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5-HT2C Receptor Agonists and the Control of Appetite

  • Jason C. G. Halford
  • Joanne A. Harrold
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 209)

Abstract

The role of serotonin (5-HT) in appetite control is well recognised. 5-HT drugs reduce food intake in rodents in a manner consistent with an enhancement of satiety. In humans, they have been shown to reduce caloric intake, an effect associated with reduced hunger and increased satiety. These effects appear to be mediated, at least in part, by the 5-HT2C receptor subtype. 5-HT-acting drugs such as fenfluramine, d-fenfluramine, and sibutramine have provided effective anti-obesity treatments in the past. However, more selective agents are needed that produce the same changes in eating behaviour and induce weight loss without unacceptable side effects. Lorcaserin, a selective 5-HT2C receptor agonist, is a novel anti-obesity agent that reduces both energy intake and body weight. The effects of lorcaserin on eating behaviour remain to be characterised as does its behavioural specificity.

Keywords

Appetite Behaviour Food intake Obesity Satiety 

References

  1. Abeniam L, Moride Y, Brenot F et al (1996) Appetite suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 335:609–616CrossRefGoogle Scholar
  2. Arterburn DE, Crane PK, Veenstra DL (2004) The efficacy and safety of sibutramine for weight loss: a systematic review. Arch Intern Med 164:994–1003PubMedCrossRefGoogle Scholar
  3. Bjenning C, Williams J, Whelan K et al (2004) Chronic oral administration of APD356 significantly reduces body weight and fat mass in obesity-prone (DIO) male and female rats. Int J Obes 28(suppl 1):214Google Scholar
  4. Blundell JE (1977) Is there a role for serotonin (5-hydroxytryptamine) in feeding? Int J Obes 1:15–42PubMedGoogle Scholar
  5. Blundell JE, Halford JCG (1998) Serotonin and appetite regulation: implications for the treatment of obesity. CNS Drugs 9:473–495CrossRefGoogle Scholar
  6. Blundell JE, Hill AJ (1990) Sensitivity of the appetite control system in obese subjects to nutritional and serotoninergic challenges. Int J Obes 14:219–233PubMedGoogle Scholar
  7. Blundell JE, Latham CJ (1978) Pharmacological manipulation of feeding behaviour: possible influences of serotonin and dopamine on food intake. In: Garattini S, Samanin R (eds) Central mechanisms of anorectic drugs. Raven, NY, pp 83–109Google Scholar
  8. Blundell JE, Latham CJ (1980) Characteristic adjustments to the structure of feeding behaviour following pharmacological treatments: effects of amphetamine and fenfluramine and the antagonism by pimozide and metergoline. Pharmacol Biochem Behav 12:717–722PubMedCrossRefGoogle Scholar
  9. Blundell JE, McArthur RA (1981) Behavioural flux and feeding: continuous monitoring of food intake and food selection, and the video-recording of appetitive and satiety sequences for the analysis of drug action. In: Samanin R, Garattini S (eds) Anorectic agents: mechanisms of action and tolerance. Raven, NY, pp 19–43Google Scholar
  10. Chapelot D, Mamonier C, Thomas F et al (2000) Modalities of the food intake-reducing effect of sibutramine in humans. Physiol Behav 68:299–308PubMedCrossRefGoogle Scholar
  11. Clifton PG (1994) The neuropharmacology of meal patterning. In: Cooper SJ (ed) Ethology and psychopharmacology. Wiley, Chichester, pp 313–328Google Scholar
  12. Cowen PJ, Sargent PA, Williams C et al (1995) Hypophagic, endocrine and subjective responses to m-chlorophenylpiperazine in healthy men and women. Hum Psychopharmacol 10:385–391CrossRefGoogle Scholar
  13. Goodall E, Silverstone T (1988) Differential effect of d-fenfluramine and metergoline on food intake in human subjects. Appetite 11:215–288PubMedCrossRefGoogle Scholar
