Serotonin and Appetite Regulation

Implications for the Pharmacological Treatment of Obesity

Summary

It is approximately 20 years since the serotonin (5-hydroxytryptamine; 5-HT) hypothesis of appetite control was formally stated. In that time, evidence has accumulated to confirm the role of serotonergic mechanisms in appetite control. At present, it is believed that serotonin 5-HT1B and 5-HT2C receptor subtypes mediate the capacity for an inhibition of food intake. Animal studies show that serotonin-induced suppression of eating generally preserves the behavioural satiety sequence, which is widely regarded as an indication of the operation of the natural physiological processes for meal termination and sustained post-meal satiety.

The precise nature of the human serotonin feeding control system is less well understood. However, the 5-HT2C receptor has been implicated in human eating, although any role for the 5-HT1Dβ (h5-HT1B) receptor has yet to be determined. A consistent pattern of reduction in hunger motivation and energy intake is seen in human studies with a variety of serotonergic agents. With some drugs, but not all, a controlled restraint of appetite can be observed for at least 1 year. Patients receiving drugs report both a lower frequency and a reduced strength of urges to eat, together with the feeling of being more in control of their eating. Some serotonergic drugs, such as dexfenfluramine, can exert a continued suppression of appetite even following substantial bodyweight loss brought about by a period of following a very low calorie diet.

Recent evidence has outlined the effects of diet composition on energy balance and bodyweight gain. This has generated interest in the effect of serotonergic drugs on preference for high fat diets and diets characterised by energy dense foods coupled with potent palatability, and carbohydrate craving. The experimental evidence is not unanimous on whether manipulation of serotonergic systems can selectively adjust macronutrient intake and food choice. Animal studies indicate that certain serotonergic drugs such as dexfenfluramine are potent inhibitors of the consumption of high fat diets. Human studies confirm that there is a suppression of the consumption of highly palatable high fat foods, and some studies indicate a possible selective avoidance of fat after the administration of dexfenfluramine and sumatriptan.

Serotonergic drugs may be particularly helpful in curtailing episodes of over-consumption. However, it remains to be clearly demonstrated whether serotonin-based interventions are appropriate for the binge eating subpopulation of obese people and for those individuals displaying binge eating disorder.

Despite the recent withdrawal from the market of appetite suppressants containing dexfenfluramine and fenfluramine, evidence suggests that serotonergic drugs can continue to play a useful role in the treatment of obesity. Their effects are achieved by adjusting biological mechanisms, which in turn reduce the impact of risk factors that facilitate the development of positive energy balance and bodyweight gain. Although the recent development of sibutramine as an appetite suppressant is encouraging, further research in this area is required to develop well tolerated and effective serotonergic appetite suppressants. Furthermore, an improvement in methodology in clinical research is required to enable detection of a selective modulation of high fat (high energy dense) foods.

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References

  1. 1.

    Gaddum JH, Picarelli ZP. Two kinds of tryptamine receptor. Br J Pharmacol 1957; 12; 323–8

    CAS  Google Scholar 

  2. 2.

    Peroutka SJ, Snyder SH. Multiple serotonin receptors: different binding of 3H-5-hydroxytryptamine, 3H-lysergic acid and diethylamide and 3H-spiroperidol. Mol Pharmacol 1979; 16; 687–99

    PubMed  CAS  Google Scholar 

  3. 3.

    Bradley P, Engel G, Feniuk W, et al. (nomenclature committee) Proposals for the classification and nomenclature of functional receptors for 5-hydroxytryptamine. Neuropharmacology 1986; 25: 563–76

    PubMed  CAS  Article  Google Scholar 

  4. 4.

    Fargin A, Raymond JR, Regan JW, et al. Effector coupling mechanisms of the cloned 5-HT1A receptor. J Biol Chem 1989; 264: 14848–52

    PubMed  CAS  Google Scholar 

  5. 5.

    Hoyer D, Pazos A, Probst A, et al. Serotonin receptors in the human brain. I. Characterisation and autoradiographic localization of 5-HT1A recognition sites: apparent absence of 5-HT1B recognition sites. Brain Res 1988; 376: 85–96

    Article  Google Scholar 

  6. 6.

    Hoyer D, Martin GR. Classification and nomenclature of 5-HT receptors: a comment on current issues. Behav Brain Res 1996; 73: 263–8

    PubMed  CAS  Article  Google Scholar 

  7. 7.

    Humphrey PPA, Hartig P, Hoyer D. A proposed new nomenclature for 5-HT receptors. Trends Pharmacol Sci 1993; 14: 233–6

    PubMed  CAS  Article  Google Scholar 

  8. 8.

    McAllister G, Charlesworth A, Snodin C, et al. Molecular cloning of a serotonin receptor from human brain (5-HT1E): a fifth 5-HT1-like sub-type. Proc Natl Acad Sci USA 1992; 89: 5517–21

    PubMed  CAS  Article  Google Scholar 

  9. 9.

    Amlaiky N, Ramboz S, Boschert U, et al. Isolation of a mouse 5-HT1E-like receptor expressed predominantly in the hippocampus. J Biol Chem 1992; 92: 19761–4

    Google Scholar 

  10. 10.

    Adham N, Kao H-T, Schechter L.E, et al. Cloning of another human serotonin receptor (5-HT1F): a fifth 5-HT1 receptor subtype coupled to the inhibition of adenylate cyclase. Proc Natl Acad Sci USA 1993; 89: 408–12

    Article  Google Scholar 

  11. 11.

