Serotonin inhibition of the NMDA receptor/nitric oxide/cyclic GMP pathway in human neocortex slices: involvement of 5-HT2C and 5-HT1A receptors

1 The NMDA receptor/nitric oxide (NO)/cyclic CMP pathway and its modulation by 5-hydroxytryptamine (5-HT) was studied in slices of neocortical samples obtained from patients undergoing neurosurgery. 2 The cyclic GMP elevation produced by 100 mu M NMDA was blocked by 100 mu M of the NO synthase inhibitor N-G-nitro-L-arginine (L-NOARG) or by 10 mu M of the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-alpha ] quinoxaline-1-one (ODQ). 3 The NMDA effect was prevented by 5-HT or by the 5-HT2 agonist (+/-)-1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane ((+/-)-DOI; EC50=22 nM). The (+/-) -DOI inhibition was insensitive to the 5-HT2A receptor antagonist MDL 10090 7 or the 5-HT2B antagonist rauwolscine; it was largely prevented by 1 mu M of the non-selective 5-HT2C antagonists mesulergine (5-HT2A,B,C), ketanseri n (5-HT2A,C) Or SE 200646A (5-HT2B,C); it was completely abolished by 0.1 m u M of the selective 5-HT2C receptor antagonist SE 242084. 4 The NMDA-induced cyclic GMP elevation also was potently inhibited by the selective 5-HT2C agonist RO 60-0175 and by the antidepressant trazodone, bo th added at 1 mu M, in an SE 242084-sensitive manner. 5 Finally, the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH -DPAT; 1 mu M) inhibited the NMDA-evoked cyclic GMP response, an effect blo cked by the selective 5-HT1A receptor antagonist WAY 100635. 6 In conclusion, the NMDA receptor/NO/cyclic GMP pathway in human neocortex slices can be potently inhibited by activation of 5-HT2C or 5-HT1A recepto rs.