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.

  • Review Article
  • Published:

Synaptic changes induced by melanocortin signalling

Nature Reviews Neuroscience volume 15, pages 98–110 (2014)Cite this article

Subjects

Key Points

  • Plastic structural changes in the melanocortin circuitries that are mediated by melanocortin 4 receptor (MC4R) have been associated with anhedonic behaviours following chronic stress, and there is pharmacological evidence that selective blockade of this receptor in the nucleus accumbens alleviates such behaviour.

  • MC4R signalling in the hippocampus induces morphological synaptic changes that lead to arborization of immature dendritic spines and enhance synaptic strength during long-term potentiation.

  • MC4R activity is associated with enhanced phosphorylation and increased surface expression of AMPA receptors, which may stimulate the transcription of plasticity-associated genes and brain-derived neurotrophic factor synthesis.

  • Mutations of the MC4R gene that lead to reduced receptor function have consistently been associated with obesity. A high occurrence of attention-deficit hyperactivity disorder has been reported in obese patients carrying mutations in MC4R.

  • Aversive emotional and physiological states during drug withdrawal and the drive to compensate these negative states are associated with disruptive changes of synaptic plasticity in MC4R signalling within dopaminergic neurons.

  • MC4R signalling contributes to the sensitization of behavioural responses to drugs of abuse, such as amphetamine, cocaine and heroin.

  • Anatomical characterization of the melanocortin system using in situ hybridization and transgenic green fluorescent protein-expressing mice shows that MC4R is expressed throughout the ascending and descending pain pathways.

  • MC4R agonists have been shown to increase mechanical and thermal hyperalgesia after chronic constriction injury, which suggests that MC4R agonists are pro-nociceptive, whereas antagonists display analgesic properties.

  • Blockade of MC4R may be a new target in the search for strategies to prevent the development of opioid tolerance, to enhance the analgesic effects of opioids and to mitigate morphine withdrawal hyperalgesia.

Abstract

The melanocortin system has a well-established role in the regulation of energy homeostasis, but there is growing evidence of its involvement in memory, nociception, mood disorders and addiction. In this Review, we focus on the role of the melanocortin 4 receptor and provide an integrative view of the molecular mechanisms that lead to melanocortin-induced changes in synaptic plasticity within these diverse physiological systems. We also highlight the importance of melanocortin peptides and receptors in chronic pain syndromes, memory impairments, depression and drug abuse, and the possibility of targeting them for therapeutic purposes.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Expression of melanocortin receptors and POMC in the brain and spinal cord.
Figure 2: Melanocortin signalling pathways during LTP at the hippocampal CA1 region.
Figure 3: Bidirectional MC4R signalling in the control of synaptic remodelling.

Similar content being viewed by others

References

  1. Caruso, C., Carniglia, L., Durand, D., Scimonelli, T. N. & Lasaga, M. in Neurodegeneration (ed. Martins, L. M.) 93–120 (InTech, 2012). This is a comprehensive review focusing on the anti-inflammatory and neuroprotective role of melanocortins in the CNS.

    Google Scholar 

  2. Tao, Y. X. The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology. Endocr. Rev. 31, 506–543 (2010). This review summarizes studies on MC4R, from its cloning to its physiological roles in energy homeostasis, lipid homeostasis and inflammation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Cone, R. D. Anatomy and regulation of the central melanocortin system. Nature Neurosci. 8, 571–578 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Bertolini, A., Tacchi, R. & Vergoni, A. V. Brain effects of melanocortins. Pharmacol. Res. 59, 13–47 (2009).

    Article  CAS  PubMed  Google Scholar 

  5. Gonzalez, P. V., Schioth, H. B., Lasaga, M. & Scimonelli, T. N. Memory impairment induced by IL-1β is reversed by α-MSH through central melanocortin-4 receptors. Brain Behav. Immun. 23, 817–822 (2009).

    Article  CAS  PubMed  Google Scholar 

  6. Bertolini, A., Poggioli, R. & Ferrari, W. ACTH-induced hyperalgesia in rats. Experientia 35, 1216–1217 (1979).

    Article  CAS  PubMed  Google Scholar 

  7. Winter, C. A. & Flataker, L. The effect of cortisone, desoxycorticosterone, and adrenocorticotrophic hormone upon the responses of animals to analgesic drugs. J. Pharmacol. Exp. Ther. 103, 93–105 (1951).

    CAS  PubMed  Google Scholar 

  8. Nakanishi, S. et al. Nucleotide sequence of cloned cDNA for bovine corticotropin-β-lipotropin precursor. Nature 278, 423–427 (1979).

    Article  CAS  PubMed  Google Scholar 

  9. Wardlaw, S. L. Hypothalamic proopiomelanocortin processing and the regulation of energy balance. Eur. J. Pharmacol. 660, 213–219 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Argiolas, A. & Melis, M. R. Neuropeptides and central control of sexual behaviour from the past to the present: a review. Prog. Neurobiol. 108, 80–107 (2013).

    Article  CAS  PubMed  Google Scholar 

  11. Vergoni, A. V., Schioth, H. B. & Bertolini, A. Melanocortins and feeding behavior. Biomed. Pharmacother. 54, 129–134 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Chhajlani, V. & Wikberg, J. E. Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA. FEBS Lett. 309, 417–420 (1992).

    Article  CAS  PubMed  Google Scholar 

  13. Mountjoy, K. G., Robbins, L. S., Mortrud, M. T. & Cone, R. D. The cloning of a family of genes that encode the melanocortin receptors. Science 257, 1248–1251 (1992).

    Article  CAS  PubMed  Google Scholar 

  14. Chhajlani, V., Muceniece, R. & Wikberg, J. E. Molecular cloning of a novel human melanocortin receptor. Biochem. Biophys. Res. Commun. 195, 866–873 (1993).

    Article  CAS  PubMed  Google Scholar 

  15. Roselli-Rehfuss, L. et al. Identification of a receptor for γ melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system. Proc. Natl Acad. Sci. USA 90, 8856–8860 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gantz, I. et al. Molecular cloning, expression, and gene localization of a fourth melanocortin receptor. J. Biol. Chem. 268, 15174–15179 (1993).

    CAS  PubMed  Google Scholar 

  17. Labbe, O., Desarnaud, F., Eggerickx, D., Vassart, G. & Parmentier, M. Molecular cloning of a mouse melanocortin 5 receptor gene widely expressed in peripheral tissues. Biochemistry 33, 4543–4549 (1994).

    Article  CAS  PubMed  Google Scholar 

  18. Schioth, H. B. The physiological role of melanocortin receptors. Vitam. Horm. 63, 195–232 (2001). This is a comprehensive review focusing on the biochemistry and physiological role of melanocortin receptors.

    Article  CAS  PubMed  Google Scholar 

  19. Yang, Y. Structure, function and regulation of the melanocortin receptors. Eur. J. Pharmacol. 660, 125–130 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gantz, I. & Fong, T. M. The melanocortin system. Am. J. Physiol. Endocrinol. Metab. 284, E468–E474 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Cone, R. D. et al. The melanocortin receptors: agonists, antagonists, and the hormonal control of pigmentation. Recent Prog. Horm. Res. 51, 287–317 (1996).

    CAS  PubMed  Google Scholar 

  22. Wikberg, J. E. & Mutulis, F. Targeting melanocortin receptors: an approach to treat weight disorders and sexual dysfunction. Nature Rev. Drug Discov. 7, 307–323 (2008).

