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

J Pharmacol Exp Ther. 1998 Jun;285(3):983-6.


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 microM N-methyl-D-aspartate. The inhibition was near complete at 10 nM trazodone. The effect of 10 nM trazodone was unaffected by 0.3 microM spiperone or rauwolscine, antagonists with selectivity for the 5-HT(serotonin)2A or the 5-HT2B subtype, respectively, but it was totally prevented by 0.01 microM 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 = 95 nM), by ketanserin, a 5-HT2A/5-HT2C receptor blocker. It is concluded that trazodone behaves as a potent full agonist at the 5-HT2C receptor mediating inhibition of the cerebellar N-methyl-D-aspartate/nitric oxide/cyclic GMP system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Anxiety Agents / pharmacology*
  • Cerebellum / drug effects*
  • Cerebellum / metabolism
  • Cyclic GMP / metabolism*
  • Dose-Response Relationship, Drug
  • Male
  • N-Methylaspartate / metabolism
  • Nitric Oxide / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT2C
  • Receptors, Serotonin / drug effects*
  • Receptors, Serotonin / metabolism
  • Trazodone / pharmacology*


  • Anti-Anxiety Agents
  • Receptor, Serotonin, 5-HT2C
  • Receptors, Serotonin
  • Nitric Oxide
  • N-Methylaspartate
  • Cyclic GMP
  • Trazodone