A cortical GABA–5HT interaction in the mechanism of action of the antidepressant trazodone

The aim of the study was to investigate whether the antidepressant trazodone (TRZ), a serotonin-2 receptor antagonist/reuptake inhibitor, modifies g-amino-butyric acid (GABA) extracellular levels in the cerebral cortex, by acting on 5-HT2A receptors, and through this mechanism increases 5-HT levels. For this purpose the effect of TRZ on the release of GABAwas studied in adult male rats in synaptosomes, cortical slices, and bin vivoQ by microdialysis. In cortical slices, the release of both GABA and 5-HT was determined. GABA and 5-HT were identified and their levels quantified by HPLC. The inhibition of 5-HT uptake by TRZ was also measured. In synaptosomes, TRZ antagonized dose-dependently, at concentrations from 1010 to 106 M, the increase in GABA release induced by (F)DOI, a 5-HT2A/2C agonist, and the a receptor agonist phenylephrine, both 106 M. The pIC50 values were 8.31F0.24, and 5.99F0.52, respectively. In the same preparation, [3H]5-HT accumulation was inhibited by citalopram and TRZ with pIC50 of 7.8F0.44 and 5.9F0.09, respectively, a finding confirming the weak activity of TRZ in comparison with a SSRI. In cortical slices, TRZ exerted a biphasic effect on GABA release. At concentrations from 1010 to 107 M it inhibited and from 106 to 104 M increased GABA release. 5-HT release was enhanced by TRZ throughout the entire range of concentrations tested. However, the increase was delayed after low and rapid after high concentrations. AMI-193, a 5-HT2A antagonist (1010 to 105 M), reduced GABA release in a dose–response manner, while it induced an increase of 5-HT outflow. On the contrary, (F)DOI (1010 to 105 M) increased GABA release and inhibited 5-HT levels. Perfusion with the GABAA receptor antagonist bicuculline was also followed by an increase in 5-HT release. In microdialysis experiments, TRZ 1.25 mg kg1 s.c. brought about a decrease in GABA extracellular levels, while an increase was found after the dose of 2.5 mg kg1. These findings demonstrate that TRZ, at concentrations which do not inhibit 5-HT uptake, reduces the cortical GABAergic tone by decreasing GABA extracellular levels, through the blockade of 5-HT2A receptors. The attenuation of GABAergic tone is responsible for an increase in 5-HT levels. A further increase also results from 5-HT uptake inhibition caused by higher doses of TRZ. The ensuing high 5-HT levels enhance GABA release, which in turn inhibits 5-HT release.