    Article  CAS  Google Scholar 

  23. Kask, A., Rägo, L., Wikberg, J. E. S. & Schiöth, H. B. Evidence for involvement of the melanocortin MC4R in the effects of leptin on food intake and body weight. Eur. J. Pharmacol. 360, 15–19 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Morton, G. J., Cummings, D. E., Baskin, D. G., Barsh, G. S. & Schwartz, M. W. Central nervous system control of food intake and body weight. Nature 443, 289–295 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Huszar, D. et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 13–141 (1997).

    Article  Google Scholar 

  26. Yaswen, L., Diehl, N., Brennan, M. B. & Hochgeschwender, U. Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nature Med. 5, 1066–1070 (1999).

    Article  CAS  PubMed  Google Scholar 

  27. Ollmann, M. M. et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278, 135–138 (1997).

    Article  CAS  PubMed  Google Scholar 

  28. Giuliani, D. et al. Melanocortins protect against progression of Alzheimer's disease in triple-transgenic mice by targeting multiple pathophysiological pathways. Neurobiol. Aging 35, 537–547 (2014).

    Article  CAS  PubMed  Google Scholar 

  29. Giuliani, D. et al. Both early and delayed treatment with MC4R-stimulating melanocortins produces neuroprotection in cerebral ischemia. Endocrinology 147, 1126–1135 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Hache, G. et al. Antinociceptive effects of fluoxetine in a mouse model of anxiety/depression. Neuroreport 23, 525–529 (2012).

    Article  CAS  PubMed  Google Scholar 

  31. Bar, K. J. et al. Pain perception in major depression depends on pain modality. Pain 117, 97–103 (2005).

    Article  PubMed  Google Scholar 

  32. Apkarian, A. V. A brain signature for acute pain. Trends Cogn. Sci. 17, 309–310 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Mansour, A. R., Farmer, M. A., Baliki, M. N. & Apkarian, A. V. Chronic pain: the role of learning and brain plasticity. Restor. Neurol. Neurosci. http://dx.doi.org/10.3233/RNN-139003 (2013).

  34. Zimmerman, M. E. et al. Hippocampal correlates of pain in healthy elderly adults: a pilot study. Neurology 73, 1567–1570 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Mutso, A. A. et al. Abnormalities in hippocampal functioning with persistent pain. J. Neurosci. 32, 5747–5756 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lim, B. K., Huang, K. W., Grueter, B. A., Rothwell, P. E. & Malenka, R. C. Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens. Nature 487, 183–189 (2012). This study demonstrates that activation of MC4R in the NAc leads to a depression of excitatory synaptic transmission accompanied by changes in the stoichiometry of AMPAR in the mouse.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Shen, Y., Fu, W. Y., Cheng, E. Y., Fu, A. K. & Ip, N. Y. Melanocortin-4 receptor regulates hippocampal synaptic plasticity through a protein kinase A-dependent mechanism. J. Neurosci. 33, 464–472 (2013). This study demonstrates that in vivo administration of MC4R agonists increases LTP in the hippocampal CA1 region of mice, elucidating its functional role in synaptic plasticity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Grueter, B. A., Rothwell, P. E. & Malenka, R. C. Integrating synaptic plasticity and striatal circuit function in addiction. Curr. Opin. Neurobiol. 22, 545–551 (2012).

    Article  CAS  PubMed  Google Scholar 

  39. Kreitzer, A. C. & Malenka, R. C. Striatal plasticity and basal ganglia circuit function. Neuron 60, 543–554 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Russo, S. J. et al. The addicted synapse: mechanisms of synaptic and structural plasticity in nucleus accumbens. Trends Neurosci. 33, 267–276 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Alvaro, J. D. et al. Morphine down-regulates melanocortin-4 receptor expression in brain regions that mediate opiate addiction. Mol. Pharmacol. 50, 583–591 (1996).

    CAS  PubMed  Google Scholar 

  42. Alvaro, J. D., Taylor, J. R. & Duman, R. S. Molecular and behavioral interactions between central melanocortins and cocaine. J. Pharmacol. Exp. Ther. 304, 391–399 (2003). This study supports the role for MC4R in the biochemical and behavioural effects of drug of abuse.

    Article  CAS  PubMed  Google Scholar 

  43. Barrientos, R. M. et al. BDNF mRNA expression in rat hippocampus following contextual learning is blocked by intrahippocampal IL-1β administration. J. Neuroimmunol. 155, 119–126 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Cui, H. & Lutter, M. The expression of MC4Rs in D1R neurons regulates food intake and locomotor sensitization to cocaine. Genes Brain Behav. 12, 658–665 (2013). This study elucidates the physiological role of MC4R-mediated signalling within D1R-expressing neurons and the behavioural response to cocaine.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ercil, N. E., Galici, R. & Kesterson, R. A. HS014, a selective melanocortin-4 (MC4) receptor antagonist, modulates the behavioral effects of morphine in mice. Psychopharmacology (Berl.) 180, 279–285 (2005).

    Article  CAS  Google Scholar 

  46. Liu, J., Garza, J. C., Li, W. & Lu, X. Y. Melanocortin-4 receptor in the medial amygdala regulates emotional stress-induced anxiety-like behaviour, anorexia and corticosterone secretion. Int. J. Neuropsychopharmacol. 16, 105–120 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Hsu, R. et al. Blockade of melanocortin transmission inhibits cocaine reward. Eur. J. Neurosci. 21, 2233–2242 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Niikura, K., Zhou, Y., Ho, A. & Kreek, M. J. Proopiomelanocortin (POMC) expression and conditioned place aversion during protracted withdrawal from chronic intermittent escalating-dose heroin in POMC-EGFP promoter transgenic mice. Neuroscience 236, 220–232 (2013).

    Article  CAS  PubMed  Google Scholar 

  49. Cabeza de Vaca, S., Kim, G. Y. & Carr, K. D. The melanocortin receptor agonist MTII augments the rewarding effect of amphetamine in ad-libitum-fed and food-restricted rats. Psychopharmacology (Berl.) 161, 77–85 (2002).

    Article  CAS  Google Scholar 

  50. Chaki, S. & Okuyama, S. Involvement of melanocortin-4 receptor in anxiety and depression. Peptides 26, 1952–1964 (2005). This study investigates the relationship between MC4R and stress related disorders, suggesting that MC4R might be related to stress-induced changes in behaviour, and blockade of MC4R may prevent stress-induced disorders such as anxiety.

    Article  CAS  PubMed  Google Scholar 

  51. McLay, R. N., Pan, W. & Kastin, A. J. Effects of peptides on animal and human behavior: a review of studies published in the first twenty years of the journal Peptides. Peptides 22, 2181–2255 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. Cheung, Z. H. & Ip, N. Y. From understanding synaptic plasticity to the development of cognitive enhancers. Int. J. Neuropsychopharmacol. 14, 1247–1256 (2011).

    Article  CAS  PubMed  Google Scholar 

  53. Bliss, T. V. & Collingridge, G. L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39 (1993).

    Article  CAS  PubMed  Google Scholar 

  54. Kandel, E. R. The molecular biology of memory storage: a dialog between genes and synapses. Biosci. Rep. 21, 565–611 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Cui, H. et al. Melanocortin 4 receptor signaling in dopamine 1 receptor neurons is required for procedural memory learning. Physiol. Behav. 106, 201–210 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Oosterom, J. et al. Common requirements for melanocortin-4 receptor selectivity of structurally unrelated melanocortin agonist and endogenous antagonist, Agouti protein. J. Biol. Chem. 276, 931–936 (2001).

