title: Sustained administration of trazodone enhances serotonergic neurotransmission: in vivo electrophysiological study in the rat brain.
abstract: Despite its clinical use for more than two decades, the mechanisms by which trazodone acts as an antidepressant are not clear, because it has affinity for a variety of 5-hydroxytryptamine (5-HT; serotonin) receptors and the 5-HT transporter. This study examined the effects of sustained trazodone administration on 5-HT neurotransmission. Electrophysiological recordings were conducted in anesthetized rats. Subcutaneously implanted minipumps delivered vehicle or trazodone (10 mg/kg/day) for 2 and 14 days. A 2-day trazodone administration suppressed the firing rate of raphe 5-HT neurons, which recovered to baseline after 14 days. This was attributable to 5-HT(1A) autoreceptor desensitization because the suppressant effect of the 5-HT autoreceptor agonist lysergic acid diethylamide was dampened in 14-day trazodone-treated rats. Prolonged trazodone administration did not change the sensitivity of postsynaptic 5-HT(1A) and α(2)-adrenergic receptors in hippocampus, but enhanced synaptic 5-HT levels because the 5-HT(1A) antagonist N-{2-[4 (2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride (WAY-100635) enhanced hippocampal firing in treated rats, but not in controls. Trazodone administration for 14 days increased the 50% recovery time value, an index of 5-HT transporter blockade in vivo, and decreased the inhibitory function of terminal 5-HT(1B) autoreceptors on the electrically evoked release of 5-HT. The agonistic action of trazodone at 5-HT(1A) receptors was characterized as being full because it did not attenuate the inhibitory action of 5-HT when coapplied locally. The enhanced 5-HT neurotransmission by trazodone is caused in part by reuptake blockade and activation of postsynaptic 5-HT(1A) receptors, which may account for its effectiveness in major depression.
authors.affiliation: University of Ottawa Institute of Mental Health Research, Ottawa, ON, Canada. ramez.ghanbari@rohcg.on.ca
authors.forename: Ramez
authors.initials: R
authors.lastname: Ghanbari
authors.forename: Mostafa
authors.initials: M
authors.lastname: El Mansari
authors.forename: Pierre
authors.initials: P
authors.lastname: Blier
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D001923:Brain Chemistry / Q000187:drug effects; D003712:Dendrites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects; D007478:Iontophoresis; D008297:Male; D017966:Pyramidal Cells / Q000187:drug effects; D011903:Raphe Nuclei / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D009435:Synaptic Transmission / Q000187:drug effects*; D014196:Trazodone / Q000494:pharmacology*
chemical_list: D018687:Antidepressive Agents, Second-Generation; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D014196:Trazodone