Chronic clomipramine and triiodothyronine increase serotonin levels in rat frontal cortex in vivo: relationship to serotonin autoreceptor activity.

Augmentation of tricyclic antidepressant (TCA) treatment with triiodothyronine (T3) has been shown to potentiate the therapeutic effect of TCA drugs in depressed patients. We have attempted to elucidate the mechanism of this potentiation by determining the effects of T3 alone and together with a TCA on serotonin (5-HT) levels in living rats, using in vivo microdialysis. A single s.c. injection of T3 at 0.1 mg/kg had no effect on 5-HT levels in frontal cortex or hippocampus. Chronic administration of clomipramine (10 mg/kg i.p. daily for 4 weeks) to rats resulted in increased basal 5-HT levels in the frontal cortex. Administration of T3 daily for 7 days at 0.1 mg/kg s.c. also resulted in elevated 5-HT levels, whereas in rats administered both clomipramine and T3, cortical 5-HT levels were significantly elevated compared with the levels in rats that had received only one treatment. Basal levels in hippocampus were unaffected by these treatments. Subcutaneous injection of the 5-HT-1a receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (0.2 mg/kg) resulted in a decrease in 5-HT levels in both cortex and hippocampus. In frontal cortex of animals that had received T3 or a combination of clomipramine and T3, the extent of the decrease was significantly reduced compared to that seen in control animals. The extent of the decrease in hippocampus was not affected by any of the treatments. Subcutaneous injection of the 5-HT-1b/1d antagonist GR 127935 (5 mg/kg) resulted in an increase in 5-HT levels in both brain areas. The extent of the increase was not affected by any of the treatments in either brain area. It is concluded that the action of T3 in potentiating the clinical response to TCA drugs may be due to its effect on 5-HT levels in the frontal cortex, which is due to desensitization of the presynaptic 5-HT-1a autoreceptors.