    Article  CAS  PubMed  Google Scholar 

  57. Abel, T. & Nguyen, P. V. Regulation of hippocampus-dependent memory by cyclic AMP-dependent protein kinase. Prog. Brain Res. 169, 97–115 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kopec, C. D., Real, E., Kessels, H. W. & Malinow, R. GluR1 links structural and functional plasticity at excitatory synapses. J. Neurosci. 27, 13706–13718 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Man, H. Y., Sekine-Aizawa, Y. & Huganir, R. L. Regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor trafficking through PKA phosphorylation of the Glu receptor 1 subunit. Proc. Natl Acad. Sci. USA 104, 3579–3584 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Caruso, C. et al. Melanocortin 4 receptor activation induces brain-derived neurotrophic factor expression in rat astrocytes through cyclic AMP–protein kinase A pathway. Mol. Cell. Endocrinol. 348, 47–54 (2012). This is the first study to show that MC4R activation in astrocytes induces BDNF expression through the cAMP–PKA–CREB pathway without involving nuclear factor-kB.

    Article  CAS  PubMed  Google Scholar 

  61. Kelley, A. E. Ventral striatal control of appetitive motivation: role in ingestive behavior and reward-related learning. Neurosci. Biobehav. Rev. 27, 765–776 (2004).

    Article  PubMed  Google Scholar 

  62. Nishi, A., Kuroiwa, M. & Shuto, T. Mechanisms for the modulation of dopamine D1 receptor signaling in striatal neurons. Front. Neuroanat. 5, 43 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Korte, M., Kang, H., Bonhoeffer, T. & Schuman, E. A role for BDNF in the late-phase of hippocampal long-term potentiation. Neuropharmacology 37, 553–559 (1998).

    Article  CAS  PubMed  Google Scholar 

  64. Kandel, E. R. The molecular biology of memory storage: a dialogue between genes and synapses. Science 294, 1030–1038 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Pang, P. T. et al. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science 306, 487–491 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Tyler, W. J., Alonso, M., Bramham, C. R. & Pozzo-Miller, L. D. From acquisition to consolidation: on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning. Learn. Mem. 9, 224–237 (2002).

    Article  PubMed  Google Scholar 

  67. Lee, J. L., Everitt, B. J. & Thomas, K. L. Independent cellular processes for hippocampal memory consolidation and reconsolidation. Science 304, 839–843 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Bekinschtein, P. et al. Persistence of long-term memory storage requires a late protein synthesis- and BDNF- dependent phase in the hippocampus. Neuron 53, 261–277 (2007).

    Article  CAS  PubMed  Google Scholar 

  69. Goshen, I. et al. A dual role for interleukin-1 in hippocampal-dependent memory processes. Psychoneuroendocrinology 32, 1106–1115 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Schneider, H. et al. A neuromodulatory role of interleukin-1β in the hippocampus. Proc. Natl Acad. Sci. USA 95, 7778–7783 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Vereker, E., O'Donnell, E. & Lynch, M. A. The inhibitory effect of interleukin-1β on long-term potentiation is coupled with increased activity of stress-activated protein kinases. J. Neurosci. 20, 6811–6819 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Yoon, S.-W. et al. α-melanocyte-stimulating hormone inhibits lipopolysaccharide-induced tumor necrosis factor-α production in leukocytes by modulating protein kinase A, p38 kinase, and nuclear factor κB signaling pathways. J. Biol. Chem. 278, 32914–32920 (2003).

    Article  CAS  PubMed  Google Scholar 

  73. Lai, A. Y., Swayze, R. D., El-Husseini, A. & Song, C. Interleukin-1 beta modulates AMPA receptor expression and phosphorylation in hippocampal neurons. J. Neuroimmunol. 175, 97–106 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. Viviani, B. et al. Interleukin-1β enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J. Neurosci. 23, 8692–8700 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Lynch, G., Larson, J., Kelso, S., Barrionuevo, G. & Schottler, F. Intracellular injections of EGTA block induction of hippocampal long-term potentiation. Nature 305, 719–721 (1983).

    Article  CAS  PubMed  Google Scholar 

  76. Dash, P. K., Hochner, B. & Kandel, E. R. Injection of the cAMP-responsive element into the nucleus of Aplysia sensory neurons blocks long-term facilitation. Nature 345, 718–721 (1990).

    Article  CAS  PubMed  Google Scholar 

  77. Breit, A. et al. Alternative G protein coupling and biased agonism: new insights into melanocortin-4 receptor signalling. Mol. Cell. Endocrinol. 331, 232–240 (2011).

    Article  CAS  PubMed  Google Scholar 

  78. Caruso, C. M., Carniglia, L., Durand, D., Scimonelli, T. N. & Lasaga, M. Astrocytes: new targets of melanocortin 4 receptor actions. J. Mol. Endocrinol. 51, R33–R50 (2013).

    Article  CAS  PubMed  Google Scholar 

  79. Spaccapelo, L. et al. Melanocortin MC4R agonists counteract late inflammatory and apoptotic responses and improve neuronal functionality after cerebral ischemia. Eur. J. Pharmacol. 670, 479–486 (2011). This study provides direct evidence that stimulation of MC4R affords neuroprotection and promotes functional recovery from stroke.

    Article  CAS  PubMed  Google Scholar 

  80. Giuliani, D. et al. Treatment of cerebral ischemia with melanocortins acting at MC4Rs induces marked neurogenesis and long-lasting functional recovery. Acta Neuropathol. 122, 443–453 (2011).

    Article  CAS  PubMed  Google Scholar 

  81. Giuliani, D. et al. Functional recovery after delayed treatment of ischemic stroke with melanocortins is associated with overexpression of the activity-dependent gene Zif268. Brain Behav. Immun. 23, 844–850 (2009).

    Article  CAS  PubMed  Google Scholar 

  82. Ferrari, W. Behavioural changes in animals after intracisternal injection with adrenocorticotrophic hormone and melanocyte-stimulating hormone. Nature 181, 925–926 (1958).

    Article  CAS  PubMed  Google Scholar 

  83. de Wied, D., Witter, A., Versteeg, D. H. & Mulder, A. H. Release of ACTH by substances of central nervous system origin. Endocrinology 85, 561–569 (1969).

    Article  CAS  PubMed  Google Scholar 

  84. Guarini, S., Bazzani, C. & Bertolini, A. Role of neuronal and vascular Ca2+-channels in the ACTH-induced reversal of haemorrhagic shock. Br. J. Pharmacol. 109, 645–650 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Giuliani, D. et al. Melanocortins and the cholinergic anti-inflammatory pathway. Adv. Exp. Med. Biol. 2681, 2071–2087 (2010).

    Google Scholar 

  86. Cole, A. J., Saffen, D. W., Baraban, J. M. & Worley, P. F. Rapid increase of an immediate early gene messenger RNA in hippocampal neurons by synaptic NMDA receptor activation. Nature 340, 474–476 (1989).

    Article  CAS  PubMed  Google Scholar 

  87. Maniam, J. & Morris, M. J. The link between stress and feeding behaviour. Neuropharmacology 63, 97–110 (2012).

    Article  CAS  PubMed  Google Scholar 

  88. Mitra, A. et al. Expression levels of genes encoding melanin concentrating hormone (MCH) and MCH receptor change in taste aversion, but MCH injections do not alleviate aversive responses. Pharmacol. Biochem. Behav. 100, 581–586 (2012).

