An exploration of the aversive properties of 2-deoxy-D-glucose in rats

Abstract

Hypoglycemia can alter arousal and negatively impact mood. This study tests the hypothesis that acute drops in glucose metabolism cause an aversive state mediated by monoamine activity. In experiment 1, male Sprague-Dawley rats were either food deprived (FD) or pre-fed (PF) and tested on conditioned place avoidance (CPA; biased place conditioning design; 3 pairings drug/vehicle, each 30 min-long) induced by the glucose antimetabolite 2-deoxy-d-glucose (2-DG; 0, 300 or 500 mg/kg, SC). Locomotion and blood glucose were also assessed. Experiment 2 examined whether clonidine (noradrenergic α2 agonist, 0, 10 or 40 μg/kg, SC) or bupropion (monoamine reuptake blocker, 0, 10 or 30 mg/kg, SC) could alter CPA induced by 500 mg/kg 2-DG. In experiment 3, blood corticosterone (CORT) was measured in response to 500 mg/kg 2-DG, alone or in combination with 40 μg/kg clonidine or 30 mg/kg bupropion. Finally, experiment 4 controlled for possible place conditioning induced by 10 or 40 μg/kg clonidine, or 10 or 30 mg/kg bupropion injected without 2-DG. It was found that 2-DG increased blood glucose and produced a robust CPA. The feeding status of the animals modulated these effects, including CORT levels. Both clonidine and bupropion attenuated the effects of 2-DG on CPA and CORT, but only bupropion reversed suppression of locomotion. Taken together, these results in rats suggest that impaired glucose metabolism can negatively impact arousal and mood via effects on HPA and monoamine systems.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. Betley JN, Xu S, Cao ZFH, Gong R, Magnus CJ, Yu Y, Sternson SM (2015) Neurons for hunger and thirst transmit a negative-valence teaching signal. Nature 521:180–185

    CAS  Article  PubMed Central  Google Scholar 

  2. Booth DA (1972) Modulation of the feeding response to peripheral insulin, 2-deoxyglucose or 3-O-methyl glucose injection. Physiol Behav 8:1069–1076

    CAS  Article  PubMed Central  Google Scholar 

  3. Breier A, Crane AM, Kennedy C, Sokoloff L (1993) The effects of pharmacologic doses of 2-deoxy-d-glucose on local cerebral blood flow in the awake, unrestrained rat. Brain Res 618:277–282

    CAS  Article  PubMed Central  Google Scholar 

  4. Bromberg-Martin ES, Matsumoto M, Hikosaka O (2010) Dopamine in motivational control: rewarding, aversive, and alerting. Neuron 68:815–834

    CAS  Article  PubMed Central  Google Scholar 

  5. Budzynska B, Biaa G (2011) Effects of bupropion on the reinstatement of nicotine-induced conditioned place preference by drug priming in rats. Pharmacol Rep 63:362–371

    CAS  Article  PubMed Central  Google Scholar 

  6. Daniels S, Marshall P, Leri F (2016) Alterations of naltrexone-induced conditioned place avoidance by pre-exposure to high fructose corn syrup or heroin in Sprague–Dawley rats. Psychopharmacology 233:425–433

    CAS  Article  PubMed Central  Google Scholar 

  7. Dean Z, Horndasch S, Giannopoulos P, McCabe C (2016) Enhanced neural response to anticipation, effort and consummation of reward and aversion during bupropion treatment. Psychol Med 46:2263–2274

    CAS  Article  PubMed Central  Google Scholar 

  8. Delprete E, Scharrer E (1992) Effects of 2-deoxy-d-glucose on food intake of rats are affected by diet composition. Physiol Behav 51:951–956

    CAS  Article  PubMed Central  Google Scholar 

  9. Dietz D, Wang H, Kabbaj M (2007) Corticosterone fails to produce conditioned place preference or conditioned place aversion in rats. Behav Brain Res 181:287–291

