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-HT1A 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-HT1A and alpha 2-adrenergic receptors in hippocampus, but enhanced synaptic 5-HT levels because the 5-HT1A 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-HT1B autoreceptors on the electrically evoked release of 5-HT. The agonistic action of trazodone at 5-HT1A 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-HT1A receptors, which may account for its effectiveness in major depression.