    Article  CAS  PubMed  Google Scholar 

  89. Kishi, T. et al. Expression of melanocortin 4 receptor mRNA in the central nervous system of the rat. J. Comp. Neurol. 457, 213–235 (2003).

    Article  CAS  PubMed  Google Scholar 

  90. Cui, G., Bernier, B. E., Harnett, M. T. & Morikawa, H. Differential regulation of action potential- and metabotropic glutamate receptor-induced Ca2+ signals by inositol 1,4,5-trisphosphate in dopaminergic neurons. J. Neurosci. 27, 4776–4785 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Woolfrey, K. M. et al. Epac2 induces synapse remodeling and depression and its disease-associated forms alter spines. Nature Neurosci. 12, 1275–1284 (2009).

    Article  CAS  PubMed  Google Scholar 

  92. Oh, M. C., Derkach, V. A., Guire, E. S. & Soderling, T. R. Extrasynaptic membrane trafficking regulated by GluR1 serine 845 phosphorylation primes AMPA receptors for long-term potentiation. J. Biol. Chem. 281, 752–758 (2006).

    Article  CAS  PubMed  Google Scholar 

  93. Adan, R. A. et al. Characterization of melanocortin receptor ligands on cloned brain melanocortin receptors and on grooming behavior in the rat. Eur. J. Pharmacol. 378, 249–258 (1999).

    Article  CAS  PubMed  Google Scholar 

  94. Mul, J. D. et al. Melanocortin receptor 4 deficiency affects body weight regulation, grooming behavior, and substrate preference in the rat. Obesity 20, 612–621 (2012).

    Article  CAS  PubMed  Google Scholar 

  95. Lu, X. Y., Barsh, G. S., Akil, H. & Watson, S. J. Interaction between α-melanocyte-stimulating hormone and corticotropin-releasing hormone in the regulation of feeding and hypothalamo–pituitary–adrenal responses. J. Neurosci. 23, 7863–7872 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Sarkar, S., Legradi, G. & Lechan, R. M. Intracerebroventricular administration of α-melanocyte stimulating hormone increases phosphorylation of CREB in TRH- and CRH-producing neurons of the hypothalamic paraventricular nucleus. Brain Res. 945, 50–59 (2002).

    Article  CAS  PubMed  Google Scholar 

  97. Yehuda, R. Status of glucocorticoid alterations in post-traumatic stress disorder. Ann. NY Acad. Sci. 1179, 2056–2069 (2009).

    Article  CAS  Google Scholar 

  98. Vecsernyes, M., Biro, E., Gardi, J., Julesz, J. & Telegdy, G. Involvement of endogenous corticotropin-releasing factor in mediation of neuroendocrine and behavioral effects to α-melanocyte-stimulating hormone. Endocr. Res. 26, 347–356 (2000).

    Article  CAS  PubMed  Google Scholar 

  99. Kas, M. J., Bruijnzeel, A. W., Haanstra, J. R., Wiegant, V. M. & Adan, R. A. Differential regulation of agouti-related protein and neuropeptide Y in hypothalamic neurons following a stressful event. J. Mol. Endocrinol. 35, 159–164 (2005).

    Article  CAS  PubMed  Google Scholar 

  100. Serova, L. I., Laukova, M., Alaluf, L. G. & Sabban, E. L. Intranasal infusion of melanocortin receptor four (MC4R) antagonist to rats ameliorates development of depression and anxiety related symptoms induced by single prolonged stress. Behav. Brain Res. 250, 139–147 (2013). This is the first study to describe the resilience effects of HS014 on the development of behavioural symptoms comorbid with post-traumatic stress disorder.

    Article  CAS  PubMed  Google Scholar 

  101. Liu, J. et al. The melanocortinergic pathway is rapidly recruited by emotional stress and contributes to stress-induced anorexia and anxiety-like behavior. Endocrinology 148, 5531–5540 (2007).

    Article  CAS  PubMed  Google Scholar 

  102. Goyal, S. N., Kokare, D. M., Chopde, C. T. & Subhedar, N. K. Alpha-melanocyte stimulating hormone antagonizes antidepressant-like effect of neuropeptide Y in Porsolt's test in rats. Pharmacol. Biochem. Behav. 85, 369–377 (2006).

    Article  CAS  PubMed  Google Scholar 

  103. Vergoni, A. V., Bertolini, A., Wikberg, J. E. & Schioth, H. B. Selective melanocortin MC4R blockage reduces immobilization stress-induced anorexia in rats. Eur. J. Pharmacol. 369, 11–15 (1999).

    Article  CAS  PubMed  Google Scholar 

  104. Farooqi, I. S. et al. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. New Engl. J. Med. 348, 1085–1095 (2003).

    Article  CAS  PubMed  Google Scholar 

  105. Stutzmann, F. et al. Prevalence of melanocortin-4 receptor deficiency in Europeans and their age-dependent penetrance in multigenerational pedigrees. Diabetes 57, 2511–2518 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Tan, K. et al. Functional characterization and structural modeling of obesity associated mutations in the melanocortin 4 receptor. Endocrinology 150, 114–125 (2009).

    Article  CAS  PubMed  Google Scholar 

  107. Yeo, G. S. et al. Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms. Hum. Mol. Genet. 12, 561–574 (2003).

    Article  CAS  PubMed  Google Scholar 

  108. Agranat-Meged, A. et al. Attention deficit hyperactivity disorder in obese melanocortin-4-receptor (MC4R) deficient subjects: a newly described expression of MC4R deficiency. Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B, 1547–1553 (2008).

    Article  CAS  PubMed  Google Scholar 

  109. Altfas, J. R. Prevalence of attention deficit/hyperactivity disorder among adults in obesity treatment. BMC Psychiatry 2, 9 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Holtkamp, K. et al. Overweight and obesity in children with Attention-Deficit/Hyperactivity Disorder. Int. J. Obes. Relat. Metab. Disord. 28, 685–689 (2004).

    Article  CAS  PubMed  Google Scholar 

  111. Pagoto, S. L. et al. Association between adult attention deficit/hyperactivity disorder and obesity in the US population. Obesity 17, 539–544 (2009).

    Article  PubMed  Google Scholar 

  112. Waring, M. E. & Lapane, K. L. Overweight in children and adolescents in relation to attention-deficit/hyperactivity disorder: results from a national sample. Pediatrics 122, e1–e6 (2008).

    Article  PubMed  Google Scholar 

  113. Pott, W., Albayrak, O., Hinney, A., Hebebrand, J. & Pauli-Pott, U. Successful treatment with atomoxetine of an adolescent boy with attention deficit/hyperactivity disorder, extreme obesity, and reduced melanocortin 4 receptor function. Obes. Facts 6, 109–115 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Cortese, S. et al. Association between symptoms of attention-deficit/hyperactivity disorder and bulimic behaviors in a clinical sample of severely obese adolescents. Int. J. Obes. (Lond.) 31, 340–346 (2007).

    Article  CAS  Google Scholar 

  115. Albayrak, O. et al. Successful methylphenidate treatment of early onset extreme obesity in a child with a melanocortin-4 receptor gene mutation and attention deficit/hyperactivity disorder. Eur. J. Pharmacol. 660, 165–170 (2011).

