Sustained administration of trazodone enhances serotonergic neurotransmission: in vivo electrophysiological study in the rat brain.
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.
Ghanbari
Ramez
R
University of Ottawa Institute of Mental Health Research, Ottawa, ON, Canada. ramez.ghanbari@rohcg.on.ca
El Mansari
Mostafa
M
Blier
Pierre
P
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*
D018687:Antidepressive Agents, Second-Generation; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D014196:Trazodone