Skip to main content Accessibility help

Differential effects of escitalopram administration on metabolic parameters of cortical and subcortical brain regions of Wistar rats

  • Cinara L. Gonçalves (a1) (a2), Gislaine T. Rezin (a1) (a2), Gabriela K. Ferreira (a1) (a2), Isabela C. Jeremias (a1) (a2), Mariane R. Cardoso (a1) (a2), Milena Carvalho-Silva (a1) (a2), Alexandra I. Zugno (a2) (a3), João Quevedo (a2) (a3) and Emilio L. Streck (a1) (a2)...


Objective: Considering that mitochondria may be drug targets and some characteristics of drug–mitochondria interactions may still be misjudged because of the difficulty in foreseeing and understanding all possible implications of the complex pathophysiology of mitochondria, our study aimed to investigate the effect of escitalopram on the activity of enzymes of mitochondrial energy metabolism.

Methods: Animals received daily administration of escitalopram dissolved in saline [10 mg/kg, intraperitoneal (IP)] at 1.0 ml/kg volume for 14 days. Control rats received an equivalent volume of saline, 1.0 ml/kg (IP), for the same treatment period. Twelve hours after last injection, rats were killed by decapitation and brain areas were rapidly isolated. The samples were homogenised and the activities of mitochondrial respiratory chain complexes, some enzymes of Krebs cycle (citrate synthase, malate dehydrogenase and succinate dehydrogenase) and creatine kinase were measured.

Results: We verified that chronic administration of escitalopram decreased the activities of complexes I and II–III in cerebellum, hippocampus, striatum and posterior cortex whereas prefrontal cortex was not affected. Complex II activity was decreased only in striatum without affecting prefrontal cortex, hippocampus, cerebellum and posterior cortex. However, chronic administration of escitalopram did not affect complex IV and enzymes of Krebs cycle activities as well as creatine kinase.

Conclusion: In this study we showed a decrease in the activities of complexes I and II–III in most of the brain structures analysed and complex II activity was decreased only in striatum. However, it remains to be determined if mitochondrial dysfunction is rather a causal or a consequential event of abnormal signalling.


Corresponding author

Emilio L. Streck, Laboratório de Bioenergética, Universidade do Extremo Sul Catarinense, 88806-000 Criciúma, SC, Brazil. Tel: +554834312539; E-mail:


