, Volume 231, Issue 23, pp 4553–4560 | Cite as

The activation of the Akt/PKB signalling pathway in the brains of clozapine-exposed rats is linked to hyperinsulinemia and not a direct drug effect

  • G. C. Smith
  • H. McEwen
  • J. D. Steinberg
  • P. R. Shepherd
Original Investigation


The second generation antipsychotic drug clozapine is a much more effective therapy for schizophrenia than first generation compounds, but the reasons for this are poorly understood. We have previously shown that one distinguishing feature of clozapine is its ability to raise glucagon levels in animal models and thus causes prolonged hyperinsulinemia without inducing hypoglycaemia. Previous studies have provided evidence that defects in Akt/PKB and GSK3 signalling can contribute to development of psychiatric diseases. Clozapine is known to activate Akt/PKB in the brain, and some studies have indicated that this is due to a direct effect of the drug on the neurons. However, we provide strong evidence that elevated insulin levels induced by clozapine are in fact the real cause of the drug’s effects on Akt/PKB and GSK3 in the brain. This suggests that the elevated levels of insulin induced by clozapine may contribute to this drug’s therapeutic efficacy.


Clozapine Brain Akt/PKB GSK3 Insulin Hippocampus 


  1. Adamo M, Raizada MK, LeRoith D (1989) Insulin and insulin-like growth factor receptors in the nervous system. Mol Neurobiol 3:71–100PubMedCrossRefGoogle Scholar
  2. Alimohamad H, Rajakumar N, Seah YH, Rushlow W (2005a) Antipsychotics alter the protein expression levels of beta-catenin and GSK-3 in the rat medial prefrontal cortex and striatum. Biol Psychiatry 57:533–542PubMedCrossRefGoogle Scholar
  3. Alimohamad H, Sutton L, Mouyal J, Rajakumar N, Rushlow WJ (2005b) The effects of antipsychotics on beta-catenin, glycogen synthase kinase-3 and dishevelled in the ventral midbrain of rats. J Neurochem 95:513–525PubMedCrossRefGoogle Scholar
  4. Banks WA, Owen JB, Erickson MA (2012) Insulin in the brain: there and back again. Pharmacol Ther 136:82–93PubMedCentralPubMedCrossRefGoogle Scholar
  5. Basta-Kaim A, Budziszewska B, Jaworska-Feil L, Tetich M, Kubera M, Leśkiewicz M, Otczyk M, Lasoń W (2006) Antipsychotic drugs inhibit the human corticotropin-releasing-hormone gene promoter activity in neuro-2A cells—an involvement of protein kinases. Neuropsychopharmacology 31:853–865PubMedCrossRefGoogle Scholar
  6. Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P (2006) Risk of dementia in diabetes mellitus: a systematic reveiw. Lancet Neurol 5:64–74PubMedCrossRefGoogle Scholar
  7. Craft S, Asthana S, Cook DG, Baker LD, Cherrier M, Purganan K, Wait C, Petrova A, Latendresses S, Watson GS, Newcomer JW, Schellenberg GD, Krohn AJ (2003) Insulin dose-response effects on memory and plasma amyloid precursor protein in Alzheimer’s disease: interations with apolipoprotein E genotype. Psychoneuroendocrinology 28:809–822PubMedCrossRefGoogle Scholar
  8. Doble RW, Woodgett JR (2003) GSK-3: tricks of the trade for a multitasking kinase. J Cell Sci 116:1175–1186PubMedCentralPubMedCrossRefGoogle Scholar
  9. Emamian ES, Hall D, Birnbaum MJ, Karayiorgou M, Gogos JA (2004) Convergent evidence for impaired AKT1-GSK3b signaling in schizophrenia. Nat Genet 36:131–137PubMedCrossRefGoogle Scholar
