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

摘要

class="enumerated" style="list-style-type:decimal">The NMDA receptoritric 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 μM NMDA was blocked by 100 μM of the NO synthase inhibitor N^G-nitro-L-arginine (L-NOARG) or by 10 μM of 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-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 100907 or the 5-HT2B antagonist rauwolscine; it was largely prevented by 1 μM of the non-selective 5-HT2C antagonists mesulergine (5-HT2A,B,C), ketanserin (5-HT2A,C) or SB 200646A (5-HT2B,C); it was completely abolished by 0.1 μM of the selective 5-HT2C receptor antagonist SB 242084.The NMDA-induced cyclic GMP elevation also was potently inhibited by the selective 5-HT2C agonist RO 60-0175 and by the antidepressant trazodone, both added at 1 μM, in an SB 242084-sensitive manner.Finally, the 5-HT1A agonist 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-HT1A receptor antagonist WAY 100635.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 receptors.