    Article  CAS  PubMed  Google Scholar 

  116. Lindblom, J. et al. The MC4 receptor mediates α-MSH induced release of nucleus accumbens dopamine. Neuroreport 12, 2155–2158 (2001).

    Article  CAS  PubMed  Google Scholar 

  117. Lindblom, J. et al. Chronic infusion of a melanocortin receptor agonist modulates dopamine receptor binding in the rat brain. Pharmacol. Res. 45, 119–124 (2002).

    Article  CAS  PubMed  Google Scholar 

  118. Von Frijtag, J. C., Croiset, G., Gispen, W. H., Adan, R. A. & Wiegant, V. M. The role of central melanocortin receptors in the activation of the hypothalamus–pituitary–adrenal-axis and the induction of excessive grooming. Br. J. Pharmacol. 123, 1503–1508 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Welch, J. M. et al. Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature 448, 894–900 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Wan, Y., Feng, G. & Calakos, N. Sapap3 deletion causes mGluR5-dependent silencing of AMPAR synapses. J. Neurosci. 31, 16685–16691 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Xu, P. et al. Double deletion of melanocortin 4 receptors and SAPAP3 corrects compulsive behavior and obesity in mice. Proc. Natl Acad. Sci. USA 110, 10759–10764 (2013). This is the first study to show that constitutive and induced genetic deletion of MC4R normalizes compulsive grooming in SAPAP3-null mice, offering insights into the treatment of compulsive behavioural and eating disorders.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Kokare, D. M., Dandekar, M. P., Singru, P. S., Gupta, G. L. & Subhedar, N. K. Involvement of α-MSH in the social isolation induced anxiety- and depression-like behaviors in rat. Neuropharmacology 58, 1009–1018 (2010).

    Article  CAS  PubMed  Google Scholar 

  123. Gonzalez, M. I., Vaziri, S. & Wilson, C. A. Behavioral effects of α-MSH and MCH after central administration in the female rat. Peptides 17, 171–177 (1996).

    Article  CAS  PubMed  Google Scholar 

  124. Rao, T. L. et al. GABAergic agents prevent alpha-melanocyte stimulating hormone induced anxiety and anorexia in rats. Pharmacol. Biochem. Behav. 76, 417–423 (2003).

    Article  CAS  PubMed  Google Scholar 

  125. Hirani, K., Khisti, R. T. & Chopde, C. T. Behavioral action of ethanol in Porsolt's forced swim test: modulation by 3alpha-hydroxy-5alpha-pregnan-20-one. Neuropharmacology 43, 1339–1350 (2002).

    Article  CAS  PubMed  Google Scholar 

  126. Polidori, C., Geary, N. & Massi, M. Effect of the melanocortin receptor stimulation or inhibition on ethanol intake in alcohol-preferring rats. Peptides 27, 144–149 (2006).

    Article  CAS  PubMed  Google Scholar 

  127. Kokare, D. M., Singru, P. S., Dandekar, M. P., Chopde, C. T. & Subhedar, N. K. Involvement of alpha-melanocyte stimulating hormone (α-MSH) in differential ethanol exposure and withdrawal related depression in rat: neuroanatomical-behavioral correlates. Brain Res. 1216, 53–67 (2008).

    Article  CAS  PubMed  Google Scholar 

  128. Hadley, M. E. et al. Discovery and development of novel melanogenic drugs. Melanotan-I and -II. Pharm. Biotechnol. 11, 575–595 (1998).

    Article  CAS  PubMed  Google Scholar 

  129. Navarro, M., Cubero, I., Knapp, D. J. & Thiele, T. E. MTII-induced reduction of voluntary ethanol drinking is blocked by pretreatment with AgRP-(83–132). Neuropeptides 37, 338–344 (2003).

    Article  CAS  PubMed  Google Scholar 

  130. Lerma-Cabrera, J. M. et al. Adolescent binge-like ethanol exposure reduces basal α-MSH expression in the hypothalamus and the amygdala of adult rats. Pharmacol. Biochem. Behav. 110, 66–74 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Szekely, J. I. et al. Attenuation of morphine tolerance and dependence by α-melanocyte stimulating hormone (α-MSH). Life Sci. 24, 1931–1938 (1979).

    Article  CAS  PubMed  Google Scholar 

  132. Contreras, P. C. & Takemori, A. E. Antagonism of morphine-induced analgesia, tolerance and dependence by alpha-melanocyte-stimulating hormone. J. Pharmacol. Exp. Ther. 229, 21–26 (1984).

    CAS  PubMed  Google Scholar 

  133. Jacquet, Y. F. Opiate effects after adrenocorticotropin or β-endorphin injection in the periaqueductal gray matter of rats. Science 201, 1032–1034 (1978).

    Article  CAS  PubMed  Google Scholar 

  134. Starowicz, K., Obara, I., Przewlocki, R. & Przewlocka, B. Inhibition of morphine tolerance by spinal melanocortin receptor blockade. Pain 117, 401–411 (2005). This study suggests that antagonism of MC4R may be a possible new target in the search for strategies that prevent the development of opioid tolerance.

    Article  CAS  PubMed  Google Scholar 

  135. Niu, Z. et al. Melanocortin 4 receptor antagonists attenuates morphine antinociceptive tolerance, astroglial activation and cytokines expression in the spinal cord of rat. Neurosci. Lett. 529, 112–117 (2012).

    Article  CAS  PubMed  Google Scholar 

  136. Bronstein, D. M., Przewlocki, R. & Akil, H. Effects of morphine treatment on pro-opiomelanocortin systems in rat brain. Brain Res. 519, 102–111 (1990).

    Article  CAS  PubMed  Google Scholar 

  137. Kalange, A. S. et al. Central administration of selective melanocortin 4 receptor antagonist HS014 prevents morphine tolerance and withdrawal hyperalgesia. Brain Res. 1181, 10–20 (2007).

    Article  CAS  PubMed  Google Scholar 

  138. Hervieu, G. J. et al. The distribution of the mRNA and protein products of the melanin-concentrating hormone (MCH) receptor gene, slc-1, in the central nervous system of the rat. Eur. J. Neurosci. 12, 1194–1216 (2000).

    Article  CAS  PubMed  Google Scholar 

  139. Saito, Y. et al. Molecular characterization of the melanin-concentrating-hormone receptor. Nature 400, 265–269 (1999).

    Article  CAS  PubMed  Google Scholar 

  140. Bittencourt, J. C. et al. The melanin-concentrating hormone system of the rat brain: an immuno- and hybridization histochemical characterization. J. Comp. Neurol. 319, 218–245 (1992).

    Article  CAS  PubMed  Google Scholar 

  141. Chaki, S., Okubo, T. & Sekiguchi, Y. Non-monoamine-based approach for the treatment of depression and anxiety disorders. Recent Pat. CNS Drug Discov. 1, 1–27 (2006).

    Article  CAS  PubMed  Google Scholar 

  142. Borowsky, B. et al. Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist. Nature Med. 8, 825–830 (2002).

    Article  CAS  PubMed  Google Scholar 

  143. Chaki, S. et al. Anxiolytic- and antidepressant-like profile of ATC0065 and ATC0175: nonpeptidic and orally active melanin-concentrating hormone receptor 1 antagonists. J. Pharmacol. Exp. Ther. 313, 831–839 (2005).