    CAS  Article  PubMed Central  Google Scholar 

  10. Domingos AI, Vaynshteyn J, Voss HU, Ren X, Gradinaru V, Zang F, Deisseroth K, de Araujo IE, Friedman J (2011) Leptin regulates the reward value of nutrient. Nat Neurosci 14:1562–1568

    CAS  Article  PubMed Central  Google Scholar 

  11. Edmonds BK, Edwards GL (1998) Dorsomedial hindbrain participation in glucoprivic feeding response to 2DG but not 2DG-induced hyperglycemia or activation of the HPA axis. Brain Res 801:21–28

    CAS  Article  PubMed Central  Google Scholar 

  12. Engberg G, Eriksson E (1991) Effects of alpha 2-adrenoceptor agonists on locus coeruleus firing rate and brain noradrenaline turnover in N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ)-treated rats. Naunyn Schmiedeberg's Arch Pharmacol 343:472–477

    CAS  Article  Google Scholar 

  13. Farooqui AA, Farooqui T (2012) Metabolic syndrome as a risk factor for neurological disorders. Cell Mol Life Sci 69:741–762

    CAS  Article  PubMed Central  Google Scholar 

  14. Ferrario CR, Labouebe G, Liu S et al (2016) Homeostasis meets motivation in the battle to control food intake. J Neurosci 36:11469–11481

    CAS  Article  PubMed Central  Google Scholar 

  15. Fortin SM, Chartoff EH, Roitman MF (2016) The aversive agent Lithium chloride suppresses phasic dopamine release through central GLP-1 receptors. Neuropsychopharmacology 41:906–915

    CAS  Article  PubMed Central  Google Scholar 

  16. Gheshlagh RG, Parizad N, Sayehmiri K (2016) The relationship between depression and metabolic syndrome: systematic review and meta-analysis study. Iran Red Crescent Med J 18:e26523

    Google Scholar 

  17. Gold AE, MacLeod KM, Frier BM, Deary IJ (1995) Changes in mood during acute hypoglycemia in healthy participants. J Pers Soc Psychol 68:498–504

    CAS  Article  PubMed Central  Google Scholar 

  18. Guiard BP, El Mansari M, Blier P (2008) Cross-talk between dopaminergic and noradrenergic systems in the rat ventral tegmental area, locus ceruleus, and dorsal hippocampus. Mol Pharmacol 74:1463–1475

    CAS  Article  PubMed Central  Google Scholar 

  19. Heiskanen TH, Niskanen LK, Hintikka JJ, Koivumaa-Honkanen HT, Honkalampi KM, Haatainen KM, Viinamäki HT (2006) Metabolic syndrome and depression: a cross-sectional analysis. J Clin Psychiatry 67:1422–1427

    Article  PubMed Central  Google Scholar 

  20. Herman JP (2011) Central nervous system regulation of the hypothalamic-pituitary-adrenal axis stress response. In: The handbook of stress. Wiley-Blackwell: Oxford, pp 29–46

    Google Scholar 

  21. 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 51:801–810

    CAS  Article  PubMed Central  Google Scholar 

  22. Iguchi A, Gotoh M, Matsunaga H et al (1990) Neither adrenergic nor cholinergic antagonists in the central nervous system affect 2-deoxy-D-glucose (2-DG)-induced hyperglycemia. Brain Res 510:321–325

    CAS  Article  PubMed Central  Google Scholar 

  23. Isingrini E, Perret L, Rainer Q, Amilhon B, Guma E, Tanti A, Martin G, Robinson J, Moquin L, Marti F, Mechawar N, Williams S, Gratton A, Giros B (2016) Resilience to chronic stress is mediated by noradrenergic regulation of dopamine neurons. Nat Neurosci 19:560–563

    CAS  Article  PubMed Central  Google Scholar 

  24. Kamibayashi T, Maze M (2000) Clinical uses of alpha2 -adrenergic agonists. Anesthesiology 93:1345–1349

    CAS  Article  PubMed Central  Google Scholar 

  25. Krashes MJ, Koda S, Ye C, Rogan SC, Adams AC, Cusher DS, Maratos-Flier E, Roth BL, Lowell BB (2011) Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J Clin Invest 121:1424–1428