    Hoyer D. Agonists and antagonists at 5-HT receptor subtypes. Adv Biosci 1992; 85: 29–47

    CAS  Google Scholar 

  12. 12.

    Dumuis A, Boulelal R, Sebben M, et al. A 5-HT receptor in the nervous system positively coupled with adenylate cyclase is antagonised by ICS 205 930. Eur J Pharmacol 1988; 146: 187–8

    PubMed  CAS  Article  Google Scholar 

  13. 13.

    Dumuis A, Sebben M, Bockaert J. The gastrointestinal pro-kinetic benzamide derivatives are agonists at a non-classical 5-HT receptor (5-HT4) positively coupled to adenylate cyclase in neurons. Naunyn Schmiedebergs Arch Pharamacol 1989; 340: 403–10

    CAS  Article  Google Scholar 

  14. 14.

    Jesperson S, Scheel-Kruger J. Evidence for a difference in mechanism of the action between fenfluramine and amphetamine induced anorexia. J Pharm Pharmacol 1973; 22: 637–8

    Article  Google Scholar 

  15. 15.

    Barrett AM, McSherry L. Inhibition of drug-induced anorexia in rats by methysergide. J Pharm Pharmacol 1975; 27: 889–95

    PubMed  CAS  Article  Google Scholar 

  16. 16.

    Pinder BM, Brogden RN, Sawyer PR, et al. Fenfluramine: a review of the pharmacological properties and therapeutic efficacy in obesity. Drugs 1975; 10: 241–323

    PubMed  CAS  Article  Google Scholar 

  17. 17.

    Garattini S, Samanin R. Anorectic drugs and brain neurotransmitters: food intake and appetite. Silverstone T, editor. Berlin: Dahlem Konferenzen, 1976: 82–208

  18. 18.

    Bray GA, York DA. Studies on food intake of genetically obese rats. Am J Physiol 1972; 223: 176–9

    PubMed  CAS  Google Scholar 

  19. 19.

    Latham CJ, Blundell JE. Evidence for the effect of tryptophan on the pattern of food consumption in rats. Life Sci 1979; 24: 1271–8

    Article  Google Scholar 

  20. 20.

    Blundell JE, Latham CJ. Serotoninergic influences on food intake: effect of 5-hydroxytryptophan on parameters of feeding behaviour in deprived and free-feeding rats. Pharmacol Biochem Behav 1979; 11: 431–7

    PubMed  CAS  Article  Google Scholar 

  21. 21.

    MacKenzie RG, Hoebel BG, Ducret RP, et al. Hyperphagia following intraventricular p-chlorophenylalanine-, leucine-or tryptophan-methyl esters: lack of correlation with whole brain serotonin level. Pharmacol Biochem Behav 1979; 10: 951–5

    PubMed  CAS  Article  Google Scholar 

  22. 22.

    Blundell JE. Is there a role for serotonin (5-hydroxytryptamine) in feeding? Int J Obes 1977; 1: 15–42

    PubMed  CAS  Google Scholar 

  23. 23.

    Jin H, Oksenberg D, Askenzai A, et al. Characterization of the human 5-HT1B receptor. J Biol Chem 1992; 267(9): 5735–8

    PubMed  CAS  Google Scholar 

  24. 24.

    Dourish CT. Multiple serotonin receptors: opportunities for new treatments for obesity. Obes Res 1995; 3 Suppl.: 449–62s

    Google Scholar 

  25. 25.

    Clifton PG. The neuropharmacology of meal patterning. In: Cooper SJ, Hendrie CA, editors. Ethology and psychopharmacology. Chichester: Wiley, 1994: 313–28

    Google Scholar 

  26. 26.

    Neill JC, Cooper SJ. Evidence that d-fenfluramine anorexia is mediated by 5-HT1 receptors. Psychopharmacology 1989; 97: 213–8

    PubMed  CAS  Article  Google Scholar 

  27. 27.

    Samanin R, Mennini T, Bendotti C, et al. Evidence that central 5-HT2 receptors do not play an important role in the anorectic activity of d-fenfluramine in the rat. Neuropharmacology 1989; 28: 465–9

    PubMed  CAS  Article  Google Scholar 

  28. 28.

    Neill JC, Bendotti C, Samanin R. Studies on the role of 5-HT receptors in satiation and the effect of d-fenfluramine in the runway test. Eur J Pharmacol 1990; 190: 105–12

    PubMed  CAS  Article  Google Scholar 

  29. 29.

    Wong DT, Reid LR, Threlkeld PG. Suppression of food intake in rats by fluoxetine: comparison of enantiomers and effects of serotonin antagonists. Pharmacol Biochem Behav 1988; 31: 475–9

    PubMed  CAS  Article  Google Scholar 

  30. 30.

    Grignaschi G, Samanin R. Role of serotonin and catecholamines in brain in feeding suppressant effects of fluoxetine. Neuropharmacology 1992; 31: 445–9

    PubMed  CAS  Article  Google Scholar 

  31. 31.

    Lee MD, Clifton PG. Partial reversal of fluoxetine anorexia by the 5-HT antagonist metergoline. Psychopharmacology 1992; 107: 359–64

    PubMed  CAS  Article  Google Scholar 

  32. 32.