  14. Haddock CK, Poston WSC, Dill PL et al (2002) Pharmacotherapy for obesity: a quantitative analysis of four decades of published randomized clinical trials. Int J Obes 26:262–273CrossRefGoogle Scholar
  15. Halford JCG, Blundell JE (1993) 5-Hydroxytryptaminergic drugs compared on the behavioural sequence associated with satiety. Br J Pharmacol 100:95Google Scholar
  16. Halford JCG, Boyland EJ, Cooper SJ et al (2010a) The effects of sibutramine on the microstructure of eating behaviour and energy expenditure in obese women. J Psychopharmacol 24:99–109PubMedCrossRefGoogle Scholar
  17. Halford JCG, Boyland EJ, Blundell JE et al (2010b) Pharmacological management of human appetite expression: evaluating the effects of novel anti-obesity agents on eating behaviour. Nat Endocrine Rev 6:255–269CrossRefGoogle Scholar
  18. Halford JCG, Harrold JA, Boyland EJ, Lawton CL, Blundell JE (2007) Serotonergic drugs: effects on appetite expression and use for the treatment of obesity. Drugs 67:27–55PubMedCrossRefGoogle Scholar
  19. Halford JCG, Blundell JE (2000) Separate systems for serotonin and leptin in appetite control. Ann Med 32:222–232PubMedCrossRefGoogle Scholar
  20. Halford JCG, Wanninayake SCD, Blundell JE (1998) Behavioural satiety sequence (BSS) for the diagnosis of drug action on food intake. Pharmacol Biochem Behav 61:159–168PubMedCrossRefGoogle Scholar
  21. Hansen DL, Toubro S, Stock MJ et al (1998) Thermogenic effects of sibutramine in humans. Am J Clin Nutr 68:1180–1186PubMedGoogle Scholar
  22. Hayashi A, Sonoda R, Kimura Y et al (2004) Antiobesity effect of YM348, a novel 5-HT2C receptor agonist, in Zucker rats. Brain Res 1011:221–227PubMedCrossRefGoogle Scholar
  23. Heisler LK, Cowley MA, Tecott LH et al (2002) Activation of Central Melanocortin pathways by Fenfluramine. Science 297:609–611PubMedCrossRefGoogle Scholar
  24. Heisler LK, Cowley MA, Kishi T et al (2003) Central serotonin and melanocortin pathways regulating energy homeostasis. N Y Acad Sci 994:169–174CrossRefGoogle Scholar
  25. Heisler LK, Jobst EE, Sutton GM et al (2006) Serotonin reciprocally regulates melanocortin neurons to modulate food intake. Neuron 51:239–249PubMedCrossRefGoogle Scholar
  26. Hewitt KN, Lee MD, Dourish CT et al (2002) Serotonin 2C receptor agonists and the behavioural satiety sequence in mice. Pharmacol Biochem Behav 71:691–700PubMedCrossRefGoogle Scholar
  27. Higgs S, Cooper AJ, Barnes NM (2011) Reversal of sibutramine-induced anorexia with a selective 5-HT2C receptor antagonist. Psychopharmacology 214:941–947PubMedCrossRefGoogle Scholar
  28. Hoyer D, Martin G (1997) 5-HT receptor classification and nomenclature: towards a harmonization with the human genome. Neuropharmacology 36:419–428PubMedCrossRefGoogle Scholar
  29. James WP, Caterson ID, Coutinho W, Finer N, Van Gaal LF, Maggioni AP, Torp-Pedersen C, Sharma AM, Shepherd GM, Rode RA, Renz CL, SCOUT Investigators (2010) Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med 363:905–917PubMedCrossRefGoogle Scholar
  30. Kennett GA, Curzon G (1988a) Evidence that the hypophagia induced by mCPP and TFMPP requires 5-HT1C and 5-HT1B receptors; hypophagia induced by RU-24969 only requires 5-HT1B receptors. Psychopharmacology 96:93–100PubMedCrossRefGoogle Scholar
  31. Kennett GA, Curzon G (1988b) Evidence that mCPP may have behavioural effects mediated by central 5-HT1C receptors. Br J Pharmacol 94:137–147PubMedGoogle Scholar
  32. Kitchener SJ, Dourish CT (1994) An examination of the behavioural specificity of hypophagia induced by 5-HT1B, 5-HT1C and 5-HT2 receptor agonists using the post-prandial sequence in rats. Psychopharmacology 113:368–377CrossRefGoogle Scholar
  33. Lawton CL, Wales JK, Hill AJ et al (1995) Serotoninergic manipulation, meal-induced satiety and eating patterns. Obes Res 3:345–356PubMedGoogle Scholar
