Effect of triiodothyronine (T(3)) augmentation of acute milnacipran administration on monoamine levels: an in vivo microdialysis study in rats

Abstract

Background: Up to 30% of depressed patients are partially or totally resistant to antidepressant therapy. The administration of triiodothyronine (T(3)) to antidepressant nonresponders can be an effective augmentation strategy, although the mechanism is not fully understood.

Methods: In vivo microdialysis was used to examine the effect of T(3) augmentation of the antidepressant, milnacipran. Basal extracellular serotonin, norepinephrine, and dopamine levels were measured before and after acute milnacipran administration in the medial prefrontal cortex and amygdala of rats which had received subchronic (7 days) T(3) treatment or control saline.

Results: Subchronic administration of T(3) at 0.1 mg/kg significantly increased basal extracellular levels of serotonin in the medial prefrontal cortex, but not in the amygdala. In contrast, subchronic administration of T(3) at 0.2 mg/kg did not alter basal extracellular serotonin levels in the medial prefrontal cortex. Basal extracellular levels of norepinephrine and dopamine were not modified by either dose of T(3) in either region. Acute administration of milnacipran, a serotonin-norepinephrine reuptake inhibitor, to control animals resulted in a significant increase of extracellular levels of serotonin, norepinephrine, and dopamine. When administered to animals treated subchronically with T(3) at 0.1 mg/kg, milnacipran produced an additional increase in extracellular serotonin levels but not in levels of norepinephrine or dopamine in the medial prefrontal cortex of rats.

Conclusion: These results suggest that the mechanism of the augmentation effect of milnacipran by T(3) administration occurs via enhancement of serotonergic neurotransmission, but not through noradrenergic or dopaminergic neurotransmission.

Keywords: depression; in vivo microdialysis; milnacipran; monoamines; triiodothyronine.

Figure 1

Effect of acute intraperitoneal administration of milnacipran 10 mg/kg on extracellular concentrations of serotonin (A), norepinephrine (B), and dopamine (C) in the medial prefrontal cortex after subchronic treatment with T₃ 0.1 mg/kg. Notes: Values represent the mean ± standard error of the mean (pg per 20-minute fraction). Black arrows indicate milnacipran administration. [n = 7 (control group), n = 6 (T₃ 0.1 mg/kg group)]. *P < 0.05 versus control group.

Figure 2

Effect of acute intraperitoneal administration of milnacipran 10 mg/kg on extracellular concentrations of serotonin (A), norepinephrine (B), and dopamine (C) in the medial prefrontal cortex after subchronic treatment with T₃ 0.2 mg/kg. Notes: Values represent the mean ± standard error of the mean (pg per 20-minute fraction). Black arrows indicate milnacipran administration. [n = 6 (control group), n = 6 (T₃ 0.2 mg/kg group)].

Figure 3

Effect of acute intraperitoneal administration of milnacipran 10 mg/kg on extracellular concentrations of serotonin (A), norepinephrine (B), and dopamine (C) in the amygdala after subchronic treatment with T₃ 0.1 mg/kg. Notes: Values represent the mean ± standard error of the mean (pg per 20-minute fraction). Black arrows indicate milnacipran administration. [n = 3 (control group), n = 4 (T₃ 0.1 mg/kg group)].