Skip to main content

Advertisement

SpringerLink
Log in

Nasal administration of leptin dose-dependently increases dopamine and serotonin outflow in the rat nucleus accumbens

  • Translational Neurosciences - Original Article
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Abstract

Leptin is an anorexigenic hormone that acts via its receptor (LepR) to regulate the hypothalamic arcuate nucleus circuitry to mediate energy homeostasis and feeding behavior. Moreover, leptin decreases the reward value of natural and artificial rewards, and low levels of circulating leptin have been implicated in several mood disorders linking leptin to the mesolimbic system. Therefore, the purpose of this study was to assess whether and to what extent an acute intranasal application of leptin is able to modulate monoamine neurotransmitters in the nucleus accumbens (NAc). Microdialysis experiments were carried out in freely moving Wistar rats and in LepR-deficient Zucker rats (LepRfa/fa). Samples were analysed for the levels of dopamine (DA), serotonin (5-HT), and their metabolites using high-performance liquid chromatography with electrochemical detection. We show that in Wistar rats, nasal application of leptin dose-dependently increased extracellular DA and 5-HT levels in the NAc. By contrast, in the LepRfa/fa rats, nasal application of 0.12 mg/kg leptin failed to increase levels of either DA or 5-HT, but their metabolites (DOPAC and HIAA, respectively) were significantly decreased. In addition, leptin interaction with the melanocortin system was tested. Nasal co-administration of leptin and the melanocortin receptor antagonist, SHU9119, completely abolished the leptin-induced increase of both DA and 5-HT outflow in the NAc. These results indicate a marked leptin effect on the basal ganglia-related reward system involving melanocortin receptors.

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

Similar content being viewed by others

References

  • Arnold JJ, Ahsan F, Meezan E, Pillion DJ (2004) Correlation of tetradecylmaltoside induced increases in nasal peptide drug delivery with morphological changes in nasal epithelial cells. J Pharm Sci 93(9):2205–2213. doi:10.1002/jps.20123

    Article  CAS  PubMed  Google Scholar 

  • Atmaca M, Kuloglu M, Tezcan E, Ustundag B, Bayik Y (2002a) Serum leptin and cholesterol levels in patients with bipolar disorder. Neuropsychobiology 46(4):176–179. doi:10.1159/000067809

    Article  CAS  PubMed  Google Scholar 

  • Atmaca M, Kuloglu M, Tezcan E, Ustundag B, Gecici O, Firidin B (2002b) Serum leptin and cholesterol values in suicide attempters. Neuropsychobiology 45(3):124–127

    Article  CAS  PubMed  Google Scholar 

  • Calapi G, Corica F, Corsonello A, Sautebin L, Di Rosa M, Campo GM, Buemi M, Mauro VN, Caputi AP (1999) Leptin increases serotonin turnover by inhibition of brain nitric oxide synthesis. J Clin Investig 104(7):975–982. doi:10.1172/JCI5867

    Article  Google Scholar 

  • Clément K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M et al (1998) A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392(6674):398–401. doi:10.1038/32911

    Article  PubMed  Google Scholar 

  • Di Leone RJ (2009) The influence of leptin on the dopamine system and implications for ingestive behavior. Int J Obes (2005). doi:10.1038/ijo.2009.68 (Nature Publishing Group: S25–29)

    Google Scholar 

  • Di Matteo V, Di Giovanni G, Pierucci M, Esposito E (2008) Serotonin control of central dopaminergic function: focus on in vivo microdialysis studies. Prog Brain Res. doi:10.1016/S0079-6123(08)00902-3

    Google Scholar 

  • Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD (1997) Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385(6612):165–168. doi:10.1038/385165a0

    Article  CAS  PubMed  Google Scholar 

  • Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, Hughes IA, McCamish MA, O’Rahilly S (1999) Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 341:879–884. doi:10.1056/NEJM199909163411204

    Article  CAS  PubMed  Google Scholar 

  • Finn PD, Cunningham MJ, Rickard DG, Clifton DK, Steiner RA (2001) Serotonergic neurons are targets for leptin in the monkey. J Clin Endocrinol Metab 86(1):422–426. doi:10.1210/jc.86.1.422

