Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Assessment of the aversive consequences of acute and chronic administration of the melanocortin agonist, MTII

Abstract

BACKGROUND: The synthetic melanocortin (MC) agonist, melanotan-II (MTII), reduces food intake and body weight for hours to days after administration. One early report on the effect of MTII suggested that part of its anorexic action may be mediated by aversive consequences. In that experiment, MTII was found to support a mild conditioned taste aversion (CTA).

OBJECTIVE: The present experiments replicate and extend those findings in two additional CTA paradigms to further characterize the aversive effects of MTII in rats.

METHODS: Experiment 1 simultaneously assessed the ability of MTII to support CTA and reduce food intake, using a small oral infusion of a novel taste as the conditioned stimulus. Experiment 2 assessed the aversive consequences of chronic MTII administration. To accomplish this, we paired implantation of lithium chloride (LiCl)-, MTII- or saline-containing osmotic minipumps with a constantly available novel flavor. After 7 days, rats received a choice test between the minipump-paired flavor and a previously available neutral flavor.

RESULTS: Rats with saline minipumps exhibited no preference for either flavor. By contrast, rats in both the LiCl and MTII minipump groups significantly preferred the neutral flavor, indicating the development of a CTA. Additionally, CTA produced by administration of MTII was found to be more resistant to extinction than that produced by LiCl.

CONCLUSIONS: The reduction in food intake caused by MTII is accompanied by aversive consequences regardless of route of administration. These results present difficulties for the development of MCs-based therapies for obesity.

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

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

References

  1. Thiele T, van DG, Yagaloff K, Fisher S, Schwartz M, Burn P, Seeley R . Central infusion of melanocortin agonist MTII in rats: assessment of c-Fos expression and taste aversion. Am J Physiol 1998; 274: R248–R254.

    CAS  PubMed  Google Scholar 

  2. Tsujii S, Bray GA . Acetylation alters the feeding response to MSH and beta-endorphin. Brain Res Bull 1989; 23: 165–169.

    Article  CAS  Google Scholar 

  3. Fan W, Boston B, Kesterson R, Hruby V, Cone R . Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 1997; 385: 165–168.

    Article  CAS  Google Scholar 

  4. Schwartz MW, Seeley RJ, Weigle DS, Burn P, Campfield LA, Baskin DG . Leptin increases hypothalamic proopiomelanocoritin (POMC) mRNA expression in the rostral arcuate nucleus. Diabetes 1997; 46: 2119–2123.

    Article  CAS  Google Scholar 

  5. Mizuno T, Kleopoulos S, Bergen H, Roberts J, Priest C, Mobbs C . Hypothalamic pro-opiomelanocortin mRNA is reduced by fasting and in ob/ob and db/db mice, but is stimulated by leptin. Diabetes 1998; 47: 294–297.

    Article  CAS  Google Scholar 

  6. Bergendahl M, Wiemann JN, Clifton DK, Huhtaniemi I, Steiner RA . Short-term starvation decreases POMC mRNA but does not alter GnRH mRNA in the brain of adult male rats. Neuroendocrinology 1992; 56: 913–920.

    Article  CAS  Google Scholar 

  7. Thornton JE, Cheung CC, Clifton DK, Steiner RA . Regulation of hypothalamic proopiomelanocortin mRNA by leptin in ob/ob mice. Endocrinology 1997; 138: 5063–5067.

    Article  CAS  Google Scholar 

  8. Huszar D, Lynch C, Fairchild-Huntress V, Dunmore J, Fang Q, Berkemeier L, Gu W, Kesterson R, Boston B, Cone R, Smith F, Campfield L, Burn P, Lee F . Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 1997; 88: 131–141.

    Article  CAS  Google Scholar 

  9. Seeley R, Yagaloff K, Fisher S, Burn P, Thiele T, van DG, Baskin D, Schwartz M . Melanocortin receptors in leptin effects. Nature 1997; 390: 349.

    Article  CAS  Google Scholar 

  10. Cone RD (ed) The melanocortin receptors.Totowa, NJ: Humana Press; 2000.

    Book  Google Scholar 

  11. Cone RD . The central melanocortin system and energy homeostasis. Trends Endocrinol Metab 1999; 10: 211–216.

    Article  CAS  Google Scholar 

  12. Woods SC, Seeley RJ . Adiposity signals and the control of energy homeostasis. Nutrition 2000; 16: 894–902.

    Article  CAS  Google Scholar 

  13. Bures J, Bermudez-Rattoni F, and Yamamoto T . Conditioned taste aversion: Memory of a special kind. New York: Oxford University Press; 1998.

    Book  Google Scholar 

  14. Hoebe C, de Munter J, Thijs C . Adverse effects and compliance with mefloquine or proguanil antimalarial chemoprophylaxis. Eur J Clin Pharmacol 1997; 52: 269–275.

    Article  CAS  Google Scholar 

  15. Wessells H, Levine N, Hadley ME, Dorr R, Hruby V . Melanocortin receptor agonists, penile erection, and sexual motivation: human studies with Melanotan II. Int J Impot Res 2000; 12: S74–S79.

    Article  Google Scholar 

  16. Wessells H, Gralnek D, Dorr R, Hruby VJ, Hadley ME, Levine N . Effect of an alpha-melanocyte stimulating hormone analog on penile erection and sexual desire in men with organic erectile dysfunction. Urology 2000; 56: 641–646.

    Article  CAS  Google Scholar 

  17. Wessells H, Fuciarelli K, Hansen J, Hadley ME, Hruby VJ, Dorr R, Levine N . Synthetic melanotropic peptide initiates erections in men with psychogenic erectile dysfunction: double-blind, placebo controlled crossover study. J Urol 1998; 160: 389–393.

    Article  CAS  Google Scholar 

  18. Cowley MA, Smart JL, Rubinstein M, Cerdan MG, Diano S, Horvath TL, Cone RD, Low MJ . Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 2001; 411: 480–484.

    Article  CAS  Google Scholar 

  19. Mizuno TM, Makimura H, Silverstein J, Roberts JL, Lopingco T, Mobbs CV . Fasting regulates hypothalamic neuropeptide Y, agouti-related peptide, and proopiomelanocortin in diabetic mice independent of changes in leptin or insulin. Endocrinology 1999; 140: 4551–4557.

    Article  CAS  Google Scholar 

  20. Benoit SC, Schwartz MW, Baskin DG, Woods SC, Seeley RJ . CNS melanocortin system involvement in the regulation of food intake and body weight. Hormones Behav 2000; 37: 299–308.

    Article  CAS  Google Scholar 

  21. Dorr RT, Lines R, Levine N, Brooks C, Xiang L, Hruby VJ, Hadley ME . Evaluation of melanotan-II, a superpotent cyclic melanotropic peptide in a pilot phase-I clinical study. Life Sci 1996; 58: 1777–1784.

    Article  CAS  Google Scholar 

  22. Chavez M, Seeley RJ, Woods SC . A comparison between the effects of intraventricular insulin and intraperitoneal LiCl on three measures sensitive to emetic agents. Behav Neurosci 1995; 109: 547–550.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to S C Benoit.

Additional information

Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati Medical Center, Cincinnati, OH, USA

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Benoit, S., Sheldon, R., Air, E. et al. Assessment of the aversive consequences of acute and chronic administration of the melanocortin agonist, MTII. Int J Obes 27, 550–556 (2003). https://doi.org/10.1038/sj.ijo.0802280

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijo.0802280

Keywords

  • obesity
  • leptin
  • food intake
  • conditioned taste aversion

This article is cited by

Search

Quick links