    Halford JCG, Blundell JE. Metergoline antagonizes fluoxetine-induced suppression of food intake but not changes in the behavioural satiety sequence. Pharmacol Biochem Behav 1996; 54: 745–51

    PubMed  CAS  Article  Google Scholar 

  33. 33.

    Curzon G, Gibson EL, Oluyomi AO. Appetite suppression by commonly used drugs depends on 5-HT receptors but not on 5-HT availability. Trends Pharmacol Sci 1997; 18: 21–5

    PubMed  CAS  Article  Google Scholar 

  34. 34.

    Raiteri M, Bonanno G, Vallebouona F. In vitro and in vivo effects of d-fenfluramine: no apparent relation between 5-hydroxytryptamine release and hypophagia. J Pharmacol Exp Ther 1995; 273: 643–9

    PubMed  CAS  Google Scholar 

  35. 35.

    Lightowler S, Kennett GA, Wood MD, et al. Hypophagic effect of fluoxetine in rats is not mediated by inhibition of 5-HT re-uptake or an agonist action at 5-HT2C receptors. Br J Pharmacol 1994; 112: 359–64

    Google Scholar 

  36. 36.

    Koe BK, Weissman A, Welch WM, et al. Sertraline, 1S,4S-N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-1-naphthy lamine, a new uptake inhibitor with selectivity for serotonin. J Pharmacol Exp Ther 1983; 266: 686–700

    Google Scholar 

  37. 37.

    Lucki I, Kreider MS, Simansky KJ. Reduction of feeding behaviour by the serotonin uptake inhibitor sertraline. Psychopharmacology 1988; 96: 289–95

    PubMed  CAS  Article  Google Scholar 

  38. 38.

    Heal DJ, Frankland ATJ, Gosden J, et al. A comparison of the effects of sibutramine hydrochloride, bupropion and methamphetamine on dopaminergic function: evidence that dopamine is not a pharmacological target for sibutramine. Psychopharmacology 1991; 107: 303–9

    Article  Google Scholar 

  39. 39.

    Jackson HC, Bearham MC, Hutchins LJ, et al. Investigation of the mechanisms underlying the hypophagic effects of the 5-HT and noradrenaline re-uptake inhibitor, sibutramine, in the rat. Br J Pharmacol 1997; 121: 1613–8

    PubMed  CAS  Article  Google Scholar 

  40. 40.

    Koe BK, Nielsen JA, Macor JE, et al. Biochemical and behavioural studies of the 5-HT1B receptor agonist, CP-94,253. Drug Dev Res 1992; 26: 241–50

    CAS  Article  Google Scholar 

  41. 41.

    Haiford JCG, Blundell JE. The 5-HT1B receptor agonist CP-94,253 reduces food intake and preserves the behavioural satiety sequence. Physiol Behav 1996; 60: 933–9

    Google Scholar 

  42. 42.

    Kennett GA, Dourish CT, Curzon G. 5-HT1B agonists induce anorexia at a post synaptic site. Eur J Pharmacol 1987; 141: 429–35

    PubMed  CAS  Article  Google Scholar 

  43. 43.

    Blundell JE, Alikhan H. Analysing the structure and sequence of feeding in animals and man. In: Christie WM, Weinman J, editors. Microcomputers, psychology and medicine. Chichester: Wiley, 1990: 203–25

    Google Scholar 

  44. 44.

    Kennett GA, Curzon G. Evidence that mCPP may have behavioural effects mediated by central 5-HT1C receptors. Br J Pharmacol 1988; 94: 137–47

    PubMed  CAS  Article  Google Scholar 

  45. 45.

    Kennett GA, Curzon G. 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 1988; 96: 93–100

    PubMed  CAS  Article  Google Scholar 

  46. 46.

    Curzon G. Serotonin and appetite. Ann NY Acad Sci 1990; 600: 521–30

    PubMed  CAS  Article  Google Scholar 

  47. 47.

    Curzon G. Effects of tryptophan and 5-hydroxytryptamine receptor subtype agonists on feeding. Adv Exp Med Biol 1991; 294: 377–88

    PubMed  CAS  Article  Google Scholar 

  48. 48.

    Kennett GA, Wood MD, Glen A, et al. In vivo properties of SB 200646A, a 5-HT2c/2b receptor antagonist. Br J Pharmacol 1994; 111: 797–802

    PubMed  CAS  Article  Google Scholar 

  49. 49.

    Clineschmidt BV, McGuffen JC, Pfleuger AB. A 5-hydroxytryptamine-like mode of action for 6-chloro-2-[l-piperazinyl]-pyrazine (MK-212) Br J Pharmacol 1978; 62: 579–89

    PubMed  CAS  Article  Google Scholar 

  50. 50.

    King BH, Brazell C, Dourish CT. MK-212 increases rat plasma ACTH concentration by activation of the 5-HT1c receptor subtype. Neurosci Lett 1989; 105: 174–6

    PubMed  CAS  Article  Google Scholar 

  51. 51.

    Aulakh CS, Mazzola-Pomietto P, Wozniak KM, et al. 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane-induced hypophagia and hyperthermia in rats is mediated by serotonin-2A receptors. J Pharmacol Exp Ther 1994; 270: 127–52

    PubMed  CAS  Google Scholar 

  52. 52.

