Chronic thyroxine treatment of rats down-regulates the noradrenergic cyclic AMP generating system in cerebral cortex.
Treatment of Sprague-Dawley rats for 9 days with 15 micrograms/kg of tri-iodo-thyronine, 50 micrograms/kg of thyroxine (T4) or 500 micrograms/kg of thyrotropin-releasing hormone decreased the number of beta receptors in cerebral cortex as measured by dihydroalprenolol binding. The dissociation constants of dihydroalprenolol (3.5 nM) were not altered by the treatment. Only tri-iodo-thyronine and T4 administration resulted in a concomitant reduction of norepinephrine (NE) elicited cyclic AMP formation in cerebral cortical slices. This process required at least a 7-day treatment period and was dose-dependent. Application of 1 microgram of T4 per kg for 9 days significantly diminished the NE responsivity of the cyclic AMP synthesizing system. Dose-response curves with NE indicate a reduction of the maximal response after T4 treatment with no change in ED50. An almost additive interaction between the effects of T4 and a low dose (3 mg/kg) of the tricyclic antidepressant imipramine was observed. Striking differences in the response of the adrenoceptor coupled adenylate cyclase to a 9-day T4 treatment were found when different rat strains, i.e., Fischer F-344, Long-Evans, Wistar and Sprague-Dawley were used. The hyperthyroid state of the animals was ascertained by measurements of plasma levels of tri-iodo-thyronine and T4. Down-regulation of NE sensitive adenylate cyclase by T4 treatment required intact synaptic structures because denervation by i.c.v. injection of 6-hydroxydopamine abolished the effect of T4 treatment. This is indicative of a postsynaptic localization of the down-regulated cyclic AMP generating system. The data stress the importance of the neuroendocrine system for adrenoceptor regulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Schmidt
B H
BH
Schultz
J E
JE
D000818:Animals; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism*; D000242:Cyclic AMP / Q000096:biosynthesis*; D004082:Dihydroalprenolol / Q000378:metabolism; D008297:Male; D009638:Norepinephrine / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology; D013974:Thyroxine / Q000097:blood / Q000494:pharmacology*; D014284:Triiodothyronine / Q000097:blood / Q000494:pharmacology
D011943:Receptors, Adrenergic, beta; D014284:Triiodothyronine; D013973:Thyrotropin-Releasing Hormone; D004082:Dihydroalprenolol; D000242:Cyclic AMP; D013974:Thyroxine; D009638:Norepinephrine