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

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Abstract
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 μM NMDA was blocked by 100 μM of the NO synthase inhibitor NG‐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. British Journal of Pharmacology (2000) 130, 1853–1858; doi:10.1038/sj.bjp.0703510

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