Horm Metab Res 2005; 37(8): 482-488
DOI: 10.1055/s-2005-870323
Original Basic
© Georg Thieme Verlag KG Stuttgart · New York

Hyperglycemia Induced by Pharmacological Activation of Central Serotonergic Pathways Depends on the Functional Integrity of Brain CRH System and 5-HT3 Receptors

F.  Carvalho1 , D.  Barros1 , J.  Silva1 , E.  Rezende1 , M.  Soares2 , J.  Fregoneze2 , E.  de Castro-e-Silva2
  • 1 Life Sciences Department, Bahia State University, 41195-001 Salvador, Bahia, Brazil
  • 2 Department of Physiology, Health Sciences Institute, Federal University of Bahia, 40110-100 Salvador, Bahia, Brazil
Further Information

Publication History

Received 20 November 2003

Accepted after revision 8 November 2004

Publication Date:
01 September 2005 (online)

Abstract

In the present study, we investigated the effect of central serotonergic pathway activation achieved through third ventricle injections of quipazine, a serotonergic agonist, on plasma glucose levels of fasted and fed adult Wistar male rats, whose third ventricles were canulated 7 days before the experiments. Central quipazine administration induced a significant increase in plasma glucose levels in fasted animals, but was unable to modify plasma glucose concentrations in fed rats. Pretreatment with α-helical CRH, a CRH antagonist, significantly attenuated quipazine-induced hyperglycemia. Pretreatment with two different 5-HT3 receptor antagonists, LY-278,584 and ondansetron, was also able to produce a significant reduction in the hyperglycemic response evoked by central administration of quipazine. None of the antagonists used was capable of modifying plasma glucose concentrations when injected alone into the third ventricle. Quipazine-treated, hyperglycemic animals did not show any increase in plasma insulin levels. We conclude that acute pharmacological serotonergic stimulation by quipazine produces hyperglycemia by mechanisms that require the functional integrity of both CRH and 5-HT3 receptors, and that impairment in insulin secretion and/or activity may explain hyperglycemia induced by third ventricle injections of quipazine.

