Skip to main content
SpringerLink
Log in

Mice overexpressing the 5-hydroxytryptamine transporter show no alterations in feeding behaviour and increased non-feeding responses to fenfluramine

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

The 5-HT transporter (5-HTT) is implicated in the regulation of appetite. Expression of the 5-HTT varies in the human population, and this variation may determine both individual differences in feeding and abnormal feeding behaviours such as eating disorders.

Objectives

The effects of 5-HTT expression on feeding and satiety were examined in a transgenic mouse model of 5-HTT overexpression.

Materials and methods

We measured free-feeding food intake and observed the behavioural satiety sequence (BSS) after food deprivation in mice at baseline and after administration of the anorectic drug fenfluramine.

Results

5-HTT overexpressing mice were both lighter and shorter than their wildtype littermates. Despite this size difference, food intake by transgenic and wildtype mice did not differ. There was no effect of genotype on the BSS or on food intake during the test at baseline. Increasing doses of fenfluramine reduced food intake in a similar manner in both transgenic and wildtype mice. After 0.3 and 1 mg/kg fenfluramine, the temporal pattern of the BSS was the same for both groups, whereas 3 and 10 mg/kg fenfluramine disrupted the BSS. In transgenic mice, this disruption was evident at the 3 mg/kg dose, while in wildtypes, it emerged only at the 10-mg/kg dose.

Conclusion

These data suggest that overexpression of the 5-HTT does not lead to alterations in feeding or satiety in food-deprived mice but does increase the occurrence of other non-feeding behaviours in response to the 5-HT releasing agent fenfluramine.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Antin J, Gibbs J, Holt J, Young RC, Smith GP (1975) Cholecystokinin elicits the complete behavioral sequence of satiety in rats. J Comp Physiol Psychol 89:784–790

    Article  PubMed  CAS  Google Scholar 

  • Bengel D, Murphy DL, Andrews AM, Wichems CH, Feltner D, Heils A, Mössner R, Westphal H, Lesch KP (1998) Altered brain serotonin homeostasis and locomotor insensitivity to 3, 4-methylenedioxymethamphetamine (“Ecstasy”) in serotonin transporter-deficient mice. Mol Pharmacol 53:649–655

    PubMed  CAS  Google Scholar 

  • Blakely R, De Felice L, Hartzell H (1994) Molecular physiology of norepinephrine and serotonin transporters. J Exp Biol 196:263–281

    PubMed  CAS  Google Scholar 

  • Blundell JE (1992) Serotonin and the biology of feeding. Am J Clin Nutr 55:155S–159S

    PubMed  CAS  Google Scholar 

  • Blundell JE, Rogers PJ, Hill AJ (1985) Behavioural structure and mechanisms of anorexia: calibration of natural and abnormal inhibition of eating. Brain Res Bull 15:371–376

    Article  PubMed  CAS  Google Scholar 

  • Bruce KR, Steiger H, Ng Ying Kin NM, Israel M (2006) Reduced platelet [3H]paroxetine binding in anorexia nervosa: relationship to eating symptoms and personality pathology. Psychiatry Res 142:225–232

    Article  PubMed  CAS  Google Scholar 

  • Di Bella DD, Catalano M, Cavallini MC, Riboldi C, Bellodi L (2000) Serotonin transporter linked polymorphic region in anorexia nervosa and bulimia nervosa. Mol Psychiatry 5:233–234

    Article  PubMed  Google Scholar 

  • Ekman A, Sundblad-Elverfors C, Landén M, Eriksson T, Eriksson E (2006) Low density and high affinity of platelet [3H]paroxetine binding in women with bulimia nervosa. Psychiatry Res 142:219–223

    Article  PubMed  CAS  Google Scholar 

  • Fuller RW, Snoddy HD, Robertson DW (1988) Mechanisms of effects of d-fenfluramine on brain serotonin metabolism in rats: uptake inhibition versus release. Pharmacol Biochem Behav 30:715–721

    Article  PubMed  CAS  Google Scholar 

  • Fumeron F, Betoulle D, Aubert R, Herbeth B, Siest G, Rigaud D (2001) Association of a functional 5-HT transporter gene polymorphism with anorexia nervosa and food intake. Mol Psychiatry 6:9–10

    Article  PubMed  CAS  Google Scholar 

  • Halford JC, Blundell JE (1996) Metergoline antagonizes fluoxetine-induced suppression of food intake but not changes in the behavioural satiety sequence. Pharmacol Biochem Behav 54:745–751

    Article  PubMed  CAS  Google Scholar 

  • Halford JC, Harrold JA, Boyland EJ, Lawton CL, Blundell JE (2007) Serotonergic drugs: effects on appetite expression and use for the treatment of obesity. Drugs 67:27–55

    Article  PubMed  CAS  Google Scholar 

  • Heils A, Teufel A, Petri S, Stöber G, Riederer P, Bengel D, Lesch KP (1996) Allelic variation of human serotonin transporter gene expression. J Neurochem 66:2621–2624