    CAS  PubMed  Google Scholar 

  • Fliedner S, Schulz C, Lehnert H (2006) Brain uptake of intranasally applied radioiodinated leptin in wistar rats. Endocrinology 147(5):2088–2094. doi:10.1210/en.2005-1016

    Article  CAS  PubMed  Google Scholar 

  • Friedman JM (2011) Leptin and the regulation of body weight. Keio J Med 60(1):1–9. doi:10.2302/kjm.60.1

    Article  CAS  PubMed  Google Scholar 

  • Fulton S, Pissios P, Manchon RP, Stiles L, Frank L, Pothos EN, Maratos-Flier E, Flier JS (2006) Leptin regulation of the mesoaccumbens dopamine pathway. Neuron 51(6):811–822. doi:10.1016/j.neuron.2006.09.006

    Article  CAS  PubMed  Google Scholar 

  • Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM (1995) Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269(June):26–29. doi:10.1126/science.7624777

    Google Scholar 

  • Hay-Schmidt A, Helboe L, Larsen PJ (2001) Leptin receptor immunoreactivity is present in ascending serotonergic and catecholaminergic neurons of the rat. Neuroendocrinology 73(4):215–226. doi:10.1159/000054638

    Article  CAS  PubMed  Google Scholar 

  • Heisler LK, Cowley MA, Tecott LH, Fan W, Low MJ, Smart JL, Rubinstein M et al (2002) Activation of central melanocortin pathways by fenfluramine. Science 297(5581):609–611. doi:10.1126/science.1072327

    Article  CAS  PubMed  Google Scholar 

  • Hommel JD, Trinko R, Sears RM, Georgescu D, Liu ZW, Gao XB, Thurmon JJ, Marinelli M, DiLeone RJ (2006) Leptin receptor signaling in midbrain dopamine neurons regulates feeding. Neuron 51(6):801–810. doi:10.1016/j.neuron.2006.08.023

    Article  CAS  PubMed  Google Scholar 

  • Hsu R, Taylor JR, Newton SS, Alvaro JD, Haile C, Han G, Hruby VJ, Nestler EJ, Duman RS (2005) Blockade of melanocortin transmission inhibits cocaine reward. Eur J Neurosci 21(8):2233–2242. doi:10.1111/j.1460-9568.2005.04038.x

    Article  PubMed  PubMed Central  Google Scholar 

  • Hurd YL, Ungerstedt U (1989) In vivo neurochemical profile of dopamine uptake inhibitors and releasers in rat caudate-putamen. Eur J Pharmacol 166(2):251–260. doi:10.1016/0014-2999(89)90066-6

    Article  CAS  PubMed  Google Scholar 

  • Kask A, Rägo L, Wikberg JES, Schiöth HB (1998) Evidence for involvement of the melanocortin MC4 receptor in the effects of leptin on food intake and body weight. Eur J Pharmacol 360(1):15–19. doi:10.1016/S0014-2999(98)00699-2

    Article  CAS  PubMed  Google Scholar 

  • Kawashima N, Chaki S, Okuyama S (2003) Electrophysiological effects of melanocortin receptor ligands on neuronal activities of monoaminergic neurons in rats. Neurosci Lett 353(2):119–122. doi:10.1016/j.neulet.2003.09.024

    Article  CAS  PubMed  Google Scholar 

  • Kenny PJ (2011) Common cellular and molecular mechanisms in obesity and drug addiction. Nat Rev Neurosci. doi:10.1038/nrn3105

    PubMed  Google Scholar 

  • Kraus T, Haack M, Schuld A, Hinze-Selch D, Pollmächer T (2001) Low leptin levels but normal body mass indices in patients with depression or schizophrenia. Neuroendocrinology 73(4):243–247

    Article  CAS  PubMed  Google Scholar 

  • Kristensen P, Judge ME, Thim L, Ribel U, Christjansen KN, Wulff BS, Clausen JT et al (1998) Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature 393(6680):72–76. doi:10.1038/29993