    CAS  Article  PubMed Central  Google Scholar 

  26. Lutter M, Sakata I, Osborne-Lawrence S, Rovinsky SA, Anderson JG, Jung S, Birnbaum S, Yanagisawa M, Elmquist JK, Nestler EJ, Zigman JM (2008) The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress. Nat Neurosci 11:752–753

    CAS  Article  PubMed Central  Google Scholar 

  27. Marin-Spiotta A, Levin BE, Tkacs NC (2004) A single episode of central glucoprivation reduces the adrenomedullary response to subsequent hypoglycemia in rats. Neurosci Lett 360:81–84

    CAS  Article  PubMed Central  Google Scholar 

  28. Marty N, Dallaporta M, Thorens B (2007) Brain glucose sensing, counterregulation, and energy homeostasis. Physiology (Bethesda) 22:241–251

    CAS  Google Scholar 

  29. Matsunaga H, Iguchi A, Yatomi A et al (1989) The relative importance of nervous system and hormones to the 2-deoxy-D-glucose-induced hyperglycemia in fed rats. Endocrinology 124:1259–1264

    CAS  Article  PubMed Central  Google Scholar 

  30. McDannald MA, Galarce EM (2011) Measuring Pavlovian fear with conditioned freezing and conditioned suppression reveals different roles for the basolateral amygdala. Brain Res 1374:82–89

    CAS  Article  PubMed Central  Google Scholar 

  31. Messier C (2004) Glucose improvement of memory: a review. Eur J Pharmacol 490:33–57

    CAS  Article  PubMed Central  Google Scholar 

  32. O’Doherty JP (2004) Reward representations and reward-related learning in the human brain: insights from neuroimaging. Curr Opin Neurobiol 14:769–776

    Article  PubMed Central  Google Scholar 

  33. Ortmann R (1985) The conditioned place preference paradigm in rats: effect of bupropion. Life Sci 37:2021–2027

    CAS  Article  PubMed Central  Google Scholar 

  34. Park MJ, Guest CB, Barnes MB, Martin J, Ahmad U, York JM, Freund GG (2008) Blocking of beta-2 adrenergic receptors hastens recovery from hypoglycemia-associated social withdrawal. Psychoneuroendocrinology 33:1411–1418

    CAS  Article  PubMed Central  Google Scholar 

  35. Park MJ, Yoo SW, Choe BS, Dantzer R, Freund GG (2012) Acute hypoglycemia causes depressive-like behaviors in mice. Metabolism 61:229–236

    CAS  Article  PubMed Central  Google Scholar 

  36. Piacentini MF, Clinckers R, Meeusen R, Sarre S, Ebinger G, Michotte Y (2003) Effect of bupropion on hippocampal neurotransmitters and on peripheral hormonal concentrations in the rat. J Appl Physiol 95:652–656. https://doi.org/10.1152/japplphysiol.01058.2002

    CAS  Article  PubMed  Google Scholar 

  37. Rauhut AS, Hawrylak M, Mardekian SK (2008) Bupropion differentially alters the aversive, locomotor and rewarding properties of nicotine in CD-1 mice. Pharmacol Biochem Behav 90:598–607

    CAS  Article  PubMed Central  Google Scholar 

  38. Ritter S, Watts AG, Dinh TT, Sanchez-Watts G, Pedrow C (2003) Immunotoxin lesion of hypothalamically projecting norepinephrine and epinephrine neurons differentially affects circadian and stressor-stimulated corticosterone secretion. Endocrinology 144:1357–1367

    CAS  Article  PubMed Central  Google Scholar 

  39. Ritter S, Dinh TT, Li A-J (2006) Hindbrain catecholamine neurons control multiple glucoregulatory responses. Physiol Behav 89:490–500

