Skip to main content

Brain serotonin deficiency and fluoxetine lead to sex-specific effects on binge-like food consumption in mice

Abstract

Rationale

Although pharmacotherapies are often effective in reducing binge eating in conditions such as bulimia nervosa and binge eating disorder, subsets of patients do not benefit sufficiently from existing treatments, and the reasons for treatment failure remain unclear.

Objectives

This study aimed to evaluate whether genetic reductions in brain serotonin influence binge eating and/or the ability of fluoxetine, a selective serotonin reuptake inhibitor, to reduce binge eating in mice.

Methods

This study used a validated model of binge-like consumption of high-fat diet to compare binge-like food intake in control and fluoxetine-treated wild-type and serotonin-deficient mice from the tryptophan hydroxylase 2 (R439H) knock-in line. In addition, real-time PCR was used to evaluate potential genotype and sex differences in the effects of fluoxetine on gene expression in the raphe nucleus.

Results

The results reveal that brain serotonin deficiency is sufficient to increase binge eating in males, but not females. However, while chronic fluoxetine reduced binge eating in both genotypes of males and in wild-type females, it failed to reduce binge eating in serotonin-deficient females. Transcriptional responses to chronic fluoxetine were also characterized by sex and genotype differences.

Conclusions

Overall, this study revealed significant sex differences in the effects of fluoxetine and brain serotonin deficiency on binge-like food intake and suggests that low brain serotonin could impact eating disorders both by promoting binge eating and by limiting the efficacy of fluoxetine to reduce binge eating.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  • Alenina N, Kikic D, Todiras M, Mosienko V, Qadri F, Plehm R, Boye P, Vilianovitch L, Sohr R, Tenner K et al (2009) Growth retardation and altered autonomic control in mice lacking brain serotonin. Proc Natl Acad Sci U S A 106:10332–10337

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Allen KL, Byrne SM, Oddy WH, Crosby RD (2013) DSM-IV-TR and DSM-5 eating disorders in adolescents: prevalence, stability, and psychosocial correlates in a population-based sample of male and female adolescents. J Abnorm Psychol 122:720–732

    PubMed  Article  Google Scholar 

  • Angoa-Perez M, Kane MJ, Briggs DI, Sykes CE, Shah MR, Francescutti DM, Rosenberg DR, Thomas DM, Kuhn DM (2012) Genetic depletion of brain 5HT reveals a common molecular pathway mediating compulsivity and impulsivity. J Neurochem 121(6):974–984

  • Anversa RG, Muthmainah M, Sketriene D, Gogos A, Sumithran P, Brown RM (2021) A review of sex differences in the mechanisms and drivers of overeating. Front Neuroendocrinol 63:100941

    CAS  PubMed  Article  Google Scholar 

  • Asarian L, Geary N (2013) Sex differences in the physiology of eating. Am J Physiol Regul Integr Comp Physiol 305:R1215-1267

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Beaulieu JM, Zhang X, Rodriguiz RM, Sotnikova TD, Cools MJ, Wetsel WC, Gainetdinov RR, Caron MG (2008) Role of GSK3 beta in behavioral abnormalities induced by serotonin deficiency. Proc Natl Acad Sci USA 105:1333–1338

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Border R, Johnson EC, Evans LM, Smolen A, Berley N, Sullivan PF, Keller MC (2019) No support for historical candidate gene or candidate gene-by-interaction hypotheses for major depression across multiple large samples. Am J Psychiatry 176:376–387

    PubMed  PubMed Central  Article  Google Scholar 

  • Carr MM, Wiedemann AA, Macdonald-Gagnon G, Potenza MN (2021) Impulsivity and compulsivity in binge eating disorder: a systematic review of behavioral studies. Prog Neuropsychopharmacol Biol Psychiatry 110:110318

    PubMed  Article  Google Scholar 

  • Coccaro EF, Kavoussi RJ, Cooper TB, Hauger R (1998) Acute tryptophan depletion attenuates the prolactin response to d-fenfluramine challenge in healthy human subjects. Psychopharmacology 138:9–15

