title: 5-Hydroxytryptamine 1A (5HT1A) receptors mediate increases in plasma glucose independent of corticosterone.
abstract: Hypothalamic 5HT1A receptors play an important role in the regulation of satiety, glycemia and endocrine status. In the present study, 8-OH-DP administered centrally and peripherally to C57/Bl6 mice and plasma glucose insulin and corticosterone were evaluated. In these studies, dose and time dependent increases in glucose and corticosterone were observed while no alterations in insulin were seen. The increases in plasma corticosterone were prevented by prior central or peripheral administration of LY426965, a specific 5HT1A antagonist. Intracerebroventricular coadministration of a 5HT1A antagonist with 8-OH-DPAT prevented the increase in plasma glucose establishing this response as a centrally mediated response in mice. Given that increases in plasma corticosterone are associated with increases in plasma glucose, we conducted experiments to determine if increased plasma corticosterone was the mechanism by which 8-OH-DPAT increased plasma glucose. Prior administration of the glucocorticoid antagonist mifepristone did not affect the increase in plasma glucose produced by 8-OH-DPAT. Prior administration of the glucocorticoid synthesis inhibitor, metyrapone, reduced basal corticosterone and the concentrations of corticosterone associated with 8-OH-DPAT administration. However, metyrapone administration did not affect the increases in plasma glucose. Therefore, 5HT1A receptors regulate glucose through brain mechanisms, but not through regulation of the hypophyseal-pituitary axis. Antagonism of brain 5HT1A receptors may enable discovery of novel antidiabetic agents.
authors.affiliation: Neuroscience and Endocrine Divisions, Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN, USA. Electronic address: Gehlert_Donald_R@Lilly.com.
authors.forename: Donald R
authors.initials: DR
authors.lastname: Gehlert
authors.affiliation: Neuroscience and Endocrine Divisions, Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Janice
authors.initials: J
authors.lastname: Shaw
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003345:Corticosterone / Q000097:blood*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D007328:Insulin / Q000097:blood; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D015735:Mifepristone / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D010880:Piperidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C078730:serotonin 5 receptor; D015735:Mifepristone; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C412310:LY 426965; D003345:Corticosterone; D008797:Metyrapone
keywords: (+/-)-8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT: Pubchem CID 1220); 11β-[p-(Dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one (Mifepristone: Pubchem CID55245); 2-methyl-1,2-di(pyridin-3-yl)propan-1-one (Metyrapone: Pubchem CID 4174); Diabetes; Glucose; Hypothalamus; Insulin; Metyrapone; Mifepristone; [(2S)-(1)-1-cyclohexyl-4-[4-(2-methoxyphenyl)-1-piperazinyl]2-methyl-2-phenyl-1-butanone monohydrochloride] (LY426965: Pubchem CID 9845807)