    CAS  Article  PubMed Central  Google Scholar 

  40. Ritter S, Li AJ, Wang Q, Dinh TT (2011) Minireview: the value of looking backward: the essential role of the hindbrain in counterregulatory responses to glucose deficit. Endocrinology 152:4019–4032

    CAS  Article  PubMed Central  Google Scholar 

  41. Scheurink A, Ritter S (1993) Sympathoadrenal responses to glucoprivation and lipoprivation in rats. Physiol Behav 53:995–1000

    CAS  Article  PubMed Central  Google Scholar 

  42. Smith GP, Epstein AN (1969) Increased feeding in response to decreased glucose utilization in the rat and monkey. Am J Phys 217:1083–1087

    CAS  Google Scholar 

  43. Solecki WB, Szklarczyk K, Pradel K et al (2017) Alpha 1-adrenergic receptor blockade in the VTA modulates fear memories and stress responses. Eur Neuropsychopharmacol 27:782–794

    CAS  Article  PubMed Central  Google Scholar 

  44. Stephan FK, Smith JC, Fisher E (1999) Profound conditioned taste aversion induced by oral consumption of 2-deoxy-D-glucose. Physiol Behav 68:221–226

    CAS  Article  PubMed Central  Google Scholar 

  45. Strekalova T, Spanagel R, Bartsch D, Henn FA, Gass P (2004) Stress-induced anhedonia in mice is associated with deficits in forced swimming and exploration. Neuropsychopharmacology 29:2007–2017

    Article  PubMed Central  Google Scholar 

  46. Takahashi A, Ishimaru H, Ikarashi Y, Kishi E, Maruyama Y (1997) Hypothalamic cholinergic activity and 2-deoxyglucose-induced hyperglycemia. Brain Res Bull 43:65–68.

    CAS  Article  PubMed Central  Google Scholar 

  47. Tan KR, Yvon C, Turiault M, Mirzabekov JJ, Doehner J, Labouèbe G, Deisseroth K, Tye KM, Lüscher C (2012) GABA neurons of the VTA drive conditioned place aversion. Neuron 73:1173–1183

    CAS  Article  PubMed Central  Google Scholar 

  48. Treit D, Fundytus M (1988) Thigmotaxis as a test for anxiolytic activity in rats. Pharmacol Biochem Behav 31:959–962

    CAS  Article  PubMed Central  Google Scholar 

  49. Vreeburg S, Hoogendijk W, van Pelt J, DeRijk R (2013) Major depressive disorder and hypothalamic-pituitary-adrenal axis activity. Arch Gen Psychiatry 66:617–626

    Article  Google Scholar 

  50. Xirouchaki CE, Mangiafico SP, Bate K, Ruan Z, Huang AM, Tedjosiswoyo BW, Lamont B, Pong W, Favaloro J, Blair AR, Zajac JD, Proietto J, Andrikopoulos S (2016) Impaired glucose metabolism and exercise capacity with muscle-specific glycogen synthase 1 (gys1) deletion in adult mice. Mol Metab 5:221–232

    CAS  Article  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was part of the Canadian Biomarker Integration Network in Depression (CAN-BIND) program (www.canbind.ca). CAN-BIND is an Integrated Discovery Program carried out in partnership with, and financial support from, the Ontario Brain Institute, an independent non-profit corporation, funded partially by the Ontario government. The opinions, results, and conclusions are those of the authors, and no endorsement by the Ontario Brain Institute is intended or should be inferred.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Francesco Leri.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Horman, T., Fernandes, M.F., Zhou, Y. et al. An exploration of the aversive properties of 2-deoxy-D-glucose in rats. Psychopharmacology 235, 3055–3063 (2018). https://doi.org/10.1007/s00213-018-4998-1

Download citation

Keywords

  • Place avoidance
  • 2-Deoxy-d-glucose
  • Corticosterone
  • Blood glucose
  • Clonidine
  • Bupropion