    CAS  PubMed  Article  Google Scholar 

  • Coppen A (1967) The biochemistry of affective disorders. Br J Psychiatry 113:1237–1264

    CAS  PubMed  Article  Google Scholar 

  • Cowen PJ (2008) Serotonin and depression: pathophysiological mechanism or marketing myth? Trends Pharmacol Sci 29:433–436

    CAS  PubMed  Article  Google Scholar 

  • Culbert KM, Sisk CL, Klump KL (2021) A narrative review of sex differences in eating disorders: is there a biological basis? Clin Ther 43:95–111

    CAS  PubMed  Article  Google Scholar 

  • Cyr M, Charbonneau C, Morissette M, Rochford J, Barden N, Di Paolo T (2001) Central 5-hydroxytryptamine-2A receptor expression in transgenic mice bearing a glucocorticoid receptor antisense. Neuroendocrinology 73:37–45

    CAS  PubMed  Article  Google Scholar 

  • Czyzyk TA, Sahr AE, Statnick MA (2010) A model of binge-like eating behavior in mice that does not require food deprivation or stress. Obesity (silver Spring) 18:1710–1717

    Article  Google Scholar 

  • Dzirasa K, Kumar S, Sachs BD, Caron MG, Nicolelis MA (2013) Cortical-amygdalar circuit dysfunction in a genetic mouse model of serotonin deficiency. J Neurosci 33:4505–4513

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Egeland M, Warner-Schmidt J, Greengard P, Svenningsson P (2010) Neurogenic effects of fluoxetine are attenuated in p11 (S100A10) knockout mice. Biol Psychiatry 67:1048–1056

    CAS  PubMed  Article  Google Scholar 

  • Galmiche M, Dechelotte P, Lambert G, Tavolacci MP (2019) Prevalence of eating disorders over the 2000–2018 period: a systematic literature review. Am J Clin Nutr 109:1402–1413

    PubMed  Article  Google Scholar 

  • Goracci A, di Volo S, Casamassima F, Bolognesi S, Benbow J, Fagiolini A (2015) Pharmacotherapy of binge-eating disorder: a review. J Addict Med 9:1–19

    CAS  PubMed  Article  Google Scholar 

  • Gutknecht L, Waider J, Kraft S, Kriegebaum C, Holtmann B, Reif A, Schmitt A, Lesch KP (2008) Deficiency of brain 5-HT synthesis but serotonergic neuron formation in Tph2 knockout mice. J Neural Transm (vienna) 115:1127–1132

    CAS  Article  Google Scholar 

  • Huq SN, Warner AK, Buckhaults K, Sachs BD (2021) The effects of brain serotonin deficiency on responses to high fat diet in female mice. Front Neurosci 15:683103

  • Jacobsen JP, Siesser WB, Sachs BD, Peterson S, Cools MJ, Setola V, Folgering JH, Flik G, Caron MG (2012) Deficient serotonin neurotransmission and depression-like serotonin biomarker alterations in tryptophan hydroxylase 2 (Tph2) loss-of-function mice. Mol Psychiatry 17:694–704

    CAS  PubMed  Article  Google Scholar 

  • Jimenez Chavez CL, Bryant CD, Munn-Chernoff MA, Szumlinski KK (2021) Selective inhibition of PDE4B reduces binge drinking in two C57BL/6 substrains. Int J Mol Sci 22:5443

  • Jimerson DC, Lesem MD, Hegg AP, Brewerton TD (1990) Serotonin in human eating disorders. Ann N Y Acad Sci 600:532–544

    CAS  PubMed  Article  Google Scholar 

  • Karth MM, Baugher BJ, Daly N, Karth MD, Gironda SC, Sachs BD (2019) Brain 5-HT deficiency prevents antidepressant-like effects of high-fat-diet and blocks high-fat-diet-induced GSK3beta phosphorylation in the hippocampus. Front Mol Neurosci 12:298

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Kirkpatrick SL, Goldberg LR, Yazdani N, Babbs RK, Wu J, Reed ER, Jenkins DF, Bolgioni AF, Landaverde KI, Luttik KP et al (2017) Cytoplasmic FMR1-interacting protein 2 is a major genetic factor underlying binge eating. Biol Psychiatry 81:757–769

