CNS Drugs

, Volume 9, Issue 6, pp 473–495 | Cite as

Serotonin and Appetite Regulation

Implications for the Pharmacological Treatment of Obesity
Pharmacology and Pathophysiology

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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Gaddum JH, Picarelli ZP. Two kinds of tryptamine receptor. Br J Pharmacol 1957; 12; 323–8Google 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; 687–99PubMedGoogle 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: 563–76PubMedCrossRefGoogle 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: 14848–52PubMedGoogle 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: 85–96CrossRefGoogle Scholar
  6. 6.
    Hoyer D, Martin GR. Classification and nomenclature of 5-HT receptors: a comment on current issues. Behav Brain Res 1996; 73: 263–8PubMedCrossRefGoogle Scholar
  7. 7.
    Humphrey PPA, Hartig P, Hoyer D. A proposed new nomenclature for 5-HT receptors. Trends Pharmacol Sci 1993; 14: 233–6PubMedCrossRefGoogle 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: 5517–21PubMedCrossRefGoogle 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: 19761–4Google 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: 408–12CrossRefGoogle Scholar
  11. 11.
    Hoyer D. Agonists and antagonists at 5-HT receptor subtypes. Adv Biosci 1992; 85: 29–47Google 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: 187–8PubMedCrossRefGoogle 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: 403–10CrossRefGoogle 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: 637–8CrossRefGoogle Scholar
  15. 15.
    Barrett AM, McSherry L. Inhibition of drug-induced anorexia in rats by methysergide. J Pharm Pharmacol 1975; 27: 889–95PubMedCrossRefGoogle 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: 241–323PubMedCrossRefGoogle Scholar
  17. 17.
    Garattini S, Samanin R. Anorectic drugs and brain neurotransmitters: food intake and appetite. Silverstone T, editor. Berlin: Dahlem Konferenzen, 1976: 82–208Google Scholar
  18. 18.
    Bray GA, York DA. Studies on food intake of genetically obese rats. Am J Physiol 1972; 223: 176–9PubMedGoogle 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: 1271–8CrossRefGoogle 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: 431–7PubMedCrossRefGoogle 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: 951–5PubMedCrossRefGoogle Scholar
  22. 22.
    Blundell JE. Is there a role for serotonin (5-hydroxytryptamine) in feeding? Int J Obes 1977; 1: 15–42PubMedGoogle Scholar
  23. 23.
    Jin H, Oksenberg D, Askenzai A, et al. Characterization of the human 5-HT1B receptor. J Biol Chem 1992; 267(9): 5735–8PubMedGoogle Scholar
  24. 24.
    Dourish CT. Multiple serotonin receptors: opportunities for new treatments for obesity. Obes Res 1995; 3 Suppl.: 449–62sGoogle Scholar
  25. 25.
    Clifton PG. The neuropharmacology of meal patterning. In: Cooper SJ, Hendrie CA, editors. Ethology and psychopharmacology. Chichester: Wiley, 1994: 313–28Google Scholar
  26. 26.
    Neill JC, Cooper SJ. Evidence that d-fenfluramine anorexia is mediated by 5-HT1 receptors. Psychopharmacology 1989; 97: 213–8PubMedCrossRefGoogle 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: 465–9PubMedCrossRefGoogle 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: 105–12PubMedCrossRefGoogle 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: 475–9PubMedCrossRefGoogle Scholar
  30. 30.
    Grignaschi G, Samanin R. Role of serotonin and catecholamines in brain in feeding suppressant effects of fluoxetine. Neuropharmacology 1992; 31: 445–9PubMedCrossRefGoogle Scholar
  31. 31.
    Lee MD, Clifton PG. Partial reversal of fluoxetine anorexia by the 5-HT antagonist metergoline. Psychopharmacology 1992; 107: 359–64PubMedCrossRefGoogle 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: 745–51PubMedCrossRefGoogle 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: 21–5PubMedCrossRefGoogle 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: 643–9PubMedGoogle 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: 359–64Google 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: 686–700Google Scholar
  37. 37.
    Lucki I, Kreider MS, Simansky KJ. Reduction of feeding behaviour by the serotonin uptake inhibitor sertraline. Psychopharmacology 1988; 96: 289–95PubMedCrossRefGoogle 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: 303–9CrossRefGoogle 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: 1613–8PubMedCrossRefGoogle 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: 241–50CrossRefGoogle 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: 933–9Google Scholar
  42. 42.
    Kennett GA, Dourish CT, Curzon G. 5-HT1B agonists induce anorexia at a post synaptic site. Eur J Pharmacol 1987; 141: 429–35PubMedCrossRefGoogle 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: 203–25Google 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: 137–47PubMedCrossRefGoogle 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: 93–100PubMedCrossRefGoogle Scholar
  46. 46.
    Curzon G. Serotonin and appetite. Ann NY Acad Sci 1990; 600: 521–30PubMedCrossRefGoogle Scholar
  47. 47.
