Thyroid hormones are concentrated, retained, and metabolized in discrete neural systems in rat brain. To determine how iodothyronine requirements of brain compare with those of other thyroid hormone-dependent tissues, we measured effects of chronic thyroid hormone deficiency or excess on brain iodothyronine economy and particularly on the intracerebral rate of triiodothyronine formation from thyroxine. The results demonstrate that despite extremes of thyroxine availability, brain thyroxine and triiodothyronine concentrations and brain triiodothyronine production and turnover rates are kept within narrow limits. Adjustments in the activity of both brain and liver help to maintain these relatively stable conditions. Following thyroidectomy, fractional rates of triiodothyronine formation from thyroxine decrease to low levels in liver, whereas they increase markedly in brain; exactly the opposite direction of change occurs in brain and liver during hyperthyroidism. These responses suggest that brain iodothyronine homeostasis is important for the function of the whole organism. Because signs of nervous system dysfunction develop in hypothyroid and hyperthyroid individuals, it is possible that even relatively small deviations of brain iodocompound economy can produce significant changes in behavior and autonomic nervous system function.

During brain development, before the apparatus of neurotransmission has been set into place, many neurotransmitters act as growth regulators. In adult brain, their role in neurotransmission comes to the fore but neuronal plasticity and other growth-related processes are their continuing responsibility. This has been clearly demonstrated for catecholamines. Previous as well as recent evidence now indicates that thyroid hormones may participate in the developing and adult brain through similar mechanisms. Immunohistochemical mapping of brain triiodothyronine (antibody specificity established by numerous appropriate tests) demonstrated that the hormone was concentrated in both noradrenergic centers and noradrenergic projection sites. In the centers (locus coeruleus and lateral tegmental system) triiodothyronine staining, like that of tyrosine hydroxylase, was heavily concentrated in cytosol and cell processes. By contrast, in noradrenergic targets, label was most prominent in cell nuclei. Combined biochemical and morphologic data allows a construct of thyroid hormone circuitry to unfold: The locus coeruleus is conveniently located just beneath the ependyma of the 4th ventricle. Thyroxine, entering the brain via the choroid plexus, is preferentially delivered to subependymal brain structures. High concentrations of locus coeruleus norepinephrine promote active conversion of thyroxine to triiodothyronine, leading to the preeminence of the locus coeruleus as a site of triiodothyronine concentration. Results of treatment with the locus coeruleus neurotoxin DSP-4 established that axonal transport accounts for delivery of both triiodothyronine and norepinephrine from locus coeruleus to noradrenergic terminal fields. The apparatus for transduction of thyronergic and noradrenergic signals at both membrane and nuclear sites resides in the postsynaptic target cells. Upon internalization of hormone in post-synaptic target cells, genomic effects of triiodothyronine, norepinephrine, and/or their second messengers are possible and expected. The evidence establishes a direct morphologic connection between central thyronergic and noradrenergic systems, supporting earlier proposals that triiodothyronine or its proximate metabolites may serve as cotransmitters with norepinephrine in the adrenergic nervous system.

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We administered [125I]thyroxine intravenously to adult male rats and measured uptake and subcellular distribution of the hormone and its metabolites in brain. Fractional brain uptake decreased after a large dose of iodothyronine, providing evidence for saturability of the uptake mechanism. Well-defined patterns of regional and subcellular labeling were noted within 1 h after [125I]thyroxine injection. Radioactivity in synaptosomes was always greater than in any other particle separated per gram of brain, increasing linearly relative to radioactivity in brain cytosol during the 1st h. Although [125I]triiodothyronine derived from [125I]thyroxine was not identified in serum at any time interval, it was measurable in synaptosomes within 20 min and in brain cytosol within 1 h after labeled hormone administration. Concentrations of the radioactive metabolite were twofold greater and ratios of [125I]triiodothyronine to [125I]thyroxine concentration were threefold greater in synaptosomes than in cytosol. Therefore, thyroxine may be converted to triiodothyronine within nerve terminals. Synaptosomal localization of iodothyronines and their metabolites may be relevant to the marked central and peripheral adrenergic nervous system effects of these aromatic amino acid hormones.

Radioactive triiodothyronine reaching the rat brain after intravenous administration is rapidly and selectively taken up in the nerve ending fraction. A concentration gradient of radioactivity from brain cytosol to synaptosomes is observed at 5 min, increases linearly over the first hour, and is maintained for at least 10 hr. Radioactivity in the synaptosomes is due to triiodothyronine (90%) plus a single unidentified metabolite (10%). Approximately 85% of the synaptosomal radioactivity is released by osmotic disruption of the particles. The process of selective uptake, concentration, and retention of triiodothyronine in nerve terminals of the rat brain may be related to the sympathomimetic and behavior-altering effects of the thyroid hormones.Thyroid hormones exert marked central stimulating and peripheral sympathomimetic effects, which are not explained by increased catecholamine production or enhanced adrenergic receptor sensitivity. On the contrary, circulating levels of catecholamines (1, 2), turnover rates of noradrenaline in a number of tissues (3-5), and sensitivity of at least some adrenergic receptors (6)(7)(8) cific activity approximately 500 jiCi/jig in 50% (vol/vol) propylene glycol] or 50% propylene glycol was administered as a single dose intravenously and animals were decapitated 5, 20, 60, 180, and 600 min later. Blood was collected from the decapitation site and the serum was separated and analyzed for radioactivity and radioactive iodocompounds. Subcellular fractions of whole brain minus cerebellum were prepared according to the method of Whittaker et al. (10). Briefly, following 1000 X g centrifugation of the brain homogenate for 10 min, nuclei and cellular debris were discarded, and the supernatant phase (Sl fraction) was layered on a discontinuous sucrose density gradient consisting of 1.2, 0.8, and 0.32 M sucrose, and centrifuged in a swinging bucket rotor at 50,000 X g for 1 hr. Individual gradient fractions including myelin, synaptosomes, and mitochondria were separated (see diagram, Table 1A) and diluted with 10-18 volumes of isotonic Krebs buffer (11), and pellets were separated by centrifugation at 20,000 X g for 20 min. To determine the extent of translocation of labeled T3 during the fractionation procedure, brains of animals which received intravenous propylene glycol without isotope were homogenized at 40 in sucrose containing 0.05 jgCi of [125I]T3. Approximately 75% of added ['25I]T3 was recovered in the cytosol (plus microsomes); the remainder was distributed among the various subcellular organelles as shown in Table 1B. All brain fractions labeled in vivo were corrected for in vitro uptake at 40. Radioactivity in individual subcellular fractions and in serum was studied by means of paper chromatography in three solvent systems: butanol:ethanol:0.5 M ammonia, 5:1:2; butanol:acetic acid:water, 4:1:1; and tertiary amyl alcohol:2 M ammonia:hexane, 5:6:1. Added carrier compounds were identified by means of ultraviolet light at 259 nm. After development, the radioactivit...