Are antidepressant-like effects of triiodothyronine (T3) in rodents related to an hyperthyroid state?

1. The physiological and behavioral effects of T3 and corresponding plasma T3 levels were studied in mice. 2. On the tests performed (antagonism of apomorphine- and oxotremorine-induced hypothermia, potentiation of yohimbine toxicity, L-5-HTP-induced head twitches and the learned-helplessness paradigm), T3 was active after subchronic treatment (1 injection per day for 3 days, ending 24 hours before testing). 3. In these tests T3 exhibited the same profile as antidepressant drugs in rodents. 4. The similar activity of beta-agonists in these tests and the ability of T3 to potentiate the effect of clenbuterol agree with the hypothesis that T3 can induce beta-adrenergic hypersensitivity. 5. Under the present experimental conditions these effects were obtained with doses of T3 which did not induce hyper-triiodothyroninemia. Thus, the lowest doses significantly affecting apomorphine- and oxotremorine-induced hypothermia were respectively .008 and .032 mg/kg/day. 6. Doses as low as .032 mg/kg/day were active in the yohimbine test. 7. L-5-HTP-induced head twitches were potentiated by a dose of .25 mg/kg/day and in the learned-helpless paradigm, the lowest effective dose was .06 mg/kg/day. 8. Plasma T3 values obtained in the same conditions were not significantly different from control at doses less than .5 mg/kg/day, and increased dramatically with higher doses, suggesting an accumulation of the hormone in plasma. 9. The doses inducing an hyper-triiodothyroninemia coincided with physiological signs of hyperthyroidism in the animals (i.e. loss of weight and slight hyperthermia). Thus, the active dose range of T3 was below the lowest dose required to produce a significant hyperthyroid state. 10. This results suggest that a clinical benefit could be obtained with low doses of T3 that do not significantly induce an hyperthyroidism.