title: Trazodone increases extracellular serotonin levels in the frontal cortex of rats.
abstract: The effects of the antidepressant drug, trazodone, on the extracellular 5-hydroxytryptamine (5-HT) levels in the frontal cortex of freely moving rats was investigated using microdialysis coupled to a high performance liquid chromatography (HPLC) detection method. Systemic administration of 1.25 and 2.5 mg/kg s.c. of trazodone was followed by a rise in the 5-HT level which reached a 5-fold peak over the basal level 5 h after injection, and a 3-fold peak after 1 h. Higher doses had no effect. The increase was prevented by pretreatment with fluoxetine (10 mg/kg s.c.), a 5-HT uptake inhibitor. Direct administration of trazodone (0.03, 0.1, 1, 2 microg/microl), by reverse dialysis into the frontal cortex, elicited a dose-dependent large increase in 5-HT levels. The increase was not prevented by systemic fluoxetine administration but was reduced by local perfusion of ketanserin (0.1 microg/microl) a 5-HT(2A/C) receptor antagonist. Trazodone s.c. administration for 7 days did not increase 5-HT basal levels but enhanced the effects of challenge doses of 2.5 and 5 mg/kg s.c. The present work demonstrated that trazodone increases the 5-HT extracellular level through a double mechanism which involves the 5-HT transporter and 5-HT(2A/C) receptors. This increase may trigger the chain of events which lead to the therapeutic effects, similar to the case of many other antidepressant drugs.
authors.affiliation: Department of Pharmacology, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Pazzagli
authors.forename: M G
authors.initials: MG
authors.lastname: Giovannini
authors.forename: G
authors.initials: G
authors.lastname: Pepeu
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D014196:Trazodone / Q000494:pharmacology*
chemical_list: D018687:Antidepressive Agents, Second-Generation; D002352:Carrier Proteins; D005473:Fluoxetine; D007650:Ketanserin; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D012701:Serotonin; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D014196:Trazodone; C493232:Slc6a4 protein, rat