TRAZODONE IS A POTENT AGONIST AT 5-HT2C RECEPTORS MEDIATING INHIBITION OF THE N-METHYL-D-ASPARTATE NITRIC-OXIDE CYCLIC-GMP PATHWAY IN RAT CEREBELLUM

The effects of trazodone on the cyclic GMP elevation elicited by N-met hyl-D-aspartate in rat cerebellar slices were analyzed. Trazodone inhi bited in a concentration-dependent manner (EC50 = 0.82 nM) the cyclic GMP response evoked by 0.1 mu M N-methyl-D-aspartate. The inhibition w as near complete at 10 nM trazodone, The effect of 10 nM trazodone was unaffected by 0.3 mu M spiperone or rauwolscine, antagonists with sel ectivity for the 5-HT(serotonin)(2A) or the 5-HT2B subtype, respective ly, but it was totally prevented by 0.01 mu M mesulergine, a 5-HT2A/5- HT2B/5-HT2C receptor antagonist. Trazodone was potently counteracted ( IC50 = 2.7 nM) by the selective 5-HT2B/5-HT2C receptor antagonist N-(1 -methyl-5-indolyl)-N-(3-pyridil) urea HCl and, less potently (IC50 = 9 5 nM), by ketanserin, a 5-HT2A/5-HT2C receptor blocker. It is conclude d that trazodone behaves as a potent full agonist at the 5-HT50 recept or mediating inhibition of the cerebellar N-methyl-D-aspartate/nitric oxide/cyclic GMP system.