Top

Published in:

01-09-2014 | Research Article

Insulin reverses anxiety-like behavior evoked by streptozotocin-induced diabetes in mice

Authors: Deepali Gupta, Mahesh Radhakrishnan, Yeshwant Kurhe

Published in: Metabolic Brain Disease | Issue 3/2014

Abstract

Clinical and preclinical data suggest that diabetes is often associated with anxiety. Insulin, a peptide hormone has been reported to have key functions in the brain and in alleviating several psychological impairments, occur as a consequence of diabetes. However, its effects in diabetes-induced anxiety are scanty. The present study examined whether; insulin can reverse the anxiety-like behavior in streptozotocin (STZ)-induced diabetes in mice. After 8-weeks of diabetes induced by STZ (200 mg/kg, intraperitoneally (i.p.)), mice were given insulin (1–2 IU/kg/day, i.p.)/ diazepam (1 mg/kg/day, i.p.)/ vehicle for 14 days and evaluated for behavioral effects in three validated models of anxiety viz. elevated plus maze (EPM), light–dark (L/D) and hole board (HB) tests. STZ-induced diabetic mice elicited significant behavioral effects which include, decreased percentage open arm entries and time in EPM, reduced latency and time spent in light chamber in L/D, decreased number of head dips, squares crossed and rearings in HB tests respectively. Insulin treatment attenuated the behavioral effects evoked by STZ-induced diabetes in mice as indicated by increased open arms activity in EPM, decreased aversion in light chamber during L/D test and increased exploratory behavior in HB test. In conclusion, this study revealed that insulin can reverse anxiety-like behavior in STZ-induced diabetes in mice.

Aksu I, Ates M, Baykara B, Kiray M, Sisman AR, Buyuk E et al (2012) Anxiety correlates to decreased blood and prefrontal cortex IGF-1 levels in streptozotocin induced diabetes. Neurosci Lett 531:176–181PubMedCrossRef

Antony S, Kumar TP, Kuruvilla KP, George N, Paulose CS (2010) Decreased GABA receptor binding in the cerebral cortex of insulin induced hypoglycemic and streptozotocin induced diabetic rats. Neurochem Res 35:1516–1521PubMedCrossRef

Belzung C, Griebel G (2001) Measuring normal and pathological anxiety-like behavior in mice: a review. Behav Brain Res 125:141–149PubMedCrossRef

Bhardwaj SK, Sandhu SK, Sharma P, Kaur G (1999) Impact of diabetes on CNS: role of signal transduction cascade. Brain Res Bull 49:155–162PubMedCrossRef

Biala G, Kruk M (2008) Calcium channel antagonists suppress cross-tolerance to the anxiogenic effects of D-amphetamine and nicotine in the mouse elevated plus maze test. Prog Neuropsychopharmacol Biol Psychiatry 32:54–61PubMedCrossRef

Bitar MILAD, Koulu MARKKU, Rapoport SI, Linnoila MARKKU (1986) Diabetes-induced alteration in brain monoamine metabolism in rats. J Pharmacol Exp Ther 236:432–437PubMed

Bourin M, Hascoët M (2003) The mouse light/dark box test. Eur J Pharmacol 463:55–65PubMedCrossRef

Can ÖD, Öztürk Y, Özkay ÜD (2011) Effects of insulin and St. John’s Wort treatments on anxiety, locomotor activity, depression, and active learning parameters of streptozotocin-diabetic rats. Planta Med 77:1970–1976PubMedCrossRef

Carobrez AP, Bertoglio LJ (2005) Ethological and temporal analyses of anxiety-like behavior: the elevated plus-maze model 20 years on. Neurosci Biobehav Rev 29:1193–1205PubMedCrossRef

Casarrubea M, Sorbera F, Crescimanno G (2009) Structure of rat behavior in hole-board: I) multivariate analysis of response to anxiety. Physiol Behav 96:174–179PubMedCrossRef

Chan O, Inouye K, Riddell MC, Vranic M, Matthews SG (2003) Diabetes and the hypothalamo-pituitary-adrenal (HPA) axis. Minerva Endocrinol 28:87–102PubMed

Chu PC, Lin MT, Shian LR, Leu SY (1986) Alterations in physiologic functions and in brain monoamine content in streptozocin-diabetic rats. Diabetes 35:481–485PubMedCrossRef

Clavijo M, Carvhalo JJ, Rios M, Ries de Oliveira I (2006) Psychiatric disorders in patients with diabetes type 2 at medical care and training district of Rio Branco-Acre, Brazil. Arq Neuropsiquiatr 64(3-B):807–813PubMedCrossRef

Collins MM, Corcoran P, Perry IJ (2009) Anxiety and depression symptoms in patients with diabetes. Diabetic Med 26:153–161PubMedCrossRef

Costall B, Jones BJ, Kelly ME, Naylor R, Tomkins DM (1989) Exploration of mice in a black and white test box: validation as a model of anxiety. Pharmacol Biochem Behav 32:777–785PubMedCrossRef

Craft S, Watson GS (2004) Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurol 3:169–178PubMedCrossRef

Crandall EA, Gills MA, Fernstrom JD (1981) Reduction in brain serotonin synthesis rate in streptozotocin-diabetic rats. Endocrinology 109:310–312PubMedCrossRef

Crawley JN (1985) Exploratory behavior models of anxiety in mice. Neurosci Biobehav Rev 9:37–44PubMedCrossRef

Crawley JN, Goodwin FK (1980) Preliminary report of a simple animal behavior for the anxiolytic effects of benzodiazepines. Pharmacol Biochem Behav 13:167–170PubMedCrossRef

Cruz APM, Frei F, Graeff FG (1994) Ethopharmacological analysis of rat behavior on the elevated plus-maze. Pharmacol Biochem Behav 49:171–176PubMedCrossRef

Curzon G, Fernando JCR (1977) Drugs altering insulin secretion: effects of plasma and brain concentrations of aromatic amino acids and on brain 5-hydroxytryptamine turnover. Br J Pharmacol 60:401–408PubMedCentralPubMed

Duarte A, Santos M, Seica R, Resende de Oliveira C (2000) Effect of oxidative stress on the uptake of GABA and glutamate in synaptosomes isolated from diabetic rat brain. Neuroendocrinology 72:179–186PubMedCrossRef

Francis GJ, Martinez JA, Liu WQ, Xu K, Ayer A, Fine J et al (2008) Intranasal insulin prevents cognitive decline, cerebral atrophy and white matter changes in murine type I diabetic encephalopathy. Brain 131:3311–3334PubMedCrossRef

Fraser LM, Brown RE, Hussin A, Fontana M, Whittaker A, O’Leary TP et al (2010) Measuring anxiety-and locomotion-related behaviors in mice: a new way of using old tests. Psychopharmacology 211:99–112PubMedCrossRef

Gerozissis K (2003) Brain insulin: regulation, mechanisms of action and functions. Cell Mol Neurobiol 23:1–25PubMedCrossRef

Go Y, Kitaoka H, Hanafusa T (2013). Effects of diabetes and diabetes control on susceptibility to learned helplessness in streptozotocin-induced diabetic rats. Diabetol Int 1–9.doi:10.1007/s13340.013.1032.0

Gomez R, Vargas CR, Wajner M, Barros HM (2003) Lower in vivo brain extracellular GABA concentration in diabetic rats during forced swimming. Brain Res 968:281–284PubMed

Grigsby AB, Anderson RJ, Freedland KE, Clouse RE, Lustman PJ (2002) Prevalence of anxiety in adults with diabetes: a systematic review. J Psychosom Res 53:1053–1060PubMedCrossRef

Harada K, Aota M, Inoue T, Matsuda R, Mihara T, Yamaji T et al (2006) Anxiolytic activity of a novel potent serotonin 5-HT2C receptor antagonist FR260010: a comparison with diazepam and buspirone. Eur J Pharmacol 553:171–184PubMedCrossRef

Herzer M, Hood KK (2010) Anxiety symptoms in adolescents with type 1 diabetes: association with blood glucose monitoring and glycemic control. J Pediatr Psychol 35:415–425PubMedCentralPubMedCrossRef

Hilakivi-Clarke LA, Wozniak KM, Durcan MJ, Linnoila M (1990) Behavior of streptozotocin diabetic mice in test of exploration, locomotion, anxiety, depression and aggression. Physiol Behav 48:429–433PubMedCrossRef

Ho N, Balu DT, Hilario MR, Blendy JA, Lucki I (2012) Depressive phenotypes evoked by experimental diabetes are reversed by insulin. Physiol Behav 105:702–708PubMedCentralPubMedCrossRef

Hutter N, Schnurr A, Baumeister H (2010) Healthcare costs in patients with diabetes mellitus and comorbid mental disorders-a systematic review. Diabetologia 53:2470–2479PubMedCrossRef

Kamei J, Ohsawa M, Tsuji M, Takeda H, Matsumiya T (2001) Modification of the effects of benzodiazepines on the exploratory behaviors of mice on a hole-board by diabetes. Jpn J Pharmacol 86:47–54PubMedCrossRef