    Article  CAS  PubMed  Google Scholar 

  • Krügel U, Schraft T, Kittner H, Kiess W, Illes P (2003) Basal and feeding-evoked dopamine release in the rat nucleus accumbens is depressed by leptin. Eur J Pharmacol 482(1–3):185–187. doi:10.1016/j.ejphar.2003.09.047

    Article  PubMed  Google Scholar 

  • Leinninger GM, Jo YH, Leshan RL, Louis GW (2009) Leptin acts via leptin receptor-expressing lateral hypothalamic neurons to modulate the mesolimbic dopamine system and suppress feeding. Cell Metab. doi:10.1016/j.cmet.2009.06.011

    Google Scholar 

  • Leshan RL, Opland DM, Louis GW, Leinninger GM, Patterson CM, Rhodes CJ, Münzberg H, Myers MG (2010) Ventral tegmental area leptin receptor neurons specifically project to and regulate cocaine- and amphetamine-regulated transcript neurons of the extended central amygdala. J Neurosci 30(16):5713–5723. doi:10.1523/JNEUROSCI.1001-10.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lindblom J, Opmane B, Mutulis F (2001) The MC4 receptor mediates Α-MSH induced release of nucleus accumbens dopamine. NeuroReport 12(10):2155–2158. doi:10.1097/00001756-200107200-00022

    Article  CAS  PubMed  Google Scholar 

  • Lucas JJ, Yamamoto A, Scearce-Levie K, Saudou F, Hen R (1998) Absence of fenfluramine-induced anorexia and reduced c-Fos induction in the hypothalamus and central amygdaloid complex of serotonin 1B receptor knock-out mice. J Neurosci 18(14):5537–5544

    CAS  PubMed  Google Scholar 

  • Lutter M, Nestler EJ (2009) Homeostatic and hedonic signals interact in the regulation of food intake. J Nutrition 139(3):629–632. doi:10.3945/jn.108.097618

    Article  CAS  Google Scholar 

  • Martel P, Fantino M (1996a) Influence of the amount of food ingested on mesolimbic dopaminergic system activity: a microdialysis study. Pharmacol Biochem Behav 55(2):297–302. doi:10.1016/S0091-3057(96)00087-1

    Article  CAS  PubMed  Google Scholar 

  • Martel P, Fantino M (1996b) Mesolimbic dopaminergic system activity as a function of food reward: a microdialysis study. Pharmacol Biochem Behav 53(1):221–226 (pii: 0091-3057(95)00187-5)

    Article  CAS  PubMed  Google Scholar 

  • Meguid MM, Fetissov SO, Blaha V, Yang ZJ (2000) Dopamine and serotonin VMN release is related to feeding status in obese and lean zucker rats. NeuroReport 11(10):2069–2072

    Article  CAS  PubMed  Google Scholar 

  • Montague CT, Farooqi IS, Wareham NJ, Sewter CP, Cheetham CH, Earley AR, Barnett AH, Prins JB, Rahilly SO (1997) Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387:903–908

    Article  CAS  PubMed  Google Scholar 

  • Orosco M, Rouch C, Meile MJ, Nicolaidis S (1995) Spontaneous feeding-related monoamine changes in rostromedial hypothalamus of the obese zucker rat: a microdialysis study. Physiol Behav 57((0031-9384 (Print))):1103–1106. doi:10.1016/0031-9384(94)00383-G

    Article  CAS  PubMed  Google Scholar 

  • Paxinos G, Watson, C (2005) The Rat Brain in Stereotaxic Coordinates. Elsevier Academic Press

  • Perry ML, Leinninger GM, Chen R, Luderman KD, Yang H, Gnegy ME, Myers MG, Kennedy RT (2010) Leptin promotes dopamine transporter and tyrosine hydroxylase activity in the nucleus accumbens of sprague-dawley rats: leptin promotes TH and DAT activity. J Neurochem 114(3):666–674. doi:10.1111/j.1471-4159.2010.06757.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pratt WE, Blackstone K, Connolly ME, Skelly MJ (2009) Selective serotonin receptor stimulation of the medial nucleus accumbens causes differential effects on food intake and locomotion. Behav Neurosci 123(5):1046–1057. doi:10.1037/a0016882

