Vol. 285, Issue 3, 983-986, June 1998

Trazodone is a Potent Agonist at 5-HT_2C Receptors Mediating Inhibition of the N-Methyl-D-Aspartate/Nitric Oxide/Cyclic GMP Pathway in Rat Cerebellum¹

Manuela Marcoli, Guido Maura, Massimo Tortarolo and Maurizio Raiteri

Dipartimento di Medicina Sperimentale, Sezione di Farmacologia e Tossicologia, Università di Genova, Viale Cembrano 4, 16148 Genova, Italy

The effects of trazodone on the cyclic GMP elevation elicited by N-methyl-D-aspartate in rat cerebellar slices were analyzed. Trazodone inhibited in a concentration-dependent manner (EC₅₀ = 0.82 nM) the cyclic GMP response evoked by 0.1 µM N-methyl-D-aspartate. The inhibition was near complete at 10 nM trazodone. The effect of 10 nM trazodone was unaffected by 0.3 µM spiperone or rauwolscine, antagonists with selectivity for the 5-HT(serotonin)_2A or the 5-HT_2B subtype, respectively, but it was totally prevented by 0.01 µM mesulergine, a 5-HT_2A/5-HT_2B/5-HT_2C receptor antagonist. Trazodone was potently counteracted (IC₅₀ = 2.7 nM) by the selective 5-HT_2B/5-HT_2C receptor antagonist N-(1-methyl-5-indolyl)-N-(3-pyridil) urea HCl and, less potently (IC₅₀ = 95 nM), by ketanserin, a 5-HT_2A/5-HT_2C receptor blocker. It is concluded that trazodone behaves as a potent full agonist at the 5-HT_2C receptor mediating inhibition of the cerebellar N-methyl-D-aspartate/nitric oxide/cyclic GMP system.