    Curzon G. Effects of tryptophan and 5-hydroxytryptamine receptor subtype agonists on feeding. Adv Exp Med Biol 1991; 294: 377–88PubMedCrossRefGoogle 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: 797–802PubMedCrossRefGoogle 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: 579–89PubMedCrossRefGoogle 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: 174–6PubMedCrossRefGoogle 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: 127–52PubMedGoogle 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: 1–8PubMedCrossRefGoogle 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: 41–6PubMedCrossRefGoogle 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: 953–60PubMedCrossRefGoogle 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): 542–6PubMedCrossRefGoogle 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: 83–109Google 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: 717–22PubMedCrossRefGoogle 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: 319–26CrossRefGoogle 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: 784–60CrossRefGoogle 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: 19–43Google 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, 1994Google Scholar
  62. 62.
    Halford JCG, Blundell JE. 5-hydroxytrytaminergic drugs compared on the behavioural sequence associated with satiety [abstract]. Br J Pharmacol 1993; 100: 95pGoogle Scholar
  63. 63.
    Montgomery AMJ, Willner P. Fenfluramine disrupts the behavioural satiety sequence in rats. Psychopharmacology 1988; 94: 397–401PubMedGoogle Scholar
  64. 64.
    Willner P, McGuirk J, Phillips G, et al. Behavioural analysis of the anorectic effects of fluoxetine and fenfluramine. Psychopharmacology 1990; 102: 273–7PubMedCrossRefGoogle 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: 401–7CrossRefGoogle 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: 801–5PubMedCrossRefGoogle 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: 378pGoogle 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: 369–77PubMedCrossRefGoogle 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–295sPubMedGoogle 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): 491–4PubMedCrossRefGoogle 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: 217–20PubMedCrossRefGoogle 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: R62–4PubMedGoogle 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: 541–3PubMedCrossRefGoogle 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: 2087–93PubMedCrossRefGoogle 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: 221–4CrossRefGoogle 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: 12–8PubMedCrossRefGoogle 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: 232–7PubMedCrossRefGoogle 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: 557–66PubMedCrossRefGoogle 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: 550–2Google 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: 487–91PubMedCrossRefGoogle 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: r1562–7PubMedGoogle 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: 1023–8PubMedCrossRefGoogle 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: 51–8CrossRefGoogle Scholar
  84. 84.
    Read NW, Gwee KA. The importance of 5-hydroxytryptamine receptors in the gut. Pharmacol Ther 1994; 62: 159–73PubMedCrossRefGoogle 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: 581–5PubMedCrossRefGoogle Scholar
  86. 86.
    Edwards S, Stevens R. Peripherally administered 5-hydroxytryptamine elicits the full behavioural satiety sequence. Physiol Behav 1991; 50: 1075–7PubMedCrossRefGoogle Scholar
  87. 87.
    Simansky KJ. Serotoninergic control of the organization of feeding and satiety. Behav Brain Res 1996; 73: 37–42PubMedCrossRefGoogle 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: 153–74PubMedCrossRefGoogle 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): 505–12Google 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: 19–29PubMedGoogle 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: 121–8Google Scholar
  92. 92.
    Wurtman RJ, Fernstrom JD. Effects of diet on brain neurotransmitters. Nutr Rev 1974; 32: 193–200CrossRefGoogle 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: 410–7CrossRefGoogle Scholar
  94. 94.
    Blundell JE, Hill AJ. Nutrition, serotonin and appetite: case studying the evolution of a scientific idea. Appetite 1987; 8: 183–94PubMedCrossRefGoogle 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: 513–5Google 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: 1240–5PubMedGoogle Scholar
  97. 97.
    Brewerton TD. Toward a unified theory of serotonin dysregulation in eating and related disorders. Psychoneuroendocrinology 1995; 20: 561–90PubMedCrossRefGoogle 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: 839–42PubMedCrossRefGoogle Scholar
  99. 99.
    Goodwin GM, Cowen PJ, Fairburn CJ, et al. Plasma concentrations of tryptophan and dieting. BMJ 1990; 300: 1499–500PubMedCrossRefGoogle 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: 163–222Google 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: 729–33PubMedCrossRefGoogle 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: 517–23Google 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: 375–82PubMedCrossRefGoogle Scholar
  104. 104.
    Kanarek RB. Dushkin H. Serotonin administration selectively reduces fat intake in rats. Pharmacol Biochem Behav 1988; 13: 133–22Google Scholar
  105. 105.
    Leibowitz SF, Shor-Posner G. Brain serotonin and eating behaviour. Appetite 1986; 7: 1–14PubMedCrossRefGoogle 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: 441–53PubMedCrossRefGoogle Scholar
  107. 107.
    Sclafani A. Animal models of obesity: classification and characterisation. Int J Obes 1984; 8: 491–508PubMedGoogle Scholar