    Article  CAS  PubMed  Google Scholar 

  • Pratt WE, Schall MA, Choi E (2012) Selective serotonin receptor stimulation of the medial nucleus accumbens differentially affects appetitive motivation for food on a progressive ratio schedule of reinforcement. Neurosci Lett 511(2):84–88. doi:10.1016/j.neulet.2012.01.038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roseberry AG (2013) Altered feeding and body weight following melanocortin administration to the ventral tegmental area in adult rats. Psychopharmacology 226(1):25–34. doi:10.1007/s00213-012-2879-6

    Article  CAS  PubMed  Google Scholar 

  • Russo SJ, Nestler EJ (2013) The brain reward circuitry in mood disorders. Nat Rev Neurosci 14(9):609–625. doi:10.1038/nrn3381

    Article  CAS  PubMed  Google Scholar 

  • Schwartz MW, Peskind E, Raskind M, Boyko EJ, Porte D (1996) Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Nat Med 2(5):589–593. doi:10.1038/nm0596-589

    Article  CAS  PubMed  Google Scholar 

  • Stanley BG, Kyrkouli SE, Lampert S, Leibowitz SF (1986) Neuropeptide Y chronically injected into the hypothalamus: a powerful neurochemical inducer of hyperphagia and obesity. Peptides 7(6):1189–1192. doi:10.1016/0196-9781(86)90149-X

    Article  CAS  PubMed  Google Scholar 

  • Stenfors C, Ross SB (2004) Changes in extracellular 5-HIAA concentrations as measured by in vivo microdialysis technique in relation to changes in 5-HT release. Psychopharmacology. doi:10.1007/s00213-003-1736-z

    Google Scholar 

  • Talegaonkar S, Mishra PR (2004) Intranasal delivery : an approach to bypass the blood brain barrier. Indian J Pharmacol 36(3):140–147. doi:10.1186/1471-2202-9-S3-S5

    CAS  Google Scholar 

  • Westerink BH, Teisman A, de Vries JB (1994) Increase in dopamine release from the nucleus accumbens in response to feeding: a model to study interactions between drugs and naturally activated dopaminergic neurons in the rat brain. Naunyn-Schmiedeberg’s Arch Pharmacol 349((0028-1298; 3)):230–235

    Article  CAS  Google Scholar 

  • You ZB, Wang B, Liu QR, Wu Y, Otvos L, Wise RA (2015) Reciprocal inhibitory interactions between the reward-related effects of leptin and cocaine. Neuropsychopharmacology 41(4):1024–1033. doi:10.1038/npp.2015.230 (Nature Publishing Group: 1–36)

    Article  PubMed  Google Scholar 

  • Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372(6505):425–432. doi:10.1038/372425a0

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Katharina Schnackenberg, Marie Luise Reher and Karin Wiegers for their excellent technical assistance.

Funding

This research was supported by a special research Grant of the University of Luebeck (SPP Brain and Behavior B1).

Author information

Authors and Affiliations

  1. Department of Neurology, Center of Brain, Behavior and Metabolism, Neurochemical Research Group, University of Lübeck, Lübeck, Germany

    Sonya Neto, Ramya Varatharajan, Kevin Joseph & Andreas Moser

  2. Neuropharmacology Section, Department of Neurosurgery, University of Freiburg, Freiburg, Germany

    Kevin Joseph

  3. Freiburg Institute for Advanced Studies, University of Freiburg, Freiburg, Germany

    Andreas Moser

Authors
  1. Sonya Neto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ramya Varatharajan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kevin Joseph
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andreas Moser
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sonya Neto.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Neto, S., Varatharajan, R., Joseph, K. et al. Nasal administration of leptin dose-dependently increases dopamine and serotonin outflow in the rat nucleus accumbens. J Neural Transm 123, 1247–1254 (2016). https://doi.org/10.1007/s00702-016-1591-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-016-1591-9

Keywords

Search

Navigation