    Aulakh CS, Mazzola-Pomietto P, Hulihan-Giblin BA, et al. Lack of cross tolerance for hypophagia induced by DOI versus mCPP suggests separate mediation by 5-HT2A and 5-HT2c receptors respectively. Neuropsychopharmacology 1995; 13: 1–8

    PubMed  CAS  Article  Google Scholar 

  53. 53.

    Halford JCG, Lawton CL, Blundell JE. The 5-HT receptor agonist MK-212 reduces food intake but disrupts the behavioural satiety sequence. Pharmacol Biochem Behav 1997; 56: 41–6

    PubMed  CAS  Article  Google Scholar 

  54. 54.

    Simansky KJ, Vaidya, AH. Behavioural mechanisms for the anorectic actions of the serotonin (5-HT) uptake inhibitor sertraline in rats: comparison with directly acting agonists. Brain Res Bull 1990; 25: 953–60

    PubMed  CAS  Article  Google Scholar 

  55. 55.

    Tecott LH, Sun LM, Akana SF, et al. Eating disorder and epilepsy in mice lacking 5-HT2C serotonin receptors. Nature 1995; 374(6522): 542–6

    PubMed  CAS  Article  Google Scholar 

  56. 56.

    Blundell JE, Latham CJ. Pharmacological manipulations of feeding behaviour: possible influences of serotonin and dopamine on food intake. In: Garattini S, Samanin R, editors. Central mechanisms of anorectic drugs. New York: Raven Press, 1978: 83–109

    Google Scholar 

  57. 57.

    Blundell JE, Latham CJ. Characteristic adjustments to the structure of feeding behaviour following pharmacological treatments: effects of amphetamine and fenfluramine and the antagonism produced by pimozide and metergoline. Pharmacol Biochem Behav 1980; 12: 717–22

    PubMed  CAS  Article  Google Scholar 

  58. 58.

    Blundell JE, Rogers PJ, Hill AT. Behavioural structure and mechanisms of anorexia: calibration of normal and abnormal inhibition of eating. Brain Res Bull 1985; 15: 319–26

    Article  Google Scholar 

  59. 59.

    Antin J, Gibbs J, Holt J, et al. Cholecystokinin elicits the complete behavioural sequence of satiety in rats. J Comp Physiol Psych 1975; 89: 784–60

    CAS  Article  Google Scholar 

  60. 60.

    Blundell JE, McArthur RA. 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, Garittini S, editors. Anorectic agents: mechanisms of action and tolerance. New York: Raven Press, 1981: 19–43

    Google Scholar 

  61. 61.

    Halford JCG. Analysis of the behaviour associated with feeding in drug induced anorexia in the rat. [Ph.D thesis]. Leeds: University of Leeds, 1994

    Google Scholar 

  62. 62.

    Halford JCG, Blundell JE. 5-hydroxytrytaminergic drugs compared on the behavioural sequence associated with satiety [abstract]. Br J Pharmacol 1993; 100: 95p

    Google Scholar 

  63. 63.

    Montgomery AMJ, Willner P. Fenfluramine disrupts the behavioural satiety sequence in rats. Psychopharmacology 1988; 94: 397–401

    PubMed  CAS  Google Scholar 

  64. 64.

    Willner P, McGuirk J, Phillips G, et al. Behavioural analysis of the anorectic effects of fluoxetine and fenfluramine. Psychopharmacology 1990; 102: 273–7

    PubMed  CAS  Article  Google Scholar 

  65. 65.

    McGuirk J, Muscat R, Willner P. Effects of chronically administered fluoxetine and fenfluramine on food intake, body weight and the behavioural satiety sequence. Psychopharmacology 1992; 107: 401–7

    Article  Google Scholar 

  66. 66.

    McGuirk J, Muscat R, Willner P. Effects of the 5-HT uptake inhibitors femoxitine and paroxetine, and the 5-HT1A agonist citalopram, on the behavioural satiety sequence. Pharmacol Biochem Behav 1992; 41: 801–5

    PubMed  CAS  Article  Google Scholar 

  67. 67.

    Halford JCG, Heal DJ, Blundell JE. Effects in the rat of sibutramine on food intake and the behavioural satiety sequence [abstract]. Br J Pharmacol 1995; 114: 378p

    Google Scholar 

  68. 68.

    Kitchener SJ, Dourish CT. An examination of the behavioural specificity of hypophagia induced by 5-HT1B, 5-HT1C and 5-HT2 receptor agonists using the post-prandial satiety sequence in rats. Psychopharmacology 1994; 113: 369–77

    PubMed  CAS  Article  Google Scholar 

  69. 69.

    Cooper SJ, Dourish CT, Clifton PG. CCK antagonists and CCK-monoamine interactions in the control of satiety. Am J Clin Nutr 1992; 55 Suppl.: 291s–295s

    PubMed  CAS  Google Scholar 

  70. 70.

    Grignaschi G, Mantelli B, Fracasso C, et al. Reciprocal interaction of 5-hydroxytryptamine and cholecystokinin in the control of feeding. Br J Pharmacol 1993; 109(2): 491–4

    PubMed  CAS  Article  Google Scholar 

  71. 71.

    Voigt JP, Fink H, Marsden CA. Evidence for the involvement of the 5-HT1A receptor in CCK-induced satiety in rats. Naunyn Schmiedebergs Arch Pharmacol 1995; 351: 217–20

    PubMed  CAS  Article  Google Scholar 

  72. 72.

