Brain Research, 344 (1985) 387-391 387 Elsevier BRE 21077 Central thyrotropin-releasing hormone elicits systemic hypoglycemia in mice SHIMON AMIR, AVRAHAM I. RIVKIND and MICHAL HAREL Department of Isotope Research, The Weizmann Institute of Science, Rehovot (Israel) (Accepted May 14th, 1985) Key words: thyrotropin-releasing hormone (TRH) -- central nervous system -- hypoglycemia-- parasympathetic system -- insulin - - mouse Thyrotropin-releasing hormone (TRH), injected into the central nervous system (CNS) in rats, has been shown to elicit systemic hy- perglycemia. In the present study, central TRH administration significantly decreased the plasma glucose in mice. The hypoglycemic response could be blocked by pretreatment with the muscarinic cholinergic antagonist, atropine methyl bromide, or the diabetogenic fl-cytotoxin, alloxan, implicating the involvement of the parasympathetic system and insulin-secreting cells in the endocrine pancreas. The role of TRH in the CNS in the autonomic regulation of glucose homeostasis is discussed. Thyrotropin-releasing hormone (TRH; pGlu-His- Pro-NH2) is one of several neuroactive peptides thought to play a role in the central regulation of glu- cose homeostasis 9. TRH and TRH receptors are found in central nervous system (CNS) regions impli- cated in autonomic control of the endocrine pancreas and liver 5,6.1~,19, and it has been shown that central administration of TRH elicits systemic hyperglyce- mia in rats z. The precise mechanism by which TRH produces its effect on plasma glucose has not been succinctly defined, but it has been shown that both the sympathetic and parasympathetic systems might be involved 2,15. We sought in the present study to further charac- terize the neural mechanism mediating the glucore- gulatory action of TRH by investigating the plasma glucose responses to central TRH administration in another animal species, the mouse. We found unex- pectedly that, in contrast to its hyperglycemic action in rats, central TRH administration is a potent stimu- lus for hypoglycemia in mice. Experiments were carried out in normally fed male ICR mice, 28-32 g. TRH (Sigma) was dissolved in saline and administered intracerebroventricularly (i.c.v.) according to the method of Haley and McCormick u using a Hamilton microsyringe bearing a 27-gauge needle 2.5 mm long. Control mice were injected i.c.v, with 5 ~1 saline. The mice were sacri- ficed by decapitation at different times after the i.c.v. treatment, the trunk blood was collected and centri- fuged to obtain plasma, and the plasma glucose was determined using a Beckman glucose analyzer, mod- el2. As shown in Fig. 1A, i.c.v, injection of 10 ~g of TRH produced a rapid, progressive decrease in plas- ma glucose concentrations. This hyperglycemic re- sponse could be reproduced by i.c.v, injection of much lower doses of TRH (Fig. 1B). In this study the plasma glucose was determined at 15 min post i.c.v. injection. At this time the intravenous (i.v.) adminis- tration of 1, 5, 10 or 25 ktg of TRH had no effect on plasma glucose in mice (data not shown). Previous studies have shown that central injection of the polypeptide hormone, insulin, significantly lowers the plasma glucose concentrations~4, 2~. More- over, it has been demonstrated that this centrally me- diated hypoglycemic response depends on the func- tional integrity of the parasympathetic system since it could be blocked by vagotomy or pretreatment with the muscarinic cholinergic antagonist, atropine 22,23. In order to determine the involvement of parasympa- thetic mechanisms in the hypoglycemic response to central TRH administration, this effect of TRH was evaluated in mice in which the parasympathetic sys- Correspondence: S. Amir, Department of Isotope Research, The Weizmann Institute of Science, Rehovot, Israel. 0006-8993/85/$03.30 © 1985 Elsevier Science Publishers B.V. (Biomedical Division)