    CAS  PubMed  Article  Google Scholar 

  • Klump KL, Suisman JL, Culbert KM, Kashy DA, Keel PK, Sisk CL (2011) The effects of ovariectomy on binge eating proneness in adult female rats. Horm Behav 59:585–593

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Kondaurova EM, Rodnyy AY, Ilchibaeva TV, Tsybko AS, Eremin DV, Antonov YV, Popova NK, Naumenko VS (2020) Genetic background underlying 5-HT1A receptor functioning affects the response to fluoxetine. Int J Mol Sci 21:8784

  • Kornstein SG, Bliss C, Kando J, Madhoo M (2019) Clinical characteristics and treatment response to lisdexamfetamine dimesylate versus placebo in adults with binge eating disorder: analysis by gender and age. J Clin Psychiatry 80(2):18m12378

  • Kumar V, Kim K, Joseph C, Kourrich S, Yoo SH, Huang HC, Vitaterna MH, de Villena FP, Churchill G, Bonci A et al (2013) C57BL/6N mutation in cytoplasmic FMRP interacting protein 2 regulates cocaine response. Science 342:1508–1512

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Leibowitz SF, Alexander JT (1998) Hypothalamic serotonin in control of eating behavior, meal size, and body weight. Biol Psychiatry 44:851–864

    CAS  PubMed  Article  Google Scholar 

  • Liu H, Wang C, Yu M, Yang Y, He Y, Liu H, Liang C, Tu L, Zhang N, Wang L et al (2021) TPH2 in the dorsal raphe nuclei regulates energy balance in a sex-dependent manner. Endocrinology 162(1):1–16

  • Liu Y, Jiang Y, Si Y, Kim JY, Chen ZF, Rao Y (2011) Molecular regulation of sexual preference revealed by genetic studies of 5-HT in the brains of male mice. Nature 472:95–99

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • McElroy SL, Guerdjikova AI, Mori N, Romo-Nava F (2019) Progress in developing pharmacologic agents to treat bulimia nervosa. CNS Drugs 33:31–46

    PubMed  Article  Google Scholar 

  • Migliarini S, Pacini G, Pelosi B, Lunardi G, Pasqualetti M (2013) Lack of brain serotonin affects postnatal development and serotonergic neuronal circuitry formation. Mol Psychiatry 18:1106–1118

    CAS  PubMed  Article  Google Scholar 

  • Monteleone P, Brambilla F, Bortolotti F, Ferraro C, Maj M (1998) Plasma prolactin response to D-fenfluramine is blunted in bulimic patients with frequent binge episodes. Psychol Med 28:975–983

    CAS  PubMed  Article  Google Scholar 

  • Monteleone P, Brambilla F, Bortolotti F, Maj M (2000) Serotonergic dysfunction across the eating disorders: relationship to eating behaviour, purging behaviour, nutritional status and general psychopathology. Psychol Med 30:1099–1110

    CAS  PubMed  Article  Google Scholar 

  • Nawrocki AR, Rodriguez CG, Toolan DM, Price O, Henry M, Forrest G, Szeto D, Keohane CA, Pan Y, Smith KM et al (2014) Genetic deletion and pharmacological inhibition of phosphodiesterase 10A protects mice from diet-induced obesity and insulin resistance. Diabetes 63:300–311

    CAS  PubMed  Article  Google Scholar 

  • Romano KA, Lipson SK, Beccia AL, Quatromoni PA, Gordon AR, Murgueitio J (2022) Changes in the prevalence and sociodemographic correlates of eating disorder symptoms from 2013 to 2020 among a large national sample of U.S. young adults: a repeated cross-sectional study. Int J Eat Disord 55:776–789

    PubMed  PubMed Central  Article  Google Scholar 

  • Sachs BD, Jacobsen JP, Thomas TL, Siesser WB, Roberts WL, Caron MG (2013) The effects of congenital brain serotonin deficiency on responses to chronic fluoxetine. Transl Psychiatry 3:e291

