Hypothalamic Serotoninergic Stimulation of Thyrotropin Secretion and Related Brain-Hormone and Drug Interactions in the Rat*

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Abstract
The aim of this study was to determine the specific roles of hypothalamic dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in controlling the release of TSH in hypothyroid and euthyroid states in the rat. Selected ion monitoring (computerized gas chromatography/mass spectrometry) was used to assay, simultaneously, medial basal hypothalamic concentrations of DA, NE, and 5-HT and their major metabolites. The turnover of each amine in the hypothalamus of individual animals was estimated from the ratio of the concentration of metabolite to that of its precursor amine. In hypothyroid rats an increase in 5-HT turnover at various times after propylthiouracil (PTU) induction of hypothyroidism was associated with the expected rise in TSH secretion. In a large population (n = 90) of euthyroid, hypothyroid, and hyperthyroid rats there was a linear correlation between serum TSH and the ratio in the hypothalamus of the concentration of 5- hydroxyindoleacetic acid (5-HIAA) to 5-HT. The hypothesis that high hypothalamic 5-HT activity was driving TSH release (via TRH) in hypothyroid rats and that it was not secondary to high pituitary TSH output was supported by the demonstration that both central 5-HT antagonism and synthesis inhibition significantly reduced TSH secretion. A primary deficit in hypothalamic 5-HT activity (neonatal monosodium glutamatetreated rat model) was associated with reduced TSH secretion, as were rat models with drug-induced reduction of hypothalamic 5-HT turnover. After a period of PTU-induced hypothyroidism (38 and 42 days), an increase in hypothalamic DA turnover was evident in the animals; this was associated with a marked reduction in pituitary PRL content. To establish whether changes in 5-HT turnover in hypothyroid rats could have been secondary to altered PRL secretion or DA turnover, PTU-treated rats were administered estradiol (to induce hyperprolactinemia) or MIT (to block hypothalamic. DA synthesis). Despite major changes in PRL synthesis and secretion and in DA availability after these treatments, the high 5-HT turnover and TSH levels remained unaltered. This result indicated that the PRL and DA turnover changes seen in hypothyroid rats were not the cause of the increases in 5-HT turnover and TSH secretion. The administration of T3 (0.5 μg/100 g BW) to euthyroid rats caused a significant suppression of hypothalamic 5-HIAA and the ratio of 5-HIAA to 5-HT, as well as serum GH and serum TSH, within 60 min (a time response incompatible with pituitary- mediated feedback effects). Hypothalamic DA or its turnover did not bear any relationship to TSH secretion in euthyroid or T3-treated euthyroid rats. Furthermore, there was no specific relationship between hypothalamic NE status or turnover and TSH secretion in any of the experiments. We conclude that TSH release is controlled from the central nervous system specifically by 5-HT, the neuronal activity of which is stimulatory for both TSH and GH. Furthermore, T3 exerts negative feedback effects at the level of the hypothalamus to inhibit the release of TSH and GH from the pituitary.