    Poeschla B, Gibbs J, Simansky KJ, et al. Cholecystokinin-induced satiety depends on the activation of 5-HT1C receptors. Am J Physiol 1993; 264: R62–4

    PubMed  CAS  Google Scholar 

  73. 73.

    Poeschla B, Gibbs J, Simansky KJ, et al. The 5-HT1A agonist 8-OH-DPAT attenuated the satiating action of cholecystokinin. Pharmacol Biochem Behav 1992; 42: 541–3

    PubMed  CAS  Article  Google Scholar 

  74. 74.

    Macor JE, Burkhart CA, Heym JH, et al. 3-(l,2,5,6-Tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one: a potent and selective 5-HT1B agonist and rotationally restricted phenolic analogue of 5-methoxy-3-(l,2,5,6-tetrahydropyid-4-yl)indole. J Med Chem 1990; 33: 2087–93

    PubMed  CAS  Article  Google Scholar 

  75. 75.

    Grignaschi G, Sironi F, Samanin R. The 5-HT1B receptor mediates the effect of d-fenfluramine on eating caused by intrahypothalamic injection of neuropeptide Y Eur J Pharmacol 1995; 274: 221–4

    CAS  Article  Google Scholar 

  76. 76.

    Dryden S, Wang Q, Frankish HM, et al. The serotonin (5-HT) antagonist methysergide increases neuropeptide Y (NPY) synthesis and secretion in the hypothalamus of the rat. Brain Res 1995; 699: 12–8

    PubMed  CAS  Article  Google Scholar 

  77. 77.

    Dryden S, Frankish HM, Wang Q, et al. Increased feeding and neuropeptide Y (NPY) but not NPY mRNA levels in the hypothalamus of the rat following central administration of the serotonin synthesis inhibitor p-chlorophenylalanine. Brain Res 1996; 724: 232–7

    PubMed  CAS  Article  Google Scholar 

  78. 78.

    Dryden S, Frankish HM, Wang Q, et al. The serotonergic agent fluoxetine reduces neuropeptide Y levels and neuropeptide Y secretion in the hypothalamus of lean and obese rats. Neuroscience 1996; 72: 557–66

    PubMed  CAS  Article  Google Scholar 

  79. 79.

    Hutson PH, Donohoe TP, Curzon G. Infusion of the 5-hydroxytryptamine agonists RU-24969 and TFMPP into the paraventricular nucleus of the hypothalamus causes hypophagia. Psychopharmacology 1988; 97: 550–2

    Google Scholar 

  80. 80.

    Fletcher PJ, Coscina DV. Injecting 5-HT into the PVN does not prevent feeding induced by 8-OH-DPAT into the raphe. Pharmacol Biochem Behav 1993; 46: 487–91

    PubMed  CAS  Article  Google Scholar 

  81. 81.

    Coscina DV, Feifel D, Nobrega JN, et al. Intra-ventricular but not intra-paraventricular nucleus metergoline elicits feeding in satiated rats. Am J Physiol 1994); 266: r1562–7

    PubMed  CAS  Google Scholar 

  82. 82.

    Currie PJ, Coscina DV. Metergoline potentiates natural feeding and antagonizes the anorectic action of medial hypothalamic 5-HT. Pharmacol Biochem Behav 1996; 53: 1023–8

    PubMed  CAS  Article  Google Scholar 

  83. 83.

    Dryden S, Williams G. The role of hypothalamic peptides in the control of energy balance and body weight. Curr Opin Endocrinol Diabetes 1996; 3: 51–8

    CAS  Article  Google Scholar 

  84. 84.

    Read NW, Gwee KA. The importance of 5-hydroxytryptamine receptors in the gut. Pharmacol Ther 1994; 62: 159–73

    PubMed  CAS  Article  Google Scholar 

  85. 85.

    Francis J, Critchley D, Dourish CT, et al. Comparisons between the effects of 5-HT and dl-fenfluramine on food intake and gastric emptying in the rat. Pharmacol Biochem Behav 1995; 50: 581–5

    PubMed  CAS  Article  Google Scholar 

  86. 86.

    Edwards S, Stevens R. Peripherally administered 5-hydroxytryptamine elicits the full behavioural satiety sequence. Physiol Behav 1991; 50: 1075–7

    PubMed  CAS  Article  Google Scholar 

  87. 87.

    Simansky KJ. Serotoninergic control of the organization of feeding and satiety. Behav Brain Res 1996; 73: 37–42

    PubMed  CAS  Article  Google Scholar 

  88. 88.

    Poppitt SD, Prentice AM. Energy density and its role in the control of food intake: evidence from metabolic and community studies. Appetite 1996; 26: 153–74

    PubMed  CAS  Article  Google Scholar 

  89. 89.

    MacDiaramid JI, Cade JE, Blundell JE. High and low fat consumers, their macronutrient intake and body mass index: further analysis of the National Diet and Nutrition Survey of British adults. Eur J Clin Nutr 1997; 50(8): 505–12

    Google Scholar 

  90. 90.

    Horton TJ, Drougas H, Brachey A, et al. Fat and carbohydrate overfeeding in humans: different effects on energy storage. Am J Clin Nutr 1995; 62: 19–29

    PubMed  CAS  Google Scholar 

  91. 91.

