The thyroid hormone triiodothyronine (T3) may accelerate and augment the action of antidepressants. Antidepressants up-regulate neurogenesis in adult rodent hippocampus. We studied the effect of T3 and T3+fluoxetine in enhancement of hippocampal neurogenesis beyond that induced by fluoxetine alone and the correlation with antidepressant behaviour in the novelty suppressed feeding test (NSFT). Rats were administered fluoxetine (5 mg/kg.d), T3 (50 mug/kg.d), fluoxetine (5 mg/kg.d)+T3 (50 mug/kg.d) or saline, for 21 d. Neurogenesis was studied by doublecortin (DCX) immunohistochemistry in the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ). In the NSFT, latency to feeding in animals deprived of food was measured. Fluoxetine and fluoxetine+T3 increased the number of doublecortin-positive (DCX+) cells in the SGZ compared to saline (p=0.00005, p=0.008, respectively). There was a trend towards an increased number of DCX+ cells by T3 compared to saline (p=0.06). Combined treatment with fluoxetine+T3 further increased the number of DCX+ cells compared to T3 or fluoxetine alone (p=0.001, p=0.014, respectively). There was no effect of any of the treatments on number of DCX+ cells in the SVZ. In the NSFT, all treatments (T3, fluoxetine+T3 and fluoxetine) reduced latency to feeding compared to saline (p=0.0004, p=0.00001, p=0.00009, respectively). Fluoxetine+T3 further reduced latency to feeding compared to T3 alone (p=0.05). The results suggest that enhancement of antidepressant action by T3 may be related to its effect of increasing hippocampal neurogenesis and that the antidepressant effect of these treatments is specific to the hippocampus and does not represent a general effect on cell proliferation.
Although triiodothyronine (T3) is widely used clinically, preclinical support for its antidepressant-like effects is limited, and the mechanisms are unknown. We evaluated 1) the antidepressantlike effects of T3 in the novelty suppressed feeding test (NSFT), tail suspension test (TST), and forced swim test (FST), 2) the role of presynaptic 5-HT 1A receptors in the antidepressant-like mechanism of T3 by the hypothermic response to the 5-HT 1A receptor agonist, 8-hydroxy-N,N-dipropyl-2-aminotetralin (8-OH-DPAT), 3) the thyroid hormone receptor type mediating the antidepressant-like effects by concurrent administration of the specific thyroid hormone ␣ receptor (TR␣) antagonist, dronedarone, and 4) the presence of these effects in both genders. Male and female BALB/c mice were administered 1) T3 (20, 50, 200, or 500 g/kg per day) or vehicle or 2) T3 (50 g/kg per day), dronedarone (100 M/day), or the combination intraperitoneally for 21 days and then underwent a behavioral test battery. The NSFT showed a shortened latency to feed in males at the two lower T3 doses. The TST and FST showed decreased immobility in male mice at T3 doses Ͼ20 g/kg per day and in females at all T3 doses. Concurrent dronedarone prevented T3 effects in males on the NSFT and in the TST and FST in both genders. Attenuation of 8-OH-DPAT-induced hypothermia was observed in males only and may be reduced by concurrent dronedarone. These findings support an antidepressant-like effect of T3. Attenuation of 8-OH-DPAT-induced hypothermia in males only suggests the need to evaluate a possible gender disparity in the role of presynaptic 5-HT 1A receptors in T3 antidepressant mechanisms. Blockade by dronedarone of the antidepressant-like effects of T3 suggests that these effects are TR␣ receptor-mediated.
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