THYROID-HORMONES AS NEUROTRANSMITTERS

During brain development, before the apparatus of neurotransmission ha s been set into place, many neurotransmitters act as growth regulators . In adult brain, their role in neurotransmission comes to the fore bu t neuronal plasticity and other growth-related processes are their con tinuing responsibility. This has been clearly demonstrated for catecho lamines. Previous as well as recent evidence now indicates that thyroi d hormones may participate in the developing and adult brain through s imilar mechanisms. Immunohistochemical mapping of brain triiodothyroni ne (antibody specificity established by numerous appropriate tests) de monstrated that the hormone was concentrated in both noradrenergic cen ters and noradrenergic projection sites. In the centers (locus coerule us 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 promi nent in cell nuclei. Combined biochemical and morphologic data allows a construct of thyroid hormone circuitry to unfold: The locus coeruleu s is conveniently located just beneath the ependyma of the 4th ventric le. Thyroxine, entering the brain via the choroid plexus, is preferent ially delivered to subependymal brain structures. High concentrations of locus coeruleus norepinephrine promote active conversion of thyroxi ne to triiodothyronine, leading to the preeminence of the locus coerul eus as a site of triiodothyronine concentration. Results of treatment with the locus coeruleus neurotoxin DSP-4 established that axonal tran sport accounts for delivery of both triiodothyronine and norepinephrin e from locus coeruleus to noradrenergic terminal fields. The apparatus for transduction of thyronergic and noradrenergic signals at both mem brane and nuclear sites resides in the postsynaptic target cells. Upon internalization of hormone in post-synaptic target cells, genomic eff ects of triiodothyronine, norepinephrine, and/or their second messenge rs are possible and expected. The evidence establishes a direct morpho logic connection between central thyronergic and noradrenergic systems , supporting earlier proposals that triiodothyronine or its proximate metabolites may serve as cotransmitters with norepinephrine in the adr energic nervous system.