Preventive Effect of Serotonergic Drugs on LPS-Induced Acute Anorexia in Rats

  • Park, So-Young (Departments of Physiology, College of Medicine, Yeungnam University) ;
  • Kim, Keon-Ho (Departments of Orthopedic Surgery, College of Medicine, Yeungnam University) ;
  • Ahn, Dong-Kuk (Deportment of Oral Physiology, School of Dentistry, Kyungpook National University) ;
  • Park, Tae-Im (Departments of Physiology, College of Medicine, Yeungnam University) ;
  • Kim, Jong-Yeon (Departments of Physiology, College of Medicine, Yeungnam University) ;
  • Kim, Yong-Woon (Departments of Physiology, College of Medicine, Yeungnam University) ;
  • Lee, Dong-Chul (Departments of Orthopedic Surgery, College of Medicine, Yeungnam University) ;
  • Lee, Suck-Kang (Departments of Physiology, College of Medicine, Yeungnam University)
  • Published : 2005.06.21


The aim of the present study was to determine whether serotonergic drugs could reverse lipopolysaccharide (LPS)-induced anorexia in rats. LPS ($500{\mu}g$/kg body weight) and all serotonergic drugs, except for 8-OH-DPAT (subcutaneous), were injected intraperitoneally into Sprague-Dawley rats. Without the LPS injection, 8-OH-DPAT (1A agonist), metergoline (1/2 antagonist), and mianserin (2A/2C antagonist) exerted no effects on food intake at any of the doses tested, but ketanserin (2A antagonist) caused an increase of food intake at 4 mg/kg. RS-102221 (2C antagonist) reduced food intake at 2 and 4 mg/kg. LPS reduced food intake 1 hour after injection, and food intake remained low until the end of measurement period (24 hours) (p<0.05). Pretreatment of rats with 8-OH-DPAT partially recovered of cumulative food intake at all measured times (2, 4, 6, 8, and 24 hours after LPS injection). Pretreatment with metergoline resulted in a partial recovery of cumulative food intake at 2, 4, 6, and 8 hours, but not at 24 hours. Ketanserin caused partial recovery at 2 and 4 hours only. Mianserin and RS-102221 had no effects on LPS-reduced food intake. A variety of serotonergic drugs ameliorated anorexic symptoms, which suggesting that the serotonin system plays a role in LPS-induced anorexia.