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Sachs BD, Ni JR, Caron MG (2015) Brain 5-HT deficiency increases stress vulnerability and impairs antidepressant responses following psychosocial stress. Proc Natl Acad Sci USA 112(8):2557–2562

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Sachs BD, Tran HL, Folse E, Caron MG (2018) Brain-region-specific molecular responses to maternal separation and social defeat stress in mice. Neuroscience 373:122–136

    CAS  PubMed  Article  Google Scholar 

  • Statnick MA, Chen Y, Ansonoff M, Witkin JM, Rorick-Kehn L, Suter TM, Song M, Hu C, Lafuente C, Jimenez A et al (2016) A novel nociceptin receptor antagonist LY2940094 inhibits excessive feeding behavior in rodents: a possible mechanism for the treatment of binge eating disorder. J Pharmacol Exp Ther 356:493–502

    PubMed  Article  Google Scholar 

  • Statnick MA, Tinsley FC, Eastwood BJ, Suter TM, Mitch CH, Heiman ML (2003) Peptides that regulate food intake: antagonism of opioid receptors reduces body fat in obese rats by decreasing food intake and stimulating lipid utilization. Am J Physiol Regul Integr Comp Physiol 284:R1399-1408

    CAS  PubMed  Article  Google Scholar 

  • Stringer S, Polderman TJC, Posthuma D (2017) Majority of human traits do not show evidence for sex-specific genetic and environmental effects. Sci Rep 7:8688

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Svenningsson P, Chergui K, Rachleff I, Flajolet M, Zhang X, El Yacoubi M, Vaugeois JM, Nomikos GG, Greengard P (2006) Alterations in 5-HT1B receptor function by p11 in depression-like states. Science 311:77–80

    CAS  PubMed  Article  Google Scholar 

  • Svenningsson P, Greengard P (2007) p11 (S100A10)–an inducible adaptor protein that modulates neuronal functions. Curr Opin Pharmacol 7:27–32

    CAS  PubMed  Article  Google Scholar 

  • Takenawa T, Suetsugu S (2007) The WASP-WAVE protein network: connecting the membrane to the cytoskeleton. Nat Rev Mol Cell Biol 8:37–48

    CAS  PubMed  Article  Google Scholar 

  • Tata AL, Kockler DR (2006) Topiramate for binge-eating disorder associated with obesity. Ann Pharmacother 40:1993–1997

    CAS  PubMed  Article  Google Scholar 

  • Udo T, Grilo CM (2018) Prevalence and correlates of DSM-5-defined eating disorders in a nationally representative sample of U.S. Adults. Biol Psychiatry 84:345–354

    PubMed  PubMed Central  Article  Google Scholar 

  • Wang X, Spandidos A, Wang H, Seed B (2012) PrimerBank: a PCR primer database for quantitative gene expression analysis, 2012 update. Nucleic Acids Res 40:D1144-1149

    CAS  PubMed  Article  Google Scholar 

  • Wurtman JJ (1984) The involvement of brain serotonin in excessive carbohydrate snacking by obese carbohydrate cravers. J Am Diet Assoc 84:1004–1007

    CAS  PubMed  Article  Google Scholar 

  • Yadav VK, Oury F, Suda N, Liu ZW, Gao XB, Confavreux C, Klemenhagen KC, Tanaka KF, Gingrich JA, Guo XE et al (2009) A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure. Cell 138:976–989

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Yu Z, Geary N, Corwin RL (2008) Ovarian hormones inhibit fat intake under binge-type conditions in ovariectomized rats. Physiol Behav 95:501–507

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Zhang X, Gainetdinov RR, Beaulieu JM, Sotnikova TD, Burch LH, Williams RB, Schwartz DA, Krishnan KR, Caron MG (2005) Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 45:11–16

    CAS  PubMed  Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Benjamin D. Sachs.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Karth, M.D., Baugher, B.J., Pellechia, S.A. et al. Brain serotonin deficiency and fluoxetine lead to sex-specific effects on binge-like food consumption in mice. Psychopharmacology (2022). https://doi.org/10.1007/s00213-022-06181-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00213-022-06181-x

Keywords

  • Serotonin
  • Binge eating
  • Antidepressants
  • Sex differences