    Article  CAS  PubMed  Google Scholar 

  144. Walker, J. M., Akil, H. & Watson, S. J. Evidence for homologous actions of pro-opiocortin products. Science 210, 1247–1249 (1980).

    Article  CAS  PubMed  Google Scholar 

  145. Sandman, C. A. & Kastin, A. J. Intraventricular administration of MSH induces hyperalgesia in rats. Peptides 2, 231–233 (1981).

    Article  CAS  PubMed  Google Scholar 

  146. Ohkubo, T., Shibata, M., Takahashi, H. & Naruse, S. Naloxone prevents the analgesic action of α-MSH in mice. Experientia 41, 627–628 (1985).

    Article  CAS  PubMed  Google Scholar 

  147. Vrinten, D. H., Kalkman, C. J., Adan, R. A. & Gispen, W. H. Neuropathic pain: a possible role for the melanocortin system? Eur. J. Pharmacol. 429, 61–69 (2001).

    Article  CAS  PubMed  Google Scholar 

  148. Liu, H. et al. Transgenic mice expressing green fluorescent protein under the control of the melanocortin-4 receptor promoter. J. Neurosci. 23, 7143–7154 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Mountjoy, K. G. & Wild, J. M. Melanocortin-4 receptor mRNA expression in the developing autonomic and central nervous systems. Brain Res. Dev. Brain Res. 107, 309–314 (1998).

    Article  CAS  PubMed  Google Scholar 

  150. Starowicz, K., Przewlocki, R., Gispen, W. H. & Przewlocka, B. Modulation of melanocortin-induced changes in spinal nociception by μ-opioid receptor agonist and antagonist in neuropathic rats. Neuroreport 13, 2447–2452 (2002).

    Article  CAS  PubMed  Google Scholar 

  151. Beltramo, M. et al. Gene expression profiling of melanocortin system in neuropathic rats supports a role in nociception. Brain Res. Mol. Brain Res. 118, 111–118 (2003).

    Article  CAS  PubMed  Google Scholar 

  152. Mountjoy, K. G. The human melanocyte stimulating hormone receptor has evolved to become “super-sensitive” to melanocortin peptides. Mol. Cell. Endocrinol. 102, R7–R11 (1994).

    Article  CAS  PubMed  Google Scholar 

  153. Gautron, L., Lee, C. E., Lee, S. & Elmquist, J. K. Melanocortin-4 receptor expression in different classes of spinal and vagal primary afferent neurons in the mouse. J. Comp. Neurol. 520, 3933–3948 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Starowicz, K., Bilecki, W., Sieja, A., Przewlocka, B. & Przewlocki, R. MC4R is expressed in the dorsal root ganglions and down-regulated in neuropathic rats. Neurosci. Lett. 358, 79–82 (2004).

    Article  CAS  PubMed  Google Scholar 

  155. Chu, H., Sun, J., Xu, H., Niu, Z. & Xu, M. Effect of periaqueductal gray melanocortin 4 receptor in pain facilitation and glial activation in rat model of chronic constriction injury. Neurol. Res. 34, 871–888 (2012).

    Article  CAS  PubMed  Google Scholar 

  156. Vrinten, D. H., Gispen, W. H., Kalkman, C. J. & Adan, R. A. Interaction between the spinal melanocortin and opioid systems in a rat model of neuropathic pain. Anesthesiology 99, 449–454 (2003).

    Article  CAS  PubMed  Google Scholar 

  157. Starowicz, K. et al. Peripheral antinociceptive effects of MC4R antagonists in a rat model of neuropathic pain — a biochemical and behavioral study. Pharmacol. Rep. 61, 1086–1095 (2009).

    Article  CAS  PubMed  Google Scholar 

  158. Vrinten, D. H., Gispen, W. H., Groen, G. J. & Adan, R. A. Antagonism of the melanocortin system reduces cold and mechanical allodynia in mononeuropathic rats. J. Neurosci. 20, 8131–8137 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Chu, H., Xia, J., Yang, Z. & Gao, J. Melanocortin 4 receptor induces hyperalgesia and allodynia after chronic constriction injury by activation of p38 MAPK in DRG. Int. J. Neurosci. 122, 74–81 (2012). This study suggests a sequential role for MC4R that seems to depend on p38 MAPK activation in the induction and maintenance of neuropathic pain.

    Article  CAS  PubMed  Google Scholar 

  160. Bellasio, S., Nicolussi, E., Bertorelli, R. & Reggiani, A. Melanocortin receptor agonists and antagonists modulate nociceptive sensitivity in the mouse formalin test. Eur. J. Pharmacol. 482, 127–132 (2003).

    Article  CAS  PubMed  Google Scholar 

  161. Matthes, H. W. et al. Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the μ-opioid-receptor gene. Nature 383, 819–823 (1996).

    Article  CAS  PubMed  Google Scholar 

  162. Arvidsson, U. et al. Distribution and targeting of a μ-opioid receptor (MOR1) in brain and spinal cord. J. Neurosci. 15, 3328–3341 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Kalyuzhny, A. E., Arvidsson, U., Wu, W. & Wessendorf, M. W. μ-Opioid and δ-opioid receptors are expressed in brainstem antinociceptive circuits: studies using immunocytochemistry and retrograde tract-tracing. J. Neurosci. 16, 6490–6503 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Alsio, J. et al. Enhanced sucrose and cocaine self-administration and cue-induced drug seeking after loss of VGLUT2 in midbrain dopamine neurons in mice. J. Neurosci. 31, 12593–12603 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. McHugh, T. J. et al. Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network. Science 317, 94–99 (2007).

    Article  CAS  PubMed  Google Scholar 

  166. Aponte, Y., Atasoy, D. & Sternson, S. M. AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nature Neurosci. 14, 351–355 (2011).

    Article  CAS  PubMed  Google Scholar 

  167. Xu, A. W. et al. PI3K integrates the action of insulin and leptin on hypothalamic neurons. J. Clin. Invest. 115, 951–958 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Begriche, K., Girardet, C., McDonald, P. & Butler, A. A. Melanocortin-3 receptors and metabolic homeostasis. Prog. Mol. Biol. Transl. Sci. 114, 109–146 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Zhang, F. et al. Optogenetic interrogation of neural circuits: technology for probing mammalian brain structures. Nature Protoc. 5, 439–456 (2010).

    Article  CAS  Google Scholar 

  170. Sohn, J. W. et al. Melanocortin 4 receptors reciprocally regulate sympathetic and parasympathetic preganglionic neurons. Cell 152, 612–619 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Lee, Y. S. et al. Design and synthesis of trivalent ligands targeting opioid, cholecystokinin, and melanocortin receptors for the treatment of pain. Bioorg. Med. Chem. Lett. 20, 4080–4084 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Leone, S., Noera, G. & Bertolini, A. Melanocortins as innovative drugs for ischemic diseases and neurodegenerative disorders: established data and perspectives. Curr. Med. Chem. 20, 735–750 (2013).

    CAS  PubMed  Google Scholar 

  173. Spaccapelo, L. et al. Up-regulation of the canonical Wnt-3A and Sonic hedgehog signaling underlies melanocortin-induced neurogenesis after cerebral ischemia. Eur. J. Pharmacol. 707, 78–86 (2013).

