Thyroid hormones influence the expression of transmitter-specific enzymes by 
central cholinergic neurons. Based on the fact that these cholinergic neurons 
degenerate selectively in human Alzheimer's disease, it was hypothesized that 
thyroid hormones might be beneficial in its treatment. However, since thyroid 
hormones influence the function of most peripheral organs, derivatives selective 
for central cholinergic neurons are necessary. The structural requirements of 
the receptor mediating the effects of the thyroid hormones on central 
cholinergic neurons were therefore compared with those of the receptors 
mediating actions on peripheral organs. Cultures were prepared of dissociated 
neurons from the septal area of fetal rat brains, and the differentiation of 
cholinergic neurons was assessed by measuring the activity of choline 
acetyltransferase (ChAT). Triiodothyronine (T3) was found to stimulate ChAT 
activity in a dose-dependent manner. The effect of T3 was additive to that of 
nerve growth factor. The potency of derivatives of T3 in elevating ChAT activity 
in the cultures was compared with their known anti-goiter activity determined in 
vivo and their binding affinity to the hepatic nuclear receptor measured in 
vitro. The findings indicate that the structural requirements of central and 
peripheral receptors are similar and that it therefore appears unlikely that 
analogs of thyroid hormones can be developed which selectively affect 
cholinergic neurons.