    Fernstrom JD, Wurtman RJ. Control of brain 5-HT content by dietary carbohydrates. In: Barchas J, Usdin E, editors. Serotonin and behaviour. New York: Academic Press, 1973: 121–8

    Google Scholar 

  92. 92.

    Wurtman RJ, Fernstrom JD. Effects of diet on brain neurotransmitters. Nutr Rev 1974; 32: 193–200

    CAS  Article  Google Scholar 

  93. 93.

    Teff KL, Young SN, Blundell JE. The effect of protein or carbohydrate breakfasts on subsequent plasma amino acid levels, satiety and nutrient selection in normal males. Pharmacol Biochem Behav 1989; 34: 410–7

    Article  Google Scholar 

  94. 94.

    Blundell JE, Hill AJ. Nutrition, serotonin and appetite: case studying the evolution of a scientific idea. Appetite 1987; 8: 183–94

    PubMed  CAS  Article  Google Scholar 

  95. 95.

    Pirke KM, Schweiger U, Laessle RG. Effect of diet composition on affective state in anorexia nervosa and bulimia. Clin Neuropharmacol 1986; 9: 513–5

    Google Scholar 

  96. 96.

    Ashley DVM, Fleury MO, Golay A, et al. Evidence for diminished brain 5-HT biosynthesis in obese diabetic and non-diabetic humans. Am J Clin Nutr 1985; 42: 1240–5

    PubMed  CAS  Google Scholar 

  97. 97.

    Brewerton TD. Toward a unified theory of serotonin dysregulation in eating and related disorders. Psychoneuroendocrinology 1995; 20: 561–90

    PubMed  CAS  Article  Google Scholar 

  98. 98.

    Goodwin GM, Fairburn CG, Cowen PJ. Dieting changes 5-HT function in women, not in men: implications for the aetiology of anorexia nervosa? Psychol Med 1987; 17: 839–42

    PubMed  CAS  Article  Google Scholar 

  99. 99.

    Goodwin GM, Cowen PJ, Fairburn CJ, et al. Plasma concentrations of tryptophan and dieting. BMJ 1990; 300: 1499–500

    PubMed  CAS  Article  Google Scholar 

  100. 100.

    Blundell JE. Problems and processes underlying the control of food selection and nutrient intake. In: Wurtman RJ, Wurtman JJ, editors. Nutrition and the brain. Vol 6. New York: Raven Press, 1983: 163–222

    Google Scholar 

  101. 101.

    Luo S, Li ETS. Food intake and selection pattern of rats treated with dexfenfluramine, fluoxetine and RU-24969. Brain Res Bull 1990; 24: 729–33

    PubMed  CAS  Article  Google Scholar 

  102. 102.

    Lawton CL, Blundell JE. The effects of d-fenfluramine on intake of carbohydrate supplements is influenced by the hydration of the test diets. Physiol Behav 1992; 3: 517–23

    CAS  Google Scholar 

  103. 103.

    Lawton CL, Blundell JE. 5-HT manipulation and dietary choice: variable carbohydrate (polycose) suppression demonstrated only under specific experimental conditions. Psychopharmacology 1993; 112: 375–82

    PubMed  CAS  Article  Google Scholar 

  104. 104.

    Kanarek RB. Dushkin H. Serotonin administration selectively reduces fat intake in rats. Pharmacol Biochem Behav 1988; 13: 133–22

    Google Scholar 

  105. 105.

    Leibowitz SF, Shor-Posner G. Brain serotonin and eating behaviour. Appetite 1986; 7: 1–14

    PubMed  CAS  Article  Google Scholar 

  106. 106.

    Rogers PJ, Blundell JE. Meal patterns and food selection during the development of obesity in rats fed a cafeteria diet. Neurosci Biobehav Rev 1984: 8: 441–53

    PubMed  CAS  Article  Google Scholar 

  107. 107.

    Sclafani A. Animal models of obesity: classification and characterisation. Int J Obes 1984; 8: 491–508

    PubMed  CAS  Google Scholar 

  108. 108.

    Prats E, Monfar M, Castella J, et al. Energy intake of rats fed a cafeteria diet. Physiol Behav 1989; 45: 2263–72

    Article  Google Scholar 

  109. 109.

    Blundell JE, Hill AJ. Effects of dexfenfluramine in feeding and body weight: relationship with food consumption and palatability. In: Vague J, Guy-Grand B, Bjontroup P, editors. Metabolic complication of human obesities. Nordlolland: Elsevier, 1985: 199–206

    Google Scholar 

  110. 110.

    Fisler JS, Underberger SJ, York DA, et al. d-fenfluramine in a rat model of dietary fat-induced obesity. Pharmacol Biochem Behav 1993; 45: 487–93

    PubMed  CAS  Article  Google Scholar 

  111. 111.

    Blundell JE, Hill AJ. Do serotoninergic drugs decrease energy intake by reducing fat or carbohydrate intake? Effect of d-fenfluramine with supplemented weight increase diets. Pharmacol Biochem Behav 1989; 31: 773–8

    Article  Google Scholar 

  112. 112.

    Blundell JE, Lawton CL, Haiford JCG. Serotonin, eating behaviour and fat intake. Obes Res 1995; 3 Suppl. 4: 471–6

    Google Scholar 

  113. 113.