    Article  CAS  PubMed  Google Scholar 

  174. Arnason, B. G., Berkovich, R., Catania, A., Lisak, R. P. & Zaidi, M. Mechanisms of action of adrenocorticotropic hormone and other melanocortins relevant to the clinical management of patients with multiple sclerosis. Mult. Scler. 19, 130–136 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Kuo, J. J., da Silva, A. A., Tallam, L. S. & Hall, J. E. Role of adrenergic activity in pressor responses to chronic melanocortin receptor activation. Hypertension 43, 370–375 (2004).

    Article  CAS  PubMed  Google Scholar 

  176. Kievit, P. et al. Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques. Diabetes 62, 490–497 (2013). This study demonstrates, for the first time, that highly selective melanocortin peptide drugs can be used for the treatment of weight loss.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Rask-Andersen, M., Masuram, S. & Schioth, H. B. The druggable genome: evaluation of drug targetsin clinical trials suggests major shifts in molecular class and indication. Annu. Rev. Pharmacol. Toxicol. 54, 9–26 (2014).

    Article  CAS  PubMed  Google Scholar 

  178. Grove, K. L. & Smith, M. S. Ontogeny of the hypothalamic neuropeptide Y system. Physiol. Behav. 79, 47–63 (2003).

    Article  CAS  PubMed  Google Scholar 

  179. Sebag, J. A., Zhang, C., Hinkle, P. M., Bradshaw, A. M. & Cone, R. D. Developmental control of the melanocortin-4 receptor by MRAP2 proteins in zebrafish. Science 341, 278–281 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Morris, M. J. Early life influences on obesity risk: maternal overnutrition and programming of obesity. Expert Rev. Endocrinol. Metab. 4, 625–637 (2009). This review provides a clear and comprehensive picture of the involvement of the intra-uterine environment in neurocircuit development.

    Article  PubMed  Google Scholar 

  181. Mcmillen, I. C. & Robinson, J. S. Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. Physiol. Rev. 85, 571–633 (2005).

    Article  CAS  PubMed  Google Scholar 

  182. Poston, L. Developmental programming and diabetes — the human experience and insight from animal models. Best Pract. Res. Clin. Endocrinol. Metab. 24, 541–552 (2010).

    Article  PubMed  Google Scholar 

  183. Gluckman, P. D., Hanson, M. A., Spencer, H. G. & Bateson, P. Environmental influences during development and their later consequences for health and disease: implications for the interpretation of empirical studies. Proc. R. Soc. B 272, 671–677 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  184. Lucas, A. Programming by early nutrition in man. Ciba Found Symp. 156, 38–50 (1991).

    CAS  PubMed  Google Scholar 

  185. Barker, D. J. P., Bull, A. R., Osmond, C. & Simmonds, S. J. Fetal and placental size and risk of hypertension in adult life. Int. J. Gynecol. Obstetr. 35, 97–98 (1991).

    Article  Google Scholar 

  186. Grove, K. L., Grayson, B. E., Glavas, M. M., Xiao, X. Q. & Smith, M. S. Development of metabolic systems. Physiol. Behav. 86, 646–660 (2005).

    Article  CAS  PubMed  Google Scholar 

  187. Gluckman, P. D. & Hanson, M. A. Developmental and epigenetic pathways to obesity: an evolutionary-developmental perspective. Int. J. Obes. 32 (Suppl. 7), 62–71 (2005).

    Google Scholar 

  188. Dobbing, J. & Sands, J. Comparative aspects of the brain growth spurt. Early Hum. Dev. 3, 79–83 (1979).

    Article  CAS  PubMed  Google Scholar 

  189. Grayson, B. E. et al. Prenatal development of hypothalamic neuropeptide systems in the nonhuman primate. Neuroscience 143, 975–986 (2006).

    Article  CAS  PubMed  Google Scholar 

  190. Catania, A. et al. The neuropeptide α-MSH has specific receptors on neutrophils and reduces chemotaxis in vitro. Peptides 17, 675–679 (1996).

    Article  CAS  PubMed  Google Scholar 

  191. Bhardwaj, R. et al. Evidence for the differential expression of the functional α-melanocyte-stimulating hormone receptor MC-1 on human monocytes. J. Immunol. 158, 3378–3384 (1997).

    CAS  PubMed  Google Scholar 

  192. Xia, Y., Wikberg, J. E. & Chhajlani, V. Expression of melanocortin 1 receptor in periaqueductal gray matter. Neuroreport 6, 2193–2196 (1995).

    Article  CAS  PubMed  Google Scholar 

  193. Catania, A., Gatti, S., Colombo, G. & Lipton, J. M. Targeting melanocortin receptors as a novel strategy to control inflammation. Pharmacol. Rev. 56, 1–29 (2004).

    Article  CAS  PubMed  Google Scholar 

  194. Isales, C. M., Zaidi, M. & Blair, H. C. ACTH is a novel regulator of bone mass. Ann. NY Acad. Sci. 1192, 110–116 (2010).

    Article  CAS  PubMed  Google Scholar 

  195. Zaidi, M. et al. ACTH protects against glucocorticoid-induced osteonecrosis of bone. Proc. Natl Acad. Sci. USA 107, 8782–8787 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  196. Pan, X. C., Song, Y. T., Liu, C., Xiang, H. B. & Lu, C. J. Melanocortin-4 receptor expression in the rostral ventromedial medulla involved in modulation of nociception in transgenic mice. J. Huazhong Univ. Sci. Technolog. Med. Sci. 33, 195–198 (2013).

    Article  CAS  PubMed  Google Scholar 

  197. Kistler-Heer, V., Lauber, M. E. & Lichtensteiger, W. Different developmental patterns of melanocortin MC3 and MC4 receptor mRNA: predominance of Mc4 in fetal rat nervous system. J. Neuroendocrinol. 10, 133–146 (1998).

    Article  CAS  PubMed  Google Scholar 

  198. Padilla, S. L., Reef, D. & Zeltser, L. M. Defining POMC neurons using transgenic reagents: impact of transient Pomc expression in diverse immature neuronal populations. Endocrinology 153, 1219–1231 (2012).

    Article  CAS  PubMed  Google Scholar 

  199. Van der Kraan, M. et al. Expression of melanocortin receptors and pro-opiomelanocortin in the rat spinal cord in relation to neurotrophic effects of melanocortins. Mol. Brain Res. 63, 276–286 (1999).

    Article  CAS  PubMed  Google Scholar 

  200. Overstreet, L. S. et al. A transgenic marker for newly born granule cells in dentate gyrus. J. Neurosci. 24, 3251–3259 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Okamoto, K., Nagai, T., Miyawaki, A. & Hayashi, Y. Rapid and persistent modulation of actin dynamics regulates postsynaptic reorganization underlying bidirectional plasticity. Nature Neurosci. 7, 1104–1112 (2004).

    Article  CAS  PubMed  Google Scholar 

  202. Zuo, Y., Lin, A., Chang, P. & Gan, W. B. Development of long-term dendritic spine stability in diverse regions of cerebral cortex. Neuron 46, 181–189 (2005).

    Article  CAS  PubMed  Google Scholar 

  203. Boudreau, A. C., Reimers, J. M., Milovanovic, M. & Wolf, M. E. Cell surface AMPA receptors in the rat nucleus accumbens increase during cocaine withdrawal but internalize after cocaine challenge in association with altered activation of mitogen-activated protein kinases. J. Neurosci. 27, 10621–10635 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Waltereit, R. & Weller, M. Signaling from cAMP/PKA to MAPK and synaptic plasticity. Mol. Neurobiol. 27, 99–106 (2003).

