Study of the Role of Dopamine Receptors in Streptozotocin-Induced Depressive-Like Behavior Using the Forced Swim Test Model

Afshin Roostaei, Gholamhassan Vaezi, Mohammad Nasehi, Ali Haeri-Rohani, Mohammad-Reza Zarrindast
Background: Diabetes is one of the most common endocrine diseases characterized by hyperglycemia. It is caused by an absolute or relative insulin deficiency or an insulin function deficiency. It is one of the major risk factors of depression, with the rate of depression in diabetic patients amounting to as high as 30%. This study examined the role of dopamine receptors in streptozotocin (STZ)-induced depressive-like behavior using the forced swim test (FST). Materials and Methods: This study was performed on 56 Wistar male rats. STZ at doses of 30 and 60 mg/kg body weight was administered via intraperitoneal (IP) route to induce diabetes and depression in rats. Thereafter, by using halobenzazepine (SCH23390) (D1 dopamine receptor antagonist) and sulpiride (D2 receptor dopamine receptor antagonist), the role of dopamine receptors in STZ-induced depression was studied. The one-way analysis of variance technique, Tukey’s range test, and t-test were used to analyze the data. The P-value less than 0.05 was regarded as statistically significant. Results: Our study showed that STZ at doses of 30 and 60 mg/kg, two weeks after injection, caused prolonged immobility in FST, indicating depressive-like behavior (P<0.05 and P<0.01, respectively). SCH23390 (0.001 mg/mL/kg) and sulpiride (0.1mg/mL/kg) did not change the variables of depression in animals that received STZ (at doses of 30 and 60 mg/mL/kg) two weeks before (P>0.05). Conclusion: According to our study, STZ has a depressive-like behavior two weeks after injection, and dopamine receptors do not play a role in depression associated with STZ use. [GMJ.2018;7:e954]
Streptozotocin; Depression; Dopamine Receptors

Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005;54(6):1615-25.


L'Heveder R, Nolan T. International Diabetes Federation. Diabetes Res Clin Pract. 2013;101(3):349-51.


Lenart L, Hodrea J, Hosszu A, Koszegi S, Zelena D, Balogh D et al. The role of sigma-1 receptor and brain-derived neurotrophic factor in the development of diabetes and comorbid depression in streptozotocin-induced diabetic rats. Psychopharmacology (Berl). 2016;233(7):1269-78.


Cukierman T, Gerstein HC, Williamson JD. Cognitive decline and dementia in diabetes--systematic overview of prospective observational studies. Diabetologia. 2005;48(12):2460-9.


Lloyd CE, Roy T, Nouwen A, Chauhan AM. Epidemiology of depression in diabetes: international and cross-cultural issues. J Affect Disord. 2012;142 Suppl:S22-9.

Park M, Katon WJ, Wolf FM. Depression and risk of mortality in individuals with diabetes: a meta-analysis and systematic review. Gen Hosp Psychiatry. 2013;35(3):217-25.

PMid:23415577 PMCid:PMC3644308

Shrestha SS, Zhang P, Li R, Thompson TJ, Chapman DP, Barker L. Medical expenditures associated with major depressive disorder among privately insured working-age adults with diagnosed diabetes in the United States, 2008. Diabetes Res Clin Pract. 2013;100(1):102-10.

PMid:23490596 PMCid:PMC5304910

Musselman DL, Betan E, Larsen H, Phillips LS. Relationship of depression to diabetes types 1 and 2: epidemiology, biology, and treatment. Biol Psychiatry. 2003;54(3):317-29.

Rubin RR, Ciechanowski P, Egede LE, Lin EH, Lustman PJ. Recognizing and treating depression in patients with diabetes. Curr Diab Rep. 2004;4(2):119-25.


Peng WH, Lo KL, Lee YH, Hung TH, Lin YC. Berberine produces antidepressant-like effects in the forced swim test and in the tail suspension test in mice. Life Sci. 2007;81(11):933-8.


Connor TJ, Kelliher P, Harkin A, Kelly JP, Leonard BE. Reboxetine attenuates forced swim test-induced behavioural and neurochemical alterations in the rat. Eur J Pharmacol. 1999;379(2-3):125-33.

Hirano S, Miyata S, Kamei J. Antidepressant-like effect of leptin in streptozotocin-induced diabetic mice. Pharmacol Biochem Behav. 2007;86(1):27-31.


Caletti G, Olguins DB, Pedrollo EF, Barros HM, Gomez R. Antidepressant effect of taurine in diabetic rats. Amino Acids. 2012;43(4):1525-33.


Gupta D, Kurhe Y, Radhakrishnan M. Antidepressant effects of insulin in streptozotocin induced diabetic mice: Modulation of brain serotonin system. Physiol Behav. 2014;129:73-8.