Hide All
1.Kessler, RC, Walters, EE.Epidemiology of DSM-III-R major depression and minor depression among adolescents and young adults in the National Comorbidity Survey. Depress Anxiety 1998;7:314.
2.Turner, JR, Gil, AG.Psychiatric and substance use disorders in South Florida racial/ethnic and gender contrasts in a young adult cohort. Arch Gen Psychiatry 2002;59:4350.
3.Kessler, RC, Berglund, P, Demler, O, Jin, R, Kr, Merikans, Walters, EE.Lifetime prevalence and age-of-onset distributions of DSM-IV disorder in the national comorbidity survey replication. Arch Gen Psychiatry 2005;62:593768.
4.Rex, A, Schickert, R, Fink, H.Antidepressant-like effect of nicotinamide adenine dinucleotide in the forced swim test in rats. Pharmacol Biochem Behav 2004;77:303307.
5.Kiss, JP.Theory of active antidepressants: a nonsynaptic approach to the treatment of depression, Neurochem Int 2008;52:3439.
6.Longone, P, Rupprecht, R, Manieri, GA, Bernardi, G, Romeo, E, Pasini, A.The complex roles of neurosteroids in depression and anxiety disorders. Neurochem Int 2008;52:596601.
7.Greenberg, PE, Stiglin, LE, Finkelstein, SN, Berndt, ER, 1993. The economic burden of depression in 1990. J Clin Psychiatry 1990;54:405418.
8.World Health Organization: Programmes and projects/mental health/disorders management/depression. Retrieved March 1, 2010, from URL
9.Cannon, TD, Keller, MC.Endophenotypes in the genetic analyses of mental disorders. Annu Rev Clin Psychol 2006;2:267290.
10.Skolnick, P.Beyond monoamine-based therapies: clues to new approaches. J Clin Psychiatry 2002;63:1923.
11.Charney, DS.Monoamine dysfunction and the pathophysiology and treatment of depression. J Clin Psychiatry 1998;59:1114.
12.Brunello, N, Mendlewicz, J, Kasper, S et al. The role of noradrenaline and selective noradrenaline reuptake inhibition in depression. Eur Neuropsychopharmacology 2002;12:461475.
13.Johnson, AM.Paroxetine: a pharmacological review. Int Clin Psychopharmacol 1992;6:1524.
14.Richelson, E.Pharmacology of anti-depressants – characteristics of the ideal drug. Mayo Clin Proc 1999;69: 10691081.
15.David, DJ, Bourin, M, Jego, G, Przybylski, C, Jolliet, P, Gardier, AM.Effects of acute treatment with paroxetine, citalopram and venlafaxine in vivo on noradrenaline and serotonin outflow: a microdialysis study in Swiss mice. Br J Pharmacol 2003;140:11281136.
16.Borsini, F, Podhorna, J, Marazziti, D.Do animal models of anxiety predict anxiolytic-like effects of antidepressants? Psychopharmacology 2002;163:121141.
17.Brennan, WA, Bird, ED, Aprille, JR.Regional mitochondrial respiratory activity in Huntington's disease brain. J Neurochem 1985;44:1948.
18.Heales, SJ, Bolanõs, JP, Stewart, VC, Brookes, PS, Land, JM, Clark, JB.Nitric oxide, mitochondria and neurological disease. Biochim Biophys Acta 1999;1410: 215228.
19.Blass, JP.Brain metabolism and brain disease: is metabolic deficiency the proximate cause of Alzheimer dementia? J Neurosci Res 2001;66:851856.
20.Schurr, A.Energy metabolism, stress hormones and neural recovery from cerebral ischemia/hypoxia. Neurochem Int 2002;41:18.
21.Monsalve, M, Borniquel, S, Valle, I, Lamas, S.Mitochondrial dysfunction in human pathologies. Front Biosci 2007;12:11311153.
22.Moreira, PI, Santos, MS, Oliveira, CR.Alzheimer's disease: a lesson from mitochondrial dysfunction. Antioxid Redox Signal 2007;9:16211630.
23.Moreira, PI, Santos, MS, Seiça, R, Oliveira, CR.Brain mitochondrial dysfunction as a link between Alzheimer's disease and diabetes. J Neurol Sci 2007;257:206214.
24.Calabrese, V, Scapagnini, G, Giuffrida-Stella, AM, Bates, TE, Clark, JB.Mitochondrial involvement in brain function and dysfunction: relevance to aging, neurodegenerative disorders and longevity. Neurochem Res 2001;26:739764.
25.Boekema, EJ, Braun, HP.Supramolecular structure of the mitochondrial oxidative phosphorylation system. J Biol Chem 2007;282:14.
26.Kelly, D, Gordon, J, Alpers, R, Strauss, AW.The tissue-specific expression and developmental regulation of two nuclear genes encoding rat mitochondrial proteins. Medium chain acyl-CoA dehydrogenase and mitochondrial malate dehydrogenase. J Biol Chem 1989;264:1892118925.
27.Shepherd, D, Garland, PB.The kinetic properties of citrate synthase from rat liver mitochondria. Biochem J 1969;114:597610.
28.Labrou, NE, Clonis, YD.L-Malate dehydrogenase from Pseudomonas stutzeri: purification and characterization. Arch Biochem Biophys 1997;337:103114.
29.Tyler, D.The mitochondrion in health and diseases. New York: VCH Publishers, 1992.
30.Rustin, P, Munnich, A, Rötig, A.Succinate dehydrogenase and human diseases: newinsights into a well-known enzyme. Eur J Hum Genet 2002;10:289291.
31.Tomimoto, H, Yamamoto, K, Homburger, HA, Yanagihara, T.Immunoelectron microscopic investigation of creatine kinase BB-isoenzyme after cerebral ischemia in gerbils, Acta Neuropathol 1993;86:447455.