References

  • 1 Barnes N M, Sharp T. A review of central 5-HT receptors and their function.  Neuropharmacology. 1999;  38 1083-1152
  • 2 Lin M T, Shian L R. Stimulation of 5-hydroxytryptamine nerve cells in dorsal and median raphe nuclei elevates blood glucose in rats.  Pflugers Arch. 1991;  417 441-445
  • 3 Chaouloff F, Gunn S H, Young J B. Central 5-hydroxytryptamine2 receptors are involved in the adrenal catecholamine-releasing and hyperglycemic effects of the 5-hydroxytryptamine indirect agonist d-fenfluramine in the conscious rat.  J Pharmacol Exp Ther. 1992;  260 1008-1016
  • 4 Wong K L, Tyce G M. Effect of the administration of L-5-hydroxytryptophan and a monoamine oxidase inhibitor on glucose metabolism in rat brain.  J Neurochem. 1978;  31 613-620
  • 5 Chaouloff F, Jeanrenaud B. 5-HT1A and alpha-2 adrenergic receptors mediate the hyperglycemic and hypoinsulinemic effects of 8-hydroxy-2-(di-n-propylamino)tetralin in conscious rat.  J Pharmacol Exp Ther. 1987;  243 1159-1166
  • 6 Chaouloff F, Laude D, Baudrie V. Effects of the 5-HT1C/5-HT2 receptor agonists DOI and α-methyl-5-HT on plasma glucose and insulin levels in the rat.  Eur J Pharmacol. 1990;  187 435-443
  • 7 Baudrie T, Chaouloff F. Mechanisms involved in the hyperglycemic effect of the 5-HT1C/5-HT2 receptor agonist DOI.  Eur J Pharmacol. 1992;  213 41-46
  • 8 Sugimoto Y, Yamada J, Yoshikawa T, Horisaka K. Effects of the 5-HT2C/2B receptor agonist 1-(3-chlorophenyl)piperazine on the plasma glucose levels of rats.  Eur J Pharmacol. 1996;  307 75-80
  • 9 Carvalho F, Macêdo D, Bandeira I, Maldonado I, Salles L, Azevedo M F, Rocha M A Jr, Fregoneze J B, de Castro-e-Silva E. Central 5-HT3 receptor stimulation by m-CPBG increases blood glucose in rats.  Horm Metab Res. 2002;  34 55-61
  • 10 Eckart C, Radulovic J, Radulovic M, Jahn O, Blank T, Stiedl O, Spiess J. Actions of CRF and its analogs.  Curr Med Chem. 1999;  6 1035-1053
  • 11 Chaouloff F. Physiopharmacological interactions between stress hormones and central serotonergic systems.  Brain Res Rev. 1993;  18 1-32
  • 12 Price M L, Curtis A L, Kirby L G, Valentino R J, Lucki I. Effects of corticotropin-releasing factor on brain serotonergic activity.  Neupsychopharmacology. 1998;  18 492-502
  • 13 Brown M R, Fisher L A, Spiess J, Rivier C, Rivier J, Vale W. Corticotropin-releasing factor: Actions on the sympathetic nervous system and metabolism.  Endocrinology. 1982;  111 928
  • 14 Iguchi A, Kunoh Y, Miura H, Uemura K, Yatomi A, Tamagawa T, Kawahara H, Sakamoto N. Central nervous system control of glycogenolysis and gluconeogenesis in fed and fasted rat liver.  Metabolism. 1989;  38 1216-1221
  • 15 Harms P G, Ojeda S R. A rapid and simple procedure for chronic canulation of the rat jugular vein.  J Appl Physiol. 1974;  36 391-392
  • 16 Abi-Dargham A, Laruelle M, Wong D T, Robertson D W, Weinberg D R, Kleinman J E. Pharmacological and regional characterization of [3H]LY278584 binding sites in human brain.  J Neurochem. 1993;  60 730- 737
  • 17 Gehlert D R, Gackenheimer S L, Wong D T, Robertson D W. Localization of 5-HT3 receptor in the rat brain using [3H]LY278584.  Brain Res. 1991;  553 149-154
  • 18 Gaster L M, King F D. Serotonin 5-HT3 and 5-HT4 receptor antagonists.  Med Res Rev. 1997;  17 163-214
  • 19 Hanley N R, van de Kar L D. Serotonin and the neuroendocrine regulation of the hypothalamic-pituitary-adrenal axis in the health and disease.  Vitam Horm. 2003;  66 189-255
  • 20 Pan L, Gilbert F. Activation of 5-HT1A receptor subtype in the paraventricular nuclei of the hypothalamus induces CRH and ACTH release in the rat.  Neuroendocrinology. 1992;  56 797-802
  • 21 Feldman S, Newman M E, Gur E, Weidenfeld J. Role of serotonin in the amygdala in hypothalamo-pituitary-adrenocortical responses.  Neuroreport. 1998;  9 2007-2009
  • 22 Bovetto S, Rouillard C, Richard D. Role of CRH in the effects of 5-HT-receptor agonists on food intake and metabolic rate.  Am J Physiol. 1996;  271 R1231-R12388
  • 23 Bagdy G, Calogero A E, Szemeredi K, Gomez M T, Murphy D L, Chrousos G P, Gold P W. α-Endorphin responses to different serotonin agonists: involvement of corticotropin-releasing hormone, vasopressin and direct pituitary action.  Brain Res. 1990;  537 227-232
  • 24 Nijsen M JMA, Croiset G, Stam R, Bruijnzeel A, Diamant M, de Wied D, Wiegant V M. The role of CRH type 1 receptor in autonomic responses to corticotropin-releasing hormone in rat.  Neuropsychopharmacology. 2000;  22 388-399
  • 25 Gunion M W, Rosenthal M J, Taché Y, Miller S, Butler B, Zib B. Intrahypothalamic microinfusion of corticotropin-releasing factor elevates blood glucose and free fatty acids in rats.  J Auton Nerv Syst. 1988;  24 87-95
  • 26 Brown M R, Fisher L A, Webb V, Vale W W, River J E. Corticotropin-releasing factor: a physiologic regulator of adrenal epinephrine secretion.  Brain Res. 1985;  328 355-357
  • 27 Maeda K, Cagampang F R, Coen C W, Tsukamura H. Involvement of the catecholaminergic input to the paraventricular nucleus and corticotropin-releasing hormone in the fasting-induced suppression of luteinizing hormone release in female rats.  Endocrinology. 1994;  134 1718-1722
  • 28 Timofeeva E, Richard D. Functional activation of CRH neurons and expression of the genes encoding CRH and its receptors in food-deprived lean (Fa/?) and obese (fa/fa) Zucker rats.  Neuroendocrinology. 1997;  66 327-340
  • 29 Kasckow J W, Hagan M, Mulchahey J J, Baker D G, Ekhator N N, Strawn J R, Nicholson W, Orth D N, Loosen P T, Geracioti T D Jr. The effect of feeding on cerebrospinal fluid corticotropin-releasing hormone levels in humans.  Brain Res. 2001;  904 218-224
  • 30 Wieczorek I, Schulz C, Jarry H, Lehnert H. The effects of the selective serotonin reuptake-inhibitor fluvoxamine on body weight in Zucker rats are mediated by corticotropin-releasing hormone.  Int J Obes Relat Metab Disord. 2001;  25 1566-1569
  • 31 Nandi J, Meguid M M, Inui A, Xu Y, Makarenko I G, Tada T, Chen C. Central mechanisms involved with catabolism.  Curr Opin Clin Nutr Metab Care. 2002;  5 407-418
  • 32 Landsberg L. Diabetes, obesity and hypertension: Role of insulin and sympathetic nervous system.  Cardiovasc Risk Factors. 1993;  3 153-158
  • 33 Steffens A B, Strubbe J H, Balkan B, Scheurink A JW. Neuroendocrine factors regulating blood glucose, plasma FFA and insulin in the development of obesity.  Brain Res Bull. 1991;  27 505-510

Emilio de Castro e Silva M. D., Ph. D.

Universidade Federal da Bahia, Instituto de Ciências da Saúde , Departamento de Fisiologia

40110-100 Salvador · BA, Brazil

Phone: +55 71 32357518

Fax: +55 71 3263 7067 ·

Email: emilio@ufba.br

    >