Rats were made hypo- or hyperthyroid to study the role of thyroid hormones on cerebral transthyretin (TTR) mRNA expression. TTR mRNA was detected by Northern blot in rat liver, choroid plexus and meninges but not in cultured astrocytes or cultured cerebral endothelial cells. No changes were found in the levels of TTR mRNA in liver, choroid plexus or meninges in hypo- or hyperthyroid rats compared with the controls. In order to investigate the main route of thyroxine transport from blood to brain, the distribution of [125I]thyroxine in the brain was studied after intravenous (i.v.) and intraventricular (i.v.c.) injection by both direct counting and autoradiography. While distribution of [125I]thyroxine could be seen throughout the brain parenchyma after i.v. injection, the labelling was confined to the CSF spaces after i.v.c. administration. When protein synthesis was inhibited by cycloheximide treatment and [125I]thyroxine was injected intravenously, the uptake of [125I]thyroxine in the choroid plexus decreased while the uptake in the cerebral cortex increased. This indicates that thyroxine is transported into the brain primarily through the blood-brain barrier and not via the choroid plexus and CSF. We discuss the possibility that TTR has a role in the distribution of thyroxine throughout the brain.