  1. Bendotti C, Samanin R. 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT elicits eating in free-feeding rats by acting on central serotonin neurons. Eur J Pharmacol 121: 147-150, 1986
  2. Choi SH, Kwon BS, Lee S, Houpt TA, Lee HT, Kim DG, Jahng JW. Systemic 5-hydroxy-L-tryptophan down-regulates the arcuate CART mRNA level in rats. Regul Pept 115: 73-80, 2003
  3. Dunn AJ. Endotoxin-induced activation of cerebral catecholamine and serotonin metabolism: comparison with interleukin-1. J Pharmacol Exp Ther 261: 964-969, 1992
  4. Fantino M, Wieteska L. Evidence for a direct central anorectic effect of tumor-necrosis-factor-alpha in the rat. Physiol Behav 53: 477-483, 1993
  5. Hewson G, Leighton GE, Hill RG, Hughes J. Ketanserin antagonises the anorectic effect of DL-fenfluramine in the rat. Eur J Pharmacol 145: 227-230, 1988
  6. Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ, Saxena PR, Humphrey PP. International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). Pharmacol Rev 46: 157-203, 1994
  7. Hrupka BJ, Langhans W. A role for serotonin in lipopolysaccharideinduced anorexia in rats. Pharmacol Biochem Behav 68: 355- 362, 2001
  8. Kent S, Bluthe RM, Dantzer R, Hardwick AJ, Kelley KWR, Rothwell NJ, Vannice JL. Different receptor mechanisms mediate the pyrogenic and behavioral effects of interleukin 1. Proc Natl Acad Sci USA 89: 9117-9120, 1992a
  9. Kent S, Bluthe RM, Kelley KW, Dantzer R. Sickness behavior as a new target for drug development. Trends Pharmacol 13: 24-28, 1992b
  10. Macallan G, Noble C, Baldwin C, Jebb SA, Prentice AM, Coward WA, Sawyer MB, McManus TJ, Griffin GE. Energy expenditure and wasting in human immunodeficiency virus infection. N Engl J Med 333: 83-88, 1995
  11. Park S, Harrold JA, Widdowson PS, Williams G. Increased binding at 5-HT(1A), 5-HT (1B), and 5-HT (2A) receptors and 5-HT transporters in diet-induced obese rats. Brain Res 847: 90-97, 1999
  12. Plata-Salaman CR, Borkoski JP. Chemokines/intercrines and central regulation of feeding. Am J Physiol 266(5 Pt 2): R1711- 1715, 1994
  13. Raghavendra V, Kulkarni SK. Melatonin reversal of DOI-induced hypophagia in rats; possible mechanism by suppressing 5-HT (2A) receptor-mediated activation of HPA axis. Brain Res 860: 112-118, 2000
  14. Lenczowski MJ, Van Dam AM, Poole S, Larrick JW, Tilders FJ. Role of circulating endotoxin and interleukin-6 in the ACTH and corticosterone response to intraperitoneal LPS. Am J Physiol 273: R1870-1877, 1997
  15. Grignaschi G, Sironi F, Samanin R. Stimulation of 5-HT2A receptors in the paraventricular hypothalamus attenuates neuropeptide Y-induced hyperphagia through activation of corticotropin releasing factor. Brain Res 708: 173-176, 1996
  16. McCarthy DO. Tumor necrosis factor alpha and interleukin-6 have differential effects on food intake and gastric emptying in fasted rats. Res Nurs Health 23: 222-228, 2000<222::AID-NUR6>3.0.CO;2-3
  17. Sugimoto Y, Yamada J, Yoshikawa T, Horisaka K. The involvement of 5-HT1B receptors in the inhibitory effects of nitric oxide synthase inhibitor on 2-deoxy-D-glucose-induced hyperphagia in rats. Neuroreport 8: 2735-2737, 1997
  18. Lavicky J, Dunn AJ. Endotoxin administration stimulates cerebral catecholamine release in freely moving rats as assessed by microdialysis. J Neurosci Res 40: 407-413, 1995
  19. Grunfeld C, Feingold KR. Metabolic disturbances and wasting in the acquired immunodeficiency syndrome. N Engl J Med 327: 329-337, 1992
  20. Sharp T, Hjorth S. Application of brain microdialysis to study the pharmacology of the 5-HT1A autoreceptor. J Neurosci Methods 34: 83-90, 1990
  21. Gardier AM, Malagie I, Trillat AC, Jacquot C, Artigas F. Role of 5-HT1A autoreceptors in the mechanism of action of serotoninergic antidepressant drugs: recent findings from in vivo microdialysis studies. Fundam Clin Pharmacol 10: 16-27, 1996.
  22. von Meyenburg C, Langhans W, Hrupka BJ. Evidence for a role of the 5-HT2C receptor in central lipopolysaccharide-, interleukin- 1 beta-, and leptin-induced anorexia. Pharmacol Biochem Behav 74: 1025-1031, 2003
  23. McCarthy DO, Kluger MJ, Vander AJ. The role of fever in appetite suppression after endotoxin administration. Am J Clin Nutr 40: 310-316, 1984
  24. Sugimoto Y, Yoshikawa T, Yamada J. Effects of peripheral administration of 5-hydroxytryptamine (5-HT) on 2-deoxy-D-glucoseinduced hyperphagia in rats. Biol Pharm Bull 25: 1364-1366, 2002
  25. Bonhaus DW, Weinhardt KK, Taylor M, DeSouza A, McNeeley PM, Szczepanski K, Fontana DJ, Trinh J, Rocha CL, Dawson MW, Flippin LA, Eglen RM. RS-102221: a novel high affinity and selective, 5-HT2C receptor antagonist. Neuropharmacology 36: 621-629, 1997
  26. Simansky KJ, Nicklous DM. Parabrachial infusion of D-fenfluramine reduces food intake. Blockade by the 5-HT (1B) antagonist SB-216641. Pharmacol Biochem Behav 71: 681-690, 2002
  27. Grunfeld C, Pang M, Shimizu L, Shigenaga JK, Jensen P, Feingold KR. Resting energy expenditure, caloric intake, and short-term weight change in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. Am J Clin Nutr 55: 455-460, 1992
  28. Simansky KJ, Sisk FC, Vaidya AH, Eberle-Wang K. Peripherally administered alpha-methyl-5-hydroxy-tryptamine and 5-carboxamidotryptamine reduce food intake via different mechanisms in rats. Behav Pharmacol 1: 241-246, 1989
  29. Cooney RN, Kimball SR, Vary TC. Regulation of skeletal muscle protein turnover during sepsis: mechanisms and mediators. Shock 7: 1-16, 1997
  30. Lee MD, Clifton PG. Partial reversal of fluoxetine anorexia by the 5-HT antagonist metergoline. Psychopharmacology (Berl) 107: 359-364, 1992
  31. Movat HZ, Cybulsky MI, Colditz IG, Chan MK, Dinarello CA. Acute inflammation in gram-negative infection: endotoxin, interleukin 1, tumor necrosis factor, and neutrophils. Fed Proc 46: 97-104, 1987
  32. Sergeyev V, Broberger C, Hokfelt T. Effect of LPS administration on the expression of POMC, NPY, galanin, CART and MCH mRNAs in the rat hypothalamus. Brain Res Mol Brain Res 90: 93-100, 2001
  33. Simansky KJ, Dave KD, Inemer BR, Nicklous DM, Padron JM, Aloyo VJ, Romano AG. A 5-HT2C agonist elicits hyperactivity and oral dyskinesia with hypophagia in rabbits. Physiol Behav 82: 97-107, 2004
  34. Simons JP, Schols AM, Buurman WA, Wouters EF. Weight loss and low body cell mass in males with lung cancer: relationship with systemic inflammation, acute-phase response, resting energy expenditure, and catabolic and anabolic hormones. Clin Sci 97: 215-223, 1999
  35. Leibowitz SF, Weiss GH, Shor-Posner G. Hypothalamic serotonin: pharmacological, biochemical, and behavioral analysis of its feeding-suppressive action. Clin Neuropharmacol 11: S51-S71, 1988