    Hill AJ, Blundell JE. Model system for investigating the actions of anorectic drugs: effects of d-fenfluramine on food intake, nutrient selection, food preferences, meal patterns, hunger and satiety in healthy human subjects. Advances in the bio-sciences. Oxford: Pergamon Press, 1986: 377–89

    Google Scholar 

  114. 114.

    Goodall EM, Silverstone T. Differential effect of d-fenfluramine and metergoline on food intake in human subjects. Appetite 1988; 11: 215–8

    PubMed  CAS  Article  Google Scholar 

  115. 115.

    Blundell JE, Hill AJ. On the mechanism of action of dexfen-fluramine: effect on alliesthesia and appetite motivation in lean and obese subjects. Clin Neuropharmacol 1988; 11 Suppl. 1: 121S–34S

    Google Scholar 

  116. 116.

    Hill AJ, Blundell JE. Sensitivity of the appetite control system in obese subjects to nutritional and serotoninergic challenges. Int J Obes 1990; 14: 219–33

    PubMed  CAS  Google Scholar 

  117. 117.

    Hill AJ, Rogers PJ, Blundell JE. Techniques for the experimental measurement of human eating behaviour: a practical guide. Int J Obes 1995; 19: 361–75

    CAS  Google Scholar 

  118. 118.

    Lawton CL, Wales JK, Hill AJ, et al. Serotoninergic manipulation, meal-induced satiety and eating pattern: effects of fluoxetine in obese female subjects. Obes Res 1995; 3: 345–56

    PubMed  CAS  Google Scholar 

  119. 119.

    Rolls BJ, Shide DJ, Thorwart ML, et al. Sibutramine reduces food intake in non-dieting women with obesity. Obes Res 1998; 6: 1–11

    PubMed  CAS  Google Scholar 

  120. 120.

    Cowen PJ, Clifford EM, Walsh AE, et al. Moderate dieting causes 5-HT2C supersensitization. Psychol Med 1996; 26: 1156–9

    Article  Google Scholar 

  121. 121.

    Cangiano C, Ceci F, Casinco A, et al. Eating behaviour and adherence to dietary prescription in obese adult subjects treated with 5-hydroxytryptophan. Am J Clin Nutr 1992; 56: 863–7

    PubMed  CAS  Google Scholar 

  122. 122.

    Wadden TA, Bartlett SJ, Foster GD, et al. Sertraline and relapse prevention following treatment by a very low calorie diet: a controlled clinical trial. Obes Res 1995; 3(6): 549–7

    PubMed  CAS  Google Scholar 

  123. 123.

    Silverstone T, Goodall E. The clinical pharmacology of appetite suppressant drugs. Int J Obes 1984; 8(1): 23–33

    PubMed  CAS  Google Scholar 

  124. 124.

    Rogers PJ, Blundell JE. Effect of anorexic drugs on food intake and the micro-structure of eating in human subjects. Psychopharmacology 1979; 66: 159–65

    PubMed  CAS  Article  Google Scholar 

  125. 125.

    Wurtman JJ, Wurtman RJ, Growdon JH, et al. Carbohydrate craving in obese people: suppression by treatments affecting serotoninergic transmission. Int J Eat Disord 1982; 1: 2–15

    Article  Google Scholar 

  126. 126.

    Wurtman JJ, Wurtman RJ, Mark S, et al. d-Fenfluramine selectively suppresses carbohydrate snacking in obese subjects. Int J Eat Disord 1985; 4: 89–99

    PubMed  CAS  Article  Google Scholar 

  127. 127.

    Goodall EM, Cowen PJ, Franklin M, et al. Ritanserin attenuates anorectic endocrine and thermic responses to d-fenfluramine in human volunteers. Psychopharmacology 1993; 112: 461–6

    PubMed  CAS  Article  Google Scholar 

  128. 128.

    McGuirk J, Silverstone T. The effect of 5-HT re-uptake inhibitor fluoxetine on food intake and body weight in healthy male subjects. Int J Obes 1990; 14: 361–72

    PubMed  CAS  Google Scholar 

  129. 129.

    Walsh AE, Smith KA, Oldman AD, et al. m-Chlorophenyl-piperazine decreases food intake in a test meal. Psychopharmacology 1994; 116: 120–2

    PubMed  CAS  Article  Google Scholar 

  130. 130.

    Sargent PA, Sharpley AL, Williams C, et al. 5-HT2C activation decreases appetite and bodyweight in obese subjects. Psychopharmacology 1997; 133: 309–12

    PubMed  CAS  Article  Google Scholar 

  131. 131.

    Boeles S, Williams C, Campling GM, et al. Sumatriptan decreases food intake and increases plasma growth hormone in women. Psychopharmacology 1997; 129: 179–82

    PubMed  CAS  Article  Google Scholar 

  132. 132.

    Guy-Grand B. Clinical studies with d-fenfluramine. Am J Clin Nutr 1992; 55 Suppl.: 173s–176s

    PubMed  CAS  Google Scholar 

  133. 133.

    Finer N, Finer S, Nauova RP. Drug therapy after very-low-caloric diets. Am J Clin Nutr 1992; 56: 1955–85

    Google Scholar 

  134. 134.

    Anderson IM, Parry-Billings M, Newsholme EA, et al. Dieting reduces plasma tryptophan and alters brain 5-HT functioning in women. Psychol Med 1990; 20: 785–91

    PubMed  CAS  Article  Google Scholar 

  135. 135.