    Article  CAS  PubMed  Google Scholar 

  205. Kang, H. et al. An important role of neural activity-dependent CaMKIV signaling in the consolidation of long-term memory. Cell 106, 771–783 (2001).

    Article  CAS  PubMed  Google Scholar 

  206. Zhou, Q., Homma, K. J. & Poo, M. M. Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses. Neuron 44, 749–757 (2004).

    Article  CAS  PubMed  Google Scholar 

  207. Gloerich, M. & Bos, J. L. Epac: defining a new mechanism for cAMP action. Annu. Rev. Pharmacol. Toxicol. 50, 355–375 (2010).

    Article  CAS  PubMed  Google Scholar 

  208. Schiöth, H. B. et al. Evolutionary conservation of the structural, pharmacological, and genomic characteristics of the melanocortin receptor subtypes. Peptides 26, 1886–1900 (2005).

    Article  CAS  PubMed  Google Scholar 

  209. Mountjoy, K. G., Robbins, L. S., Mortrud, M. T. & Cone, R. D. The cloning of a family of genes that encode melanocortin receptors. Science 257, 1248–1251 (1992).

    Article  CAS  PubMed  Google Scholar 

  210. Valsalan, R., Krishnan, A., Almén, M. S., Fredriksson, R. & Schiöth, H. B. Early vertebrate origin of melanocortin 2 receptor accessory proteins (MRAPs). Gen. Comp. Endocrinol. 188, 123–132 (2013).

    Article  CAS  PubMed  Google Scholar 

  211. Klovins, J. et al. The melanocortin system in Fugu: determination of POMC/AGRP/MCR gene repertoire and synteny, as well as pharmacology and anatomical distribution of the MCRs. Mol. Biol. Evol. 21, 563–579 (2004).

    Article  CAS  PubMed  Google Scholar 

  212. Schiöth, H. B. et al. Functional role, structure, and evolution of the melanocortin-4 receptor. Ann. NY Acad. Sci. 994, 74–83 (2003).

    Article  PubMed  Google Scholar 

  213. Kay, E. I., Botha, R., Montgomery, J. M. & Mountjoy, K. G. hMRAPa increases αMSH-induced hMC1R and hMC3R functional coupling and hMC4R constitutive activity. J. Mol. Endocrinol. 50, 203–215 (2013).

    Article  CAS  PubMed  Google Scholar 

  214. Kay, E. I., Botha, R., Montgomery, J. M. & Mountjoy, K. G. hMRAPa specifically alters hMC4R molecular mass and N-linked complex glycosylation in HEK293 cells. J. Mol. Endocrinol. 50, 217–227 (2013).

    Article  CAS  PubMed  Google Scholar 

  215. Mountjoy, K. G., Jenny Wu, C. S., Dumont, L. M. & Wild, J. M. Melanocortin-4 receptor messenger ribonucleic acid expression in rat cardiorespiratory, musculoskeletal, and integumentary systems. Endocrinology 144, 5488–5496 (2003).

    Article  CAS  PubMed  Google Scholar 

  216. Mountjoy, K. G., Wu, C. S., Cornish, J. & Callon, K. E. α-MSH and desacetyl-α-MSH signaling through melanocortin receptors. Ann. NY Acad. Sci. 994, 58–65 (2003).

    Article  CAS  PubMed  Google Scholar 

  217. Tanabe, K., Gamo, K., Aoki, S., Wada, K. & Kiyama, H. MC4R is induced in nerve-injured motor and sensory neurons of mouse. J. Neurochem. 101, 1145–1152 (2007).

    Article  CAS  PubMed  Google Scholar 

  218. Sawyer, T. K. et al. 4-Norleucine, 7-D-phenylalanine-α-melanocyte-stimulating hormone: a highly potent α-melanotropin with ultralong biological activity. Proc. Natl Acad. Sci. USA 77, 5754–5758 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Dorr, R. T. et al. Evaluation of Melanotan-II, a superpotent cyclic melanotropic peptide in a pilot phase-I clinical study. Life Sci. 58, 1777–1784 (1996).

    Article  CAS  PubMed  Google Scholar 

  220. Abou-Mohamed, G. et al. HP-228, a novel synthetic peptide, inhibits the induction of nitric oxide synthase in vivo but not in vitro. J. Pharmacol. Exp. Ther. 275, 584–591 (1995).

    CAS  PubMed  Google Scholar 

  221. Wikberg, J. E. S. Melanocortin receptors: perspectives for novel drugs. Eur. J. Pharmacol. 375, 295–310 (1999).

    Article  CAS  PubMed  Google Scholar 

  222. Hruby, V. J. et al. Cyclic lactam α-melanotropin analogues of Ac-Nle4-cyclo[Asp5, D-Phe7,Lys10] α-melanocyte-stimulating hormone-(4-10)-NH2 with bulky aromatic amino acids at position 7 show high antagonist potency and selectivity at specific melanocortin receptors. J. Med. Chem. 38, 3454–3461 (1995).

    Article  CAS  PubMed  Google Scholar 

  223. Schioth, H. B. et al. Further pharmacological characterization of the selective melanocortin 4 receptor antagonist HS014: comparison with SHU9119. Neuropeptides 33, 191–196 (1999).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Swedish Research Council, and the Novo Nordisk, the Åhlén and the Swedish Brain Research Foundations.

Author information

Authors and Affiliations

  1. Department of Neuroscience, Functional Pharmacology, Uppsala University, Husargatan 3, Uppsala, 75124, Sweden

    Vanni Caruso, Pawel K. Olszewski, Robert Fredriksson & Helgi B. Schiöth

  2. Department of Neuroscience, Developmental Genetics, Uppsala University, Husargatan 3, Uppsala, 75124, Sweden

    Malin C. Lagerström

  3. Department of Biological Sciences, University of Waikato, Gate 8 Hillcrest Road, Hamilton, 3240, New Zealand

    Pawel K. Olszewski

Authors
  1. Vanni Caruso
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Malin C. Lagerström
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pawel K. Olszewski
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert Fredriksson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Helgi B. Schiöth
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Helgi B. Schiöth.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Hyperalgesia

An increased or exaggerated response to a painful stimulus.

Energy homeostasis

The ability to regulate energy intake and expenditure to maintain the functioning of the organism in the ever-changing internal and external environment.

Anhedonia

A mental condition that is characterized by the absence of pleasure in response to typically rewarding and/or enjoyable activities and stimuli.

Synaptic plasticity

A key cellular response to intrinsic or extrinsic signals at a neural synapse. It consists of persistent or transient changes in morphology or signal transduction efficiency, which strengthens or weakens synapses.

Instrumental conditioning

A type of learning process in which reinforcement or punishment are used to either increase or decrease, respectively, the probability that a behaviour will occur again in the future.

Procedural learning

A type of long-term memory that is involved in both cognitive and motor skills in which the repetition of actions is automatically used for the execution of integrated tasks.

Porsolt forced swim test

A behavioural despair test that consists of two trials during which laboratory animals are forced to swim in a cylinder filled with water and from which they cannot escape. The immobility time induced by antidepressant drugs is measured as an index of positive behavioural adaptation.

Allodynia

An abnormal painful response to a normally innocuous stimulus.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Caruso, V., Lagerström, M., Olszewski, P. et al. Synaptic changes induced by melanocortin signalling. Nat Rev Neurosci 15, 98–110 (2014). https://doi.org/10.1038/nrn3657

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn3657

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing