Background: Despite its clinical use of more than two decades, the mechanisms by which trazodone acts as an antidepressant are not clear since it has affinity for a variety of serotonin (5-HT) receptors and for the 5-HT transporter. This study examined effects of sustained trazodone administration on 5-HT neurotransmission. Methods: Electrophysiological recordings were conducted in anesthetized rats. Subcutaneously implanted minipumps delivered vehicle or trazodone (10 mg/kg/day) for 2 and 14 days. Results: A 2-day trazodone administration suppressed the firing rate of raphe 5-HT neurons, which recovered to baseline following 14 days. This was attributable to 5-HT1A autoreceptor desensitization since the suppressant effect of the 5-HT autoreceptor agonist LSD was dampened in 14-day trazodone-treated rats. Prolonged trazodone administration did not change the sensitivity of postsynaptic 5-HT1A and α2-adrenergic receptors in hippocampus, but enhanced synaptic 5-HT levels since the 5-HT1A antagonist WAY 100,635 enhanced hippocampal firing in treated, but not in controls. Trazodone administration for 14 days increased the RT50 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 co-applied locally. Conclusion: The enhanced 5-HT neurotransmission by trazodone is due in part to reuptake blockade as well as activation of postsynaptic 5-HT1A receptors which may account for its effectiveness in major depression.
- Received April 16, 2010.
- Revision received July 16, 2010.
- Accepted July 19, 2010.
- The American Society for Pharmacology and Experimental Therapeutics