  10. Gerozissis K, Kyriaki G (2003) Brain insulin: regulation, mechanisms of action and functions. Cell Mol Neurobiol 23:1–25PubMedCrossRefGoogle Scholar
  11. Girault EM, Alkemade A, Foppen E, Ackermans MT, Fliers E, Kalsbeek A (2012) Acute peripheral but not central administration of olanzapine induces hyperglycemia associated with hepatic and extra-hepatic insulin resistance. PLoS One 7:e43244PubMedCentralPubMedCrossRefGoogle Scholar
  12. Gould TD, Manji HK (2005) Glycogen synthase kinase-3: a putative molecular target for litium mimetic drugs. Neuropsychopharmacology 30:1223–1237PubMedGoogle Scholar
  13. Havrankova K, Schmechel D, Roth J, Brownstein M (1978) Identification of insulin in rat brain. Proc Natl Acad Sci U S A 75:5737–5741PubMedCentralPubMedCrossRefGoogle Scholar
  14. Hillebrand JJ, de Wied D, Adan RA (2002) Neuropeptides, food intake and body weight regulation: a hypothalamic focus. Peptides 23:2283–2306PubMedCrossRefGoogle Scholar
  15. Hong M, Lee VMY (1997) Insulin and insulin-like growth factor-1 regulate Tau phosphorylation in cultured human neurons. J Biol Chem 272:19547–19553PubMedCrossRefGoogle Scholar
  16. Jope RS, Roh MS (2006) Glycogen synthase kinase-3 (GSK3) in psychiatric diseases and therapeutic interventions. Curr Drug Targets 7:1421–1434PubMedCentralPubMedCrossRefGoogle Scholar
  17. Kalkman HO (2006) The role of the phosphatidylinositide 3-kinase-protein kinase B pathway in schizophrenia. Pharmacol Ther 110:117–134PubMedCrossRefGoogle Scholar
  18. Kang UG, Seo MS, Roh MS, Kim Y, Yoon SC, Kim YS (2004) The effects of clozapine on the GSK-3-mediated signaling pathway. FEBS Lett 560:115–119PubMedCrossRefGoogle Scholar
  19. Kapur S, VanderSpek SC, Brownlee BA, Nobrega JN (2003) Antipsychotic dosing in preclinical models is often unrepresentative of the clinical condition: a suggested solution based on in vivo occupancy. J Pharmacol Exp Ther 305:625–631PubMedCrossRefGoogle Scholar
  20. Kozlovsky N, Belmaker RH, Agam G (2002) GSK-3 and the neurodevelopmental hypothesis of schizophrenia. Eur Neuropsychopharmacol 12:13–25PubMedCrossRefGoogle Scholar
  21. Li X, Rosborough KM, Friedman AB, Zhu W, Roth KA (2006) Regulation of mouse brain glycogen synthase kinase-3 by atypical antipsychotics. Int J Neuropsychopharmacol 10:7–19PubMedCrossRefGoogle Scholar
  22. Lovestone S, Killick R, Di Forti M (2007) Schizophrenia as a GSK-3 dysregulation disorder. Trends Neurosci 30:142–149PubMedCrossRefGoogle Scholar
  23. Lu XH, Dwyer DS (2005) Second-generation antipsychotic drugs, olanzapine, quetiapine, and clozapine enhance neurite outgrowth in PC12 cells via PI3K/AKT, ERK, and pertussis toxin-sensitive pathways. J Mol Neurosci 27:43–64PubMedCrossRefGoogle Scholar
  24. Lu XH, Bradley RJ, Dwyer DS (2004) Olanzapine produces trophic effects in vitro and stimulates phosphorylation of Akt/PKB, ERK1/2, and the mitogen-activated protein kinase p38. Brain Res 1011:58–68PubMedCrossRefGoogle Scholar
  25. Lykkegaard K, Larsen PJ, Vrang N, Bock C, Bock T, Knudsen LB (2008) The once-daily human GLP-1 analog, liraglutide, reduces olanzapine-induced weight gain and glucose intolerance. Schizophr Res 103:94–103PubMedCrossRefGoogle Scholar
  26. Marks JL, Porte D, Stahl WL, Baskin DG (1990) Localization of insulin receptor mRNA in rat brain by in situ hybridization. Endocrinology 127:3234–3236PubMedCrossRefGoogle Scholar
