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 gamma-amino-butyric acid (GABA) extracellular levels in the cerebral cortex, by acting on 5-HT(2A) receptors, and through this mechanism increases 5-HT levels. For this purpose the effect of TRZ on the release of GABA was studied in adult male rats in synaptosomes, cortical slices, and "in vivo" 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 10(-10) to 10(-6) M, the increase in GABA release induced by (+/-)DOI, a 5-HT(2A/2C) agonist, and the alpha receptor agonist phenylephrine, both 10(-6) M. The pIC50 values were 8.31+/-0.24, and 5.99+/-0.52, respectively. In the same preparation, [3H]5-HT accumulation was inhibited by citalopram and TRZ with pIC(50) of 7.8+/-0.44 and 5.9+/-0.09, 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 10(-10) to 10(-7) M it inhibited and from 10(-6) to 10(-4) 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-HT(2A) antagonist (10(-10) to 10(-5) M), reduced GABA release in a dose-response manner, while it induced an increase of 5-HT outflow. On the contrary, (+/-)DOI (10(-10) to 10(-5) M) increased GABA release and inhibited 5-HT levels. Perfusion with the GABA(A) receptor antagonist bicuculline was also followed by an increase in 5-HT release. In microdialysis experiments, TRZ 1.25 mg kg(-1) s.c. brought about a decrease in GABA extracellular levels, while an increase was found after the dose of 2.5 mg kg(-1). 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-HT(2A) 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.
Luparini
Maria Rita
MR
Department of Pharmacology, ACRAF-Angelini Ricerche, 00040 S. Palomba-Pomezia, Rome, Italy.
Garrone
Beatrice
B
Pazzagli
Marta
M
Pinza
Mario
M
Pepeu
Giancarlo
G
D000465:Algorithms; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D001640:Bicuculline / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D018756:GABA Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D017551:Microdialysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism / Q000502:physiology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014196:Trazodone / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000502:physiology*
D018687:Antidepressive Agents, Second-Generation; D001640:Bicuculline; D018756:GABA Antagonists; D044402:Receptor, Serotonin, 5-HT2A; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D014196:Trazodone; D005680:gamma-Aminobutyric Acid