Wayhs CA, Manfredini V, Sitta A, Deon M, Ribas G, Vanzin C et al. Protein and lipid oxidative damage in streptozotocin-induced diabetic rats submitted to forced swimming test: the insulin and clonazepam effect. Metab Brain Dis. 2010;25(3):297-304.


Scholl JL, Renner KJ, Forster GL, Tejani-Butt S. Central monoamine levels differ between rat strains used in studies of depressive behavior. Brain Res. 2010;1355:41-51.

PMid:20696147 PMCid:PMC2946061

Trulson ME, Himmel CD. Decreased brain dopamine synthesis rate and increased [3H]spiroperidol binding in streptozotocin-diabetic rats. J Neurochem. 1983;40(5):1456-9.

Bitar M, Koulu M, Rapoport SI, Linnoila M. Diabetes-induced alteration in brain monoamine metabolism in rats. J Pharmacol Exp Ther. 1986;236(2):432-7.


Arias-Carrion O, Stamelou M, Murillo-Rodriguez E, Menendez-Gonzalez M, Poppel E. Dopaminergic reward system: a short integrative review. Int Arch Med. 2010;3:24.

PMid:20925949 PMCid:PMC2958859

Takahashi H, Kato M, Takano H, Arakawa R, Okumura M, Otsuka T et al. Differential contributions of prefrontal and hippocampal dopamine D(1) and D(2) receptors in human cognitive functions. J Neurosci. 2008;28(46):12032-8.


Arias-Carrion O, Poppel E. Dopamine, learning, and reward-seeking behavior. Acta Neurobiol Exp (Wars). 2007;67(4):481-8.

Robinson R, Krishnakumar A, Paulose CS. Enhanced dopamine D1 and D2 receptor gene expression in the hippocampus of hypoglycaemic and diabetic rats. Cell Mol Neurobiol. 2009;29(3):365-72.


Serri O, Renier G, Somma M. Effects of alloxan-induced diabetes on dopaminergic receptors in rat striatum and anterior pituitary. Horm Res. 1985;21(2):95-101.


D'Aquila PS, Collu M, Gessa GL, Serra G. The role of dopamine in the mechanism of action of antidepressant drugs. Eur J Pharmacol. 2000;405(1-3):365-73.

Dunlop BW, Nemeroff CB. The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry. 2007;64(3):327-37.


Khanam R, Pillai KK. Effect of chromium picolinate on modified forced swimming test in diabetic rats: involvement of serotonergic pathways and potassium channels. Basic Clin Pharmacol Toxicol. 2006;98(2):155-9.


Bhutada P, Mundhada Y, Bansod K, Bhutada C, Tawari S, Dixit P et al. Ameliorative effect of quercetin on memory dysfunction in streptozotocin-induced diabetic rats. Neurobiol Learn Mem. 2010;94(3):293-302.


Porsolt RD, Anton G, Blavet N, Jalfre M. Behavioural despair in rats: a new model sensitive to antidepressant treatments. Eur J Pharmacol. 1978;47(4):379-91.

Gomez R, Barros HM. Ethopharmacology of the antidepressant effect of clonazepam in diabetic rats. Pharmacol Biochem Behav. 2000;66(2):329-35.

Shimomura Y, Shimizu H, Takahashi M, Sato N, Uehara Y, Suwa K et al. Changes in ambulatory activity and dopamine turnover in streptozotocin-induced diabetic rats. Endocrinology. 1988;123(6):2621-5.


Bradberry CW, Karasic DH, Deutch AY, Roth RH. Regionally-specific alterations in mesotelencephalic dopamine synthesis in diabetic rats: association with precursor tyrosine. J Neural Transm Gen Sect. 1989;78(3):221-9.


Gupta D, Radhakrishnan M, Kurhe Y. 5HT3 receptor antagonist (ondansetron) reverses depressive behavior evoked by chronic unpredictable stress in mice: modulation of hypothalamic-pituitary-adrenocortical and brain serotonergic system. Pharmacol Biochem Behav. 2014;124:129-36.


Ezzeldin E, Souror WA, El-Nahhas T, Soudi AN, Shahat AA. Biochemical and neurotransmitters changes associated with tramadol in streptozotocin-induced diabetes in rats. Biomed Res Int. 2014;2014:238780.

PMid:24971322 PMCid:PMC4058222

Lee M, Ryu YH, Cho WG, Kang YW, Lee SJ, Jeon TJ et al. Relationship between dopamine deficit and the expression of depressive behavior resulted from alteration of serotonin system. Synapse. 2015;69(9):453-60.



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