  27. Ott A, Stolk RP, Hofman A, van Harskamp F, Grobbee DE, Breteler MMB (1996) Association of diabetes mellitus and dementia: the Rotterdam study. Diabetologia 39:1392–1397PubMedCrossRefGoogle Scholar
  28. Sauter A, Goldstein M, Engel J, Ueta K (1983) Effect of insulin on central catecholamines. Brain Res 260:330–333PubMedCrossRefGoogle Scholar
  29. Schwartz MW, Baskin DG, Kaiyala KJ, Woods SC (1999) Model for the regulation of energy balance and adiposity by the central nervous system. Am J Clin Nutr 69:584–596PubMedGoogle Scholar
  30. Shepherd PR, Withers DJ, Siddle K (1998) Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling. Biochem J 333(Pt 3):471–490PubMedCentralPubMedGoogle Scholar
  31. Smith GC, Chaussade C, Vickers M, Jensen J, Shepherd PR (2008) Atypical antipsychotic drugs induce derangements in glucose homeostasis by acutely increasing glucagon secretion and hepatic glucose output in the rat. Diabetologia 51:2309–2317PubMedCrossRefGoogle Scholar
  32. Smith GC, Vickers MH, Cognard E, Shepherd PR (2009) Clozapine and quetiapine acutely reduce glucagon-like peptide-1 production and increase glucagon release in obese rats: implications for glucose metabolism and food choice behaviour. Schizophr Res 115:30–40PubMedCrossRefGoogle Scholar
  33. Smith GC, Vickers MH, Shepherd PR (2011) Olanzapine effects on body composition, food preference, glucose metabolism and insulin sensitivity in the rat. Arch Physiol Biochem 117:241–249PubMedCrossRefGoogle Scholar
  34. Ukai W, Ozawa H, Tateno M, Hashimoto E, Saito T (2004) Neurotoxic potential of haloperidol in comparison with risperidone: implication of Akt-mediated signal changes by haloperidol. J Neural Transm 111:667–681PubMedCrossRefGoogle Scholar
  35. Unger J, Moss AM, Livingston JN (1991) Immunohistochemical localization of insulin receptors and phosphotyrosin in brainstem of the adult brain. Neuroscience 42:853–861PubMedCrossRefGoogle Scholar
  36. van der Heide LP, Kamal A, Gispen WH, Ramakers GMJ (2005) Insulin modulates hippocampal activity-dependent synaptic plasticity in a N-methyl-D-aspartate receptor and phosphatidyl-inositol-3-kinase-dependent manner. J Neurochem 94:1158–1166PubMedCrossRefGoogle Scholar
  37. Yamaguchi A, Tamatani M, Matsuzaki H, Namikawa K, Kiyama H, Vitek MP, Mitsuda N, Tohyama M (2001) Akt activation protects hippocampal neurons from apoptosis by inhibiting transcriptional activity of p53. J Biol Chem 276:5256–5264PubMedCrossRefGoogle Scholar
  38. Zhao WQ, Alkon DL (2001) Role of insulin and insulin receptor in learning and memory. Mol Cell Endocrinol 177:125–134PubMedCrossRefGoogle Scholar
  39. Zhao Z, Ksiezak-Reding H, Riggio S, Haroutunian V, Pasinetti GM (2006) Insulin receptor deficiets in schizophrenia and in cellular and animal models of insulin receptor dysfunction. Schizophr Res 84:1–14PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • G. C. Smith
    • 1
    • 2
  • H. McEwen
    • 1
    • 4
  • J. D. Steinberg
    • 3
  • P. R. Shepherd
    • 1
    • 4
  1. 1.Department of Molecular Medicine and PathologyUniversity of AucklandAucklandNew Zealand
  2. 2.Department of PharmacologyUniversity of New South WalesKensingtonAustralia
  3. 3.Singapore Bioimaging ConsortiumAgency for Science, Technology and Research11 Biopolis WaySingapore
  4. 4.The Maurice Wilkins CentreAucklandNew Zealand

Personalised recommendations