32.Hamman, BL, Bittl, JA, Jacobus, WE et al. Inhibition of the creatine kinase reaction decreases the contractile reserve of isolated rat hearts. Am J Physiol 1995;269:10301036.
33.Gross, WL, Bak, MI, Ingwall, JS et al. Nitric oxide inhibits creatine kinase and regulates heart contractile reserve. Proc Natl Acad Sci U S A 1996;93:56045609.
34.David, S, Shoemaker, M, Haley, BE.Abnormal properties of creatine kinase in Alzheimer's disease brain: correlation of reduced enzyme activity and active site photolabeling with aberrant cytosol-membrane partitioning. Brain Res Mol Brain Res 1998;54:276287.
35.Aksenov, M, Aksenova, M, Butterfield, DA, Markesbery, WR.Oxidative modification of creatine kinase BB in Alzheimer's disease brain. J Neurochem 2000;74: 25202527.
36.Jayatissa, MN, Bisgaard, C, Tingström, A, Papp, M, Wiborg, O.Hippocampal cytogenesis correlates to escitalopram-mediated recovery in a chronic mild stress rat model of depression. Neuropsychopharmacology 2006;31: 23952404.
37.Lowry, OH, Rosebough, NG, Farr, AL, Randall, RJ.Protein measurement with the Folin phenol reagent. J Biol Chem 1951;193:265275.
38.Cassina, A, Radi, R.Differential inhibitory Aation of nitric oxide and peroxynitrite on mitochondrial electron transport. Arch Biochem Biophys 1996;328:309316.
39.Fischer, JC, Ruitenbeek, W, Berden, JA, Trijbels, JM.Differential investigation of the capacity of succinate oxidation in human skeletal muscle. Clin Chim Acta 1985;153:2326.
40.Rustin, P, Chretien, D, Bourgeron, T et al. Biochemical and molecular investigations in respiratory chain deficiencies. Clin Chim Acta 1994;228:3551.
41.Kitto, GB.Intra- and extramitochondrial malate dehydrogenases from chicken and tuna heart. Methods Enzymol 1969;8:106116.
42.Hughes, BP.A method for estimation of serum creatine kinase and its use in comparing creatine kinase and aldolase activity in normal and pathologic sera. Clin Chim Acta 1962;7:597604.
43.Mattson, MP, Gleichmann, M, Cheng, A.Mitochondria in neuroplasticity and neurological disorders. Neuron 2008;60:748766.
44.Retter, L, Mayer-Takacs, D, Adam-Vizi, V.The effect of bovine serum albumin on the membrane potential and reactive oxygen species generation in succinate-supported isolated brain mitochondria. Neurochem Int 2007;50:139147.
45.Petrosillo, G, Matera, M, Casanova, G, Ruggiero, FM, Paradies, G.Mitochondrial dysfunction in rat brain with aging: involvement of complex I, reactive oxygen species and cardiolipin. Neurochem Int 2008;53:126131.
46.Kanarik, M, Matrov, D, Kõiv, K, Eller, M, Tõnissaar, M, Harro, J.Changes in regional long-term oxidative metabolism induced by partial serotonergic denervation and chronic variable stress in rat brain. Neurochem Int 2008;52:432437.
47.Stanyer, L, Jorgensen, W, Hori, O, Clark, JB, Heales, SJ.Inactivation of brain mitochondrial Lon protease by peroxynitrite precedes electron transport chain dysfunction. Neurochem Int 2008;53:95101.
48.Madrigal, JL, Olivenza, R, Moro, M et al. Glutathione depletion, lipid peroxidation and mitochondrial dysfunction are induced by chronic stress in rat brain. Neuropsychopharmacology 2001;24:420429.
49.Barrett, SL, Kelly, C, Bell, R, King, DJ.Gender influences the detection of spatial working memory deficits in bipolar disorder. Bipolar Disord 2008;10:647654.
50.Quraishi, S, Walshe, M, Mcdonald, C et al. Memory functioning in familial bipolar I disorder patients and their relatives. Bipolar Disord 2009;11:209214.
51.Streck, EL, Amboni, G, Scaini, G et al. Brain Creatine kinase activity in an animal model of mania. Life Sci 2008;82:424429.
52.Burigo, M, Roza, CA, Bassani, C et al. Decreased Creatine kinase activity caused by electroconvulsive shock. Neurochem Res 2006;31:877881.
53.Gamaro, GD, Streck, EL, Matté, C, Prediger, ME, Wyse, AT, Dalmaz, C.Reduction of hippocampal Na+, K+-ATPase activity in rats subjected to an experimental model of depression. Neurochem Res 2003;28:13391344.
54.Rezin, GT, Cardoso, MR, Gonçalves, CL et al. Inhibition of mitochondrial respiratory chain in brain of rats subjected to an experimental model of depression. Neurochem Int 2008;53:395400.
55.Ferretti, V, Roullet, P, Sargolini, F et al. Ventral striatal plasticity and spatial memory. Proc Natl Acad Sci U S A 2010;107:79457950.
56.Marais, L, Stein, DJ, Daniels, WM.Exercise increases BDNF levels in the striatum and decreases depressive-like behavior in chronically stressed rats. Metab Brain Dis 2009;24:587597.
57.Gokce, O, Runne, H, Kuhn, A, Luthi-Carter, R.Short-term striatal gene expression responses to brain-derived neurotrophic factor are dependent on MEK and ERK activation. PLoS One 2009;4:5292.
58.Duman, RS, Monteggia, LM.A neurotrophic model for stress-related mood disorders. Biol Psychiatry 2006;59: 11161127.
59.Hall, J, Whalley, HC, Marwick, K et al. Hippocampal function in schizophrenia and bipolar disorder. Psychol Med 2009;7:110.
60.Hassel, S, Almeida, JR, Kerr, N et al. Elevated striatal and decreased dorsolateral prefrontal cortical activity in response to