    Article  PubMed  CAS  Google Scholar 

  • Heinz A, Jones D, Mazzanti C, Goldman D, Ragan P, Hommer D, Linnoila M, Weinberger D (2000) A relationship between serotonin transporter genotype and in vivo protein expression and alcohol neurotoxicity. Biol Psychiatry 47:643–649

    Article  PubMed  CAS  Google Scholar 

  • Holmes A, Murphy DL, Crawley JN (2002) Reduced aggression in mice lacking the serotonin transporter. Psychopharmacology 161:160–167

    Article  PubMed  CAS  Google Scholar 

  • Ishii Y, Blundell JE, Halford JC, Rodgers RJ (2003) Effects of systematic variation in presatiation and fasting on the behavioural satiety sequence in male rats. Physiol Behav 79:227–238

    Article  PubMed  CAS  Google Scholar 

  • Jennings KA, Loder M, Sheward WJ, Pei Q, Deacon R, Benson M, Olverman H, Hastie N, Harmar AJ, Shen S, Sharp T (2006) Increased expression of the 5-HT transporter confers a low-anxiety phenotype linked to decreased 5-HT transmission. J Neurosci 26:8955–8964

    Article  PubMed  CAS  Google Scholar 

  • Jennings KA, Sheward WJ, Harmar AJ, Sharp T (2008) Evidence that genetic variation in 5-HT transporter expression is linked to changes in 5-HT2A receptor function. Neuropharmacology 54:776–783

    Article  PubMed  CAS  Google Scholar 

  • Kalueff AV, Ren-Patterson RF, Murphy DL (2007) The developing use of heterozygous mutant mouse models in brain monoamine transporter research. Trends in Pharmacol Sci 28:122–127

    Article  CAS  Google Scholar 

  • Kaye W, Nagata T, Weltzin T, Hsu L, Sokol M, McConaha C, Plotnicov K, Weise J, Deep D (2001) Double-blind placebo-controlled administration of fluoxetine in restricting- and restricting-purging-type anorexia nervosa. Biol Psychiatry 49:644–652

    Article  PubMed  CAS  Google Scholar 

  • Kaye WH, Frank GK, Bailer UF, Henry SE (2005a) Neurobiology of anorexia nervosa: clinical implications of alterations of the function of serotonin and other neuronal systems. Int J Eat Disord 37:S15–S19

    Article  PubMed  Google Scholar 

  • Kaye WH, Frank GK, Bailer UF, Henry SE, Meltzer CC, Price JC, Mathis CA, Wagner A (2005b) Serotonin alterations in anorexia and bulimia nervosa: new insights from imaging studies. Physiol Behav 85:73–81

    Article  PubMed  CAS  Google Scholar 

  • Kilic F, Murphy DL, Rudnick G (2003) A human serotonin transporter mutation causes constitutive activation of transport activity. Mol Pharmacol 64:440–446

    Article  PubMed  CAS  Google Scholar 

  • Lawton CL, Wales JK, Hill AJ, Blundell JE (1995) Serotoninergic manipulation, meal-induced satiety and eating pattern: effect of fluoxetine in obese female subjects. Obes Res 3:345–356

    PubMed  CAS  Google Scholar 

  • Lee MD, Somerville EM, Kennett GA, Dourish CT, Clifton PG (2004) Reduced hypophagic effects of d-fenfluramine and the 5-HT2C receptor antagonist mCPP in 5-HT1B receptor knockout mice. Psychopharmacology 176:39–49

    Article  PubMed  CAS  Google Scholar 

  • Malison RT, Price LH, Berman R, van Dyck CH, Pelton GH, Carpenter L, Sanacora G, Owens MJ, Nemeroff CB, Rajeevan N, Baldwin RM, Seibyl JP, Innis RB, Charney DS (1998) Reduced brain serotonin transporter availability in major depression as measured by [123I]-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane and single photon emission computed tomography. Biol Psychiatry 44:1090–1098

    Article  PubMed  CAS  Google Scholar 

  • Mann JJ, Huang YY, Underwood MD, Kassir SA, Oppenheim S, Kelly TM, Dwork AJ, Arango V (2000) A serotonin transporter gene promoter polymorphism (5-HTTLPR) and prefrontal cortical binding in major depression and suicide. Arch Gen Psychiatry 57:729–738

    Article  PubMed  CAS  Google Scholar 

  • Matsushita S, Suzuki K, Murayama M, Nishiguchi N, Hishimoto A, Takeda A, Shirakawa O, Higuchi S (2004) Serotonin transporter regulatory region polymorphism is associated with anorexia nervosa. Am J Med Genet B Neuropsychiatr Genet 128:114–117

    Article  Google Scholar 

  • McGuirk J, Silverstone T (1990) The effect of the 5-HT re-uptake inhibitor fluoxetine on food intake and body weight in healthy male subjects. Int J Obes 14:361–372

    PubMed  CAS  Google Scholar 

  • McGuirk J, Muscat R, Willner P (1992) Effects of the 5-HT uptake inhibitors, femoxetine and paroxetine, and a 5-HT1A/B agonist, eltoprazine, on the behavioural satiety sequence. Pharmacol Biochem Behav 41:801–805