Kliethermes CL, Crabbe JC (2006) Pharmacological and genetic influences on hole-board behaviors in mice. Pharmacol Biochem Behav 85:57–65PubMedCrossRef

Klodzinska A, Tatarczyńska E, Chojnacka-Wójcik E, Nowak G, Cosford ND, Pilc A (2004) Anxiolytic-like effects of MTEP, a potent and selective mGlu5 receptor agonist does not involve GABA(A) signaling. Neuropharmacology 47:42–50

Kneussel M (2002) Dynamic regulation of GABA (A) receptors at synaptic sites. Brain Res Rev 39:74–83PubMedCrossRef

Kong WX, Chen SW, Li YL, Zhang YJ, Wang R, Min L, Mi X (2006) Effects of taurine on rat behaviors in three anxiety models. Pharmacol Biochem Behav 83:271–276PubMedCrossRef

Kumar TP, Antony S, Gireesh G, George N, Paulose CS (2010) Curcumin modulates dopaminergic receptor, CREB and phospholipase C gene expression in the cerebral cortex and cerebellum of streptozotocin induced diabetic rats. J Biomed Sci 17:43–53PubMedCentralPubMedCrossRef

Lenzen S (2008) The mechanisms of alloxan and streptozotocin induced diabetes. Diabetologia 51:216–226PubMedCrossRef

Li C, Barker L, Ford ES, Zhang X, Strine TW, Mokdad AH (2008) Diabetes and anxiety in US adults: findings from the 2006 Behavioral Risk Factor Surveillance System. Diabetic Med 25:878–881PubMedCrossRef

Lin EH, Korff MV (2008) Mental disorders among persons with diabetes: results from the World Mental Health Surveys. J Psychosom Res 65:571–580PubMedCentralPubMedCrossRef

Lister RG (1987) The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology 92:180–185PubMed

Lister RG (1990) Ethologically-based animal models of anxiety disorders. Pharmacol Ther 46:321–340PubMedCrossRef

MacKenzie RG, Trulson ME (1978) Effects of insulin and streptozotocin-induced diabetes on brain tryptophan and serotonin metabolism in rats. J Neurochem 30:205–211PubMedCrossRef

Mi XJ, Chen SW, Wang WJ, Wang R, Zhang YJ, Li WJ et al (2005) Anxiolytic-like effect of paeonol in mice. Pharmacol Biochem Behav 81:683–687PubMedCrossRef

Millan MJ (2003) The neurobiology and control of anxious states. Prog Neurobiol 70:83–244PubMedCrossRef

Nemeroff CB (2002) The role of GABA in the pathophysiology and treatment of anxiety disorders. Psychopharmacol Bull 37:133–146

Park CR (2001) Cognitive effects of insulin in the central nervous system. Neurosci Biobehav Rev 25:311–323PubMedCrossRef

Pellow S, Chopin P, File SE, Briley M (1985) Validation of open: closed arm entries in an elevated plus maze as a measure of anxiety in the rat. J Neurosci Methods 14:149–167PubMedCrossRef

Pijl H, Edo AM (2002) Modulation of monoaminergic neural circuits: potential for the treatment of type 2 diabetes mellitus. Treat Endocrinol 1:71–78PubMedCrossRef

Plastino M, Fava A, Pirritano D, Cotronei P, Sacco N, Sperlì T et al (2010) Effects of insulinic therapy on cognitive impairment in patients with Alzheimer disease and diabetes mellitus type-2. J Neurol Sci 288:112–116PubMedCrossRef

Ramanathan M, Jaiswal AK, Bhattachayra SK (1998) Differential effects of diazepam on anxiety in streptozotocin induced diabetic and non-diabetic rats. Psychopharmacology 135:361–367PubMedCrossRef

Reagan LP (2012) Diabetes as a chronic metabolic stressor: causes, consequences and clinical complications. Exp Neurol 233:68–78PubMedCentralPubMedCrossRef

Schulingkamp RJ, Pagano TC, Hung D, Raffa RB (2000) Insulin receptors and insulin action in the brain: review and clinical implications. Neurosci Biobehav Rev 24:855–872PubMedCrossRef

Shaban MC, Fosbury J, Kerr D, Cavan DA (2006) The prevalence of depression and anxiety in adults with type 1 diabetes. Diabetic Med 23:1381–1384PubMedCrossRef

Shekhar A, McCann UD, Meaney MJ, Blanchard DC, Davis M, Frey KA et al (2001) Summary of a National Institute of Mental Health workshop: developing animal models of anxiety disorders. Psychopharmacology (Berl) 157:327–339CrossRef