  34. Martin CK, Redman LM, Zhang J et al (2011) Lorcaserin, a 5-HT2C receptor agonist, reduced body weight by decreasing energy intake within influencing energy expenditure. J Clin Endocrinol Metab 96:837–45PubMedCrossRefGoogle Scholar
  35. McGuirk J, Silverstone T (1990) The effect of 5-HT re-uptake inhibitor fluoxetine on food intake and body weight in healthy male subjects. Int J Obes 14:361–372PubMedGoogle Scholar
  36. Nonogaki K, Abdullah L, Goulding EH et al (2003) Hyperactivity and reduced energy cost of physical activity in serotonin 5-HT2C receptor mutant mice. Diabetes 52:315–320PubMedCrossRefGoogle Scholar
  37. Padwal R, Li SK, Lau DCW (2003) Long-term pharmacotherapy for overweight and obesity: a systematic review and meta-analysis of randomized controlled trials. Int J Obes 27:1437–46CrossRefGoogle Scholar
  38. Pijl H, Koppeschaar HPF, Willekens FLA et al (1991) Effect of serotonin re-uptake inhibition by fluoxetine on body weight and spontaneous food choice in obesity. Int J Obes 15:237–242PubMedGoogle Scholar
  39. Rogers PJ, Blundell JE (1979) Effect of anorexic drugs on food intake and the micro-structure of eating in human subjects. Psychopharmacology 66:159–165PubMedCrossRefGoogle Scholar
  40. Rolls BJ, Shide DJ, Thorward ML et al (1998) Sibutramine reduces food intake in non-dieting women with obesity. Obes Res 6:1–11PubMedGoogle Scholar
  41. Sargent PA, Sharpley AL, Williams C et al (1997) 5-HT2C receptor activation decreases appetite and body weight in obese subjects. Psychopharmacology 133:309–312PubMedCrossRefGoogle Scholar
  42. Smith SR, Prosser WA, Donahue DF et al (2009) Lorcaserin (APD356), a selective 5-HT2C agonist, reducing body weight in obese men and women. Obesity 17:494–500PubMedCrossRefGoogle Scholar
  43. Smith SR, Wiessman NJ, Anderson CM et al (2010) Multicenter, placebo-controlled trial for Lorcaserin for weight management. N Engl J Med 363:245–56PubMedCrossRefGoogle Scholar
  44. Tecott LH, Sun LM, Akanna SF et al (1995) Eating disorder and epilepsy in mice lacking 5-HT2C serotonin receptors. Nature 374:542–546PubMedCrossRefGoogle Scholar
  45. Vickers SP, Benwell KR, Porter RH et al (2000) Comparative effects of continuous infusion of mCPP, Ro 60–0175 and d-fenfluramine on food intake, water intake, body weight and locomotor activity in rats. Br J Pharmacol 130:1305–1314PubMedCrossRefGoogle Scholar
  46. Vickers SP, Clifton PG, Dourish CT et al (1999) Reduced satiating effect of d-fenfluramine in serotonin 5-HT2C receptor mutant mice. Psychopharmacology 143:309–314PubMedCrossRefGoogle Scholar
  47. Vickers SP, Dourish CT (2004) Serotonin receptor ligands and the treatment of obesity. Curr Opin Investig Drugs 5:377–388PubMedGoogle Scholar
  48. Vickers SP, Dourish CT, Kennett GA (2001) Evidence that hypophagia induced by d-fenfluramine and d-norfenfluramine in the rat is mediated by 5-HT2C receptors. Neuropharmacology 41:200–209PubMedCrossRefGoogle Scholar
  49. Vickers SP, Easton N, Webster LJ et al (2003) Oral administration of the 5-HT2C receptor agonist, mCPP, reduces body weight gain in rats over 28 days as a result of maintained hypophagia. Psychopharmacology 167:274–280PubMedGoogle Scholar
  50. Walsh AE, Smith KA, Oldman AD (1994) M-Chlorophenylpiperazine decreases food intake in a test meal. Psychopharmacology 116:120–122PubMedCrossRefGoogle Scholar
  51. Ward AS, Comer SD, Haney M et al (1999) Fluoxetine-maintained obese humans: effect on food intake and body weight. Physiol Behav 66:815–821PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Kissileff Laboratory for the Study of Human Ingestive Behaviour, School of PsychologyUniversity of LiverpoolLiverpoolUK

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