    Weintraub M, Rubio A, Golik A, et al. Sibutramine in weight control: a dose-ranging, efficacy study. Clin Pharmacol Ther 1997; 50(3): 330–7

    Article  Google Scholar 

  136. 136.

    Bray GA, Ryan DH, Grodon D, et al. A double-blind randomized placebo-controlled trial of sibutramine. Obes Res 1996; 4(3): 263–70

    PubMed  CAS  Google Scholar 

  137. 137.

    Smith I, Fitchet M, Kelly F. Sibutramine: predictability of long term weight loss. Int J Obes 1997; 21 Suppl. 2; s53

    Google Scholar 

  138. 138.

    Blundell JE, Lawton CL. Serotonin and dietary fat intake: effect of dexfenfluramine. Metabol Clin Exper 1995; 44(2): 33–7

    CAS  Article  Google Scholar 

  139. 139.

    Drewnowski A. Changes in mood after carbohydrate consumption [abstract]. Am J Clin Nutr 1987; 46: 703

    PubMed  CAS  Google Scholar 

  140. 140.

    Lafreniere F, Lambert J, Rasio E, et al. Effects of dexfenfluramine treatment on body weight and postprandial thermogenesis in obese subjects: a double-blind, placebo-controlled study. Int J Obes 1993; 17: 25–30

    CAS  Google Scholar 

  141. 141.

    Poppitt SD, Murgatroyd PR, Tainsh KR, et al. The effect of dexfenfluramine on energy and macronutrient balance of obese women on high fat and low fat diets [abstract]. Int J Obes 1997; 21 Suppl. 2: s65

    Google Scholar 

  142. 142.

    Green S, Lawton C, Wales J, et al. Risk factors for overeating: dexfenfluramine suppresses the intake of sweet high fat or carbohydrate foods in obese women [abstract]. Int J Obes 1997; 21 Suppl. 2: s64

    Google Scholar 

  143. 143.

    Golay A, Bobbioli E. The role of dietary fat in obesity. Int J Obes 1997; 21(3 Suppl.): s2–11

    Google Scholar 

  144. 144.

    Drewnowski A, Kurth C, Holden-Wiltse J, et al. Food preferences in human obesity: carbohydrates verses fats. Appetite 1992; 18: 207–1

    PubMed  CAS  Article  Google Scholar 

  145. 145.

    Abenhaim L, Moride Y, Benot F, et al. Appetite suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 1996; 335: 609–16

    PubMed  CAS  Article  Google Scholar 

  146. 146.

    Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997; 337: 581–8

    PubMed  CAS  Article  Google Scholar 

  147. 147.

    Dillon KA, Putnam KG, Avorn JL. Death from irreversible pulmonary hypertension associated with short-term use of fenfluramine and phentermine [letter]. JAMA 1997; 278: 1320

    PubMed  CAS  Article  Google Scholar 

  148. 148.

    Mark EJ, Patalas ED, Chang HT, et al. Fatal pulmonary hypertension associated with short-term use of fenfluramine and phentermine. N Engl J Med 1997; 337: 602–6

    PubMed  CAS  Article  Google Scholar 

  149. 149.

    Food and Drug Administration. Health advisory on fenfluramine/phentermine for obesity. Media Release 1997 Aug 27

  150. 150.

    Cannistra LV, Davis SM, Bouman AG. Valvular heart disease associated with dexfenfluramine [letter]. New Engl J Med 1997; 337: 636

    PubMed  CAS  Article  Google Scholar 

  151. 151.

    Davis WM, Waters IW. High altitude may be synergistic with pulmonary hazards of appetite control medications fenfluramine and dexfenfluramine. Med Hypotheses 1997; 49: 509–12

    PubMed  CAS  Article  Google Scholar 

  152. 152.

    Knoll Meridia blood pressure elevation screen should be created; BP concerns outweigh weight loss benefit for 39%–50% patients, FDA committee concludes. F-D-C Pink Sheets 1996 Sept 39; 58: 10-1

  153. 153.

    Knoll’s sibutramine rejected by US panel. Marketletter 1996 Oct 7: 18

  154. 154.

    Stunkard AJ. Eating patterns in obesity. Psychiatr Q 1959; 33: 284–92

    PubMed  CAS  Article  Google Scholar 

  155. 155.

    Spitzer RL, Devlin M, Walsh BT, et al. Binge eating disorder: a multisite field study of the diagnostic criteria. Int J Eat Disord 1992; 11: 191–203

    Article  Google Scholar 

  156. 156.

    Brewerton TD, George MS. Is migraine related to the eating disorders. Int J Eat Disord 1993; 14: 75–9

    PubMed  CAS  Article  Google Scholar 

  157. 157.

    Brewerton TD, Mueller EA, Lesam MD, et al. Neuro-endocrine responses to m-chlorophenylypiperazine and l-tryptophan in bulimia. Arch Gen Psychiatry 1992; 49: 852–61

    PubMed  CAS  Article  Google Scholar 

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Blundell, J.E., Halford, J.C. Serotonin and Appetite Regulation. Mol Diag Ther 9, 473–495 (1998). https://doi.org/10.2165/00023210-199809060-00005

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Keywords

  • Adis International Limited
  • Fluoxetine
  • Binge Eating
  • Bulimia Nervosa
  • Binge Eating Disorder