Shpakov A, Chistyakova O, Derkach K, Bondareva V (2011) Hormonal signaling systems of the brain in diabetes mellitus. In: Chang RC (ed) Neurodegenerative diseases. Intech Open Access Publisher, Rijeka, Croatia, pp 349–386

Silva MI, de Aquino Neto MR, Teixeira Neto PF, Moura BA, do Amaral JF, de Sousa DP et al (2007) Central nervous system activity of acute administration of isopulegol in mice. Pharmacol Biochem Behav 88:141–147PubMedCrossRef

Smith KS, Engin E, Meloni EG, Rudolph U (2012) Benzodiazepine-induced anxiolysis and reduction of conditioned fear are mediated by distinct GABA_A receptor subtypes in mice. Neuropharmacology 63:250–258PubMedCentralPubMedCrossRef

Smith KJ, Béland M, Clyde M, Gariépy G, Pagé V, Badawi G et al (2013) Association of diabetes with anxiety: A systematic review and meta-analysis. J Psychosom Res 74:89–99PubMedCrossRef

Szkudelski T (2001) The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res 50:536–546

Torres RC, Prevatto JP, Silva PMR, Martinsand MA, Carvalho VF (2013) From Type-1 Diabetes HPA Axis to the Disease Complications. J Diabetes Metab S12:002. doi:10.4172/2155-6156.S12-002

Trulson ME, Himmel CD (1983) Decreased brain dopamine synthesis rate and increased (3H) spiroperido binding in streptozotocin-diabetic rats. J Neurochem 40:1456–1459PubMedCrossRef

Trulson ME, Jacoby JH, MacKenzie RG (1986) Streptozotocin-induced diabetes reduces brain serotonin synthesis in rats. J Neurochem 46:1068–1072PubMedCrossRef

Tsigos C, Chrousos GP (2002) Hypothalamic–pituitary–adrenal axis, neuroendocrine factors and stress. J Psychosom Res 53:865–871PubMedCrossRef

Vetiska SM, Ahmadian G, Ju W, Liu L, Wymann MP, Wang YT (2007) GABA_A receptor-associated phosphoinositide 3-kinase is required for insulin-induced recruitment of postsynaptic GABA_A receptors. Neuropharmacology 52:146–155PubMedCrossRef

Walf AA, Frye CA (2007) The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nature protocols 2:322–328PubMedCentralPubMedCrossRef

Wall PM, Messier C (2001) Methodological and conceptual issues in the use of the elevated plus-maze as a psychological measurement instrument of animal anxiety-like behavior. Neurosci Biobehav Rev 25:275–286PubMedCrossRef

Wei XY, Yang JY, Wang JH, Wu CF (2007) Anxiolytic effect of saponins from Panax quinquefolium in mice. J Ethnopharmacol 111:613–618PubMedCrossRef

Whiting DR, Guariguata L, Weil C, Shaw J (2011) IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pr 94:311–321CrossRef

Zhang Y, Wang W, Zhang J (2004) Effects of novel anxiolytic 4-butyl-alpha-agarofuran on levels of monoamine neurotransmitters in rats. Eur J Pharmacol 504:39–44PubMedCrossRef

Zhao WQ, Chen H, Quon MJ, Alkon DL (2004) Insulin and the insulin receptor in experimental models of learning and memory. Eur J Pharmacol 490:71–81PubMedCrossRef

Title: Insulin reverses anxiety-like behavior evoked by streptozotocin-induced diabetes in mice
Authors: Deepali Gupta
Mahesh Radhakrishnan
Yeshwant Kurhe
Publication date: 01-09-2014
Publisher: Springer US
Published in: Metabolic Brain Disease / Issue 3/2014
Print ISSN: 0885-7490
Electronic ISSN: 1573-7365
DOI: https://doi.org/10.1007/s11011-014-9540-5

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Insulin reverses anxiety-like behavior evoked by streptozotocin-induced diabetes in mice

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2014

Electromagnetic radiation (Wi-Fi) and epilepsy induce calcium entry and apoptosis through activation of TRPV1 channel in hippocampus and dorsal root ganglion of rats

Estradiol attenuates spinal cord injury-related central pain by decreasing glutamate levels in thalamic VPL nucleus in male rats

Aberrant interhemispheric functional coordination in patients with HBV-related cirrhosis and minimal hepatic encephalopathy

Role of iron in ischemia-induced neurodegeneration: mechanisms and insights

Antenatal taurine supplementation increases taurine content in intrauterine growth restricted fetal rat brain tissue

Molecular analysis in X-linked adrenoleukodystrophy patients: identification of a novel mutation