  108. 108.
    Prats E, Monfar M, Castella J, et al. Energy intake of rats fed a cafeteria diet. Physiol Behav 1989; 45: 2263–72CrossRefGoogle 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: 199–206Google 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: 487–93PubMedCrossRefGoogle 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: 773–8CrossRefGoogle Scholar
  112. 112.
    Blundell JE, Lawton CL, Haiford JCG. Serotonin, eating behaviour and fat intake. Obes Res 1995; 3 Suppl. 4: 471–6Google 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: 377–89Google Scholar
  114. 114.
    Goodall EM, Silverstone T. Differential effect of d-fenfluramine and metergoline on food intake in human subjects. Appetite 1988; 11: 215–8PubMedCrossRefGoogle 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–34SGoogle 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: 219–33PubMedGoogle 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: 361–75Google 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: 345–56PubMedGoogle 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: 1–11PubMedGoogle Scholar
  120. 120.
    Cowen PJ, Clifford EM, Walsh AE, et al. Moderate dieting causes 5-HT2C supersensitization. Psychol Med 1996; 26: 1156–9CrossRefGoogle 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: 863–7PubMedGoogle 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): 549–7PubMedGoogle Scholar
  123. 123.
    Silverstone T, Goodall E. The clinical pharmacology of appetite suppressant drugs. Int J Obes 1984; 8(1): 23–33PubMedGoogle 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: 159–65PubMedCrossRefGoogle 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: 2–15CrossRefGoogle 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: 89–99PubMedCrossRefGoogle 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: 461–6PubMedCrossRefGoogle 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: 361–72PubMedGoogle Scholar
  129. 129.
    Walsh AE, Smith KA, Oldman AD, et al. m-Chlorophenyl-piperazine decreases food intake in a test meal. Psychopharmacology 1994; 116: 120–2PubMedCrossRefGoogle Scholar
  130. 130.
    Sargent PA, Sharpley AL, Williams C, et al. 5-HT2C activation decreases appetite and bodyweight in obese subjects. Psychopharmacology 1997; 133: 309–12PubMedCrossRefGoogle 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: 179–82PubMedCrossRefGoogle Scholar
  132. 132.
    Guy-Grand B. Clinical studies with d-fenfluramine. Am J Clin Nutr 1992; 55 Suppl.: 173s–176sPubMedGoogle Scholar
  133. 133.
    Finer N, Finer S, Nauova RP. Drug therapy after very-low-caloric diets. Am J Clin Nutr 1992; 56: 1955–85Google 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: 785–91PubMedCrossRefGoogle 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): 330–7CrossRefGoogle 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): 263–70PubMedGoogle Scholar
  137. 137.
    Smith I, Fitchet M, Kelly F. Sibutramine: predictability of long term weight loss. Int J Obes 1997; 21 Suppl. 2; s53Google Scholar
  138. 138.
    Blundell JE, Lawton CL. Serotonin and dietary fat intake: effect of dexfenfluramine. Metabol Clin Exper 1995; 44(2): 33–7CrossRefGoogle Scholar
  139. 139.
    Drewnowski A. Changes in mood after carbohydrate consumption [abstract]. Am J Clin Nutr 1987; 46: 703PubMedGoogle 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: 25–30Google 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: s65Google 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: s64Google Scholar
  143. 143.
    Golay A, Bobbioli E. The role of dietary fat in obesity. Int J Obes 1997; 21(3 Suppl.): s2–11Google Scholar
  144. 144.
    Drewnowski A, Kurth C, Holden-Wiltse J, et al. Food preferences in human obesity: carbohydrates verses fats. Appetite 1992; 18: 207–1PubMedCrossRefGoogle 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: 609–16PubMedCrossRefGoogle Scholar
  146. 146.
    Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997; 337: 581–8PubMedCrossRefGoogle 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: 1320PubMedCrossRefGoogle 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: 602–6PubMedCrossRefGoogle Scholar
  149. 149.
    Food and Drug Administration. Health advisory on fenfluramine/phentermine for obesity. Media Release 1997 Aug 27Google Scholar
  150. 150.
    Cannistra LV, Davis SM, Bouman AG. Valvular heart disease associated with dexfenfluramine [letter]. New Engl J Med 1997; 337: 636PubMedCrossRefGoogle 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: 509–12PubMedCrossRefGoogle 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: 10-1Google Scholar
  153. 153.
    Knoll’s sibutramine rejected by US panel. Marketletter 1996 Oct 7: 18Google Scholar
  154. 154.
    Stunkard AJ. Eating patterns in obesity. Psychiatr Q 1959; 33: 284–92PubMedCrossRefGoogle 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: 191–203CrossRefGoogle Scholar
  156. 156.
    Brewerton TD, George MS. Is migraine related to the eating disorders. Int J Eat Disord 1993; 14: 75–9PubMedCrossRefGoogle 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: 852–61PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1998

Authors and Affiliations

  1. 1.Department of Psychology, University of LeedsBiopsychology GroupLeedsEngland
  2. 2.Department of PsychologyUniversity of Central LancashirePrestonEngland

Personalised recommendations