor 5‐HT1Areceptors.