    Article  PubMed  CAS  Google Scholar 

  • Monteleone P, Tortorella A, Castaldo E, Maj M (2006) Association of a functional serotonin transporter gene polymorphism with binge eating disorder. Am J Med Genet B Neuropsychiatr Genet 141:7–9

    Google Scholar 

  • Murphy DL, Lesch K (2008) Targeting the murine serotonin transporter: insights into human neurobiology. Nat Rev Neurosci 9:85–96

    Article  PubMed  CAS  Google Scholar 

  • Ogilvie AD, Battersby S, Bubb VJ, Fink G, Harmar AJ, Goodwim GM, Smith CA (1996) Polymorphism in serotonin transporter gene associated with susceptibility to major depression. Lancet 347:731–733

    Article  PubMed  CAS  Google Scholar 

  • Ozaki N, Goldman D, Kaye WH, Plotnicov K, Greenberg BD, Lappalainen J, Rudnick G, Murphy DL (2003) Serotonin transporter missense mutation associated with a complex neuropsychiatric phenotype. Mol Psychiatry 8:933–936

    Article  PubMed  CAS  Google Scholar 

  • Rankinen T, Bouchard C (2006) Genetics of food intake and eating behavior phenotypes in humans. Annu Rev Nutr 26:413–434

    Article  PubMed  CAS  Google Scholar 

  • Sookoian S, Gemma C, Garcia SI, Gianotti TF, Dieuzeide G, Roussos A, Tonietti M, Trifone L, Kanevsky D, Gonzalez CD, Pirola CJ (2007) The short allele of the serotonin transporter is a risk factor for obesity in adolescents. Obesity 15:271–276

    Article  PubMed  CAS  Google Scholar 

  • Sora I, Hall FS, Andrews AM, Itokawa M, Li XF, Wei HB, Wichems C, Lesch KP, Murphy DL, Uhl GR (2001) Molecular mechanisms of cocaine reward: combined dopamine and serotonin transporter knockouts eliminate cocaine place preference. Proc Natl Acad Sci U S A 98:5300–5305

    Article  PubMed  CAS  Google Scholar 

  • Steiger H (2004) Eating disorders and the serotonin connection: state, trait and developmental effects. J Psychiatry Neurosci 29:20–29

    PubMed  Google Scholar 

  • Steiger H, Richardson J, Israel M, Ng Ying Kin NM, Bruce K, Mansour S, Marie Parent A (2005) Reduced density of platelet-binding sites for [3H]paroxetine in remitted bulimic women. Neuropsychopharmacology 30:1028–1032

    Article  PubMed  CAS  Google Scholar 

  • Tauscher J, Pirker W, Willeit M, de Zwaan M, Bailer U, Neumeister A, Asenbaum S, Lennkh C, Praschak-Rieder N, Brücke T, Kasper S (2001) [123I] beta-CIT and single photon emission computed tomography reveal reduced brain serotonin transporter availability in bulimia nervosa. Biol Psychiatry 49:326–332

    Article  PubMed  CAS  Google Scholar 

  • Vickers SP, Clifton PG, Dourish CT (1996) Behavioural evidence that d-fenfluramine-induced anorexia in the rat is not mediated by the 5-HT1A receptor subtype. Psychopharmacology (Berl) 125:168–175

    Article  CAS  Google Scholar 

  • Vickers SP, Clifton PG, Dourish CT, Tecott LH (1999) Reduced satiating effect of d-fenfluramine in serotonin 5-HT(2C) receptor mutant mice. Psychopharmacology (Berl) 143:309–314

    Article  CAS  Google Scholar 

  • Walsh BT, Fairburn CG, Mickley D, Sysko R, Parides MK (2004) Treatment of bulimia nervosa in a primary care setting. Am J Psychiatry 161:556–561

    Article  PubMed  Google Scholar 

  • Warden SJ, Robling AG, Sanders MS, Bliziotes MM, Turner CH (2005) Inhibition of the serotonin (5-hydroxytryptamine) transporter reduces bone accrual during growth. Endocrinology 146:685–693

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Supported by an MRC studentship (AP) and EC FP6 Integrated Network (NEWMOOD LSHM-CT-2003-503474).

Author information

Authors and Affiliations

  1. Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK

    A. Pringle, K. A. Jennings, S. Line & T. Sharp

  2. Department of Experimental Psychology, University of Oxford, South Parks Road, Oxford, OX1 3UD, UK

    A. Pringle, S. Line & D. M. Bannerman

  3. School of Psychology, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK

    S. Higgs

Authors
  1. A. Pringle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K. A. Jennings
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Line
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D. M. Bannerman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. Higgs
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T. Sharp
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. Pringle.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pringle, A., Jennings, K.A., Line, S. et al. Mice overexpressing the 5-hydroxytryptamine transporter show no alterations in feeding behaviour and increased non-feeding responses to fenfluramine. Psychopharmacology 200, 291–300 (2008). https://doi.org/10.1007/s00213-008-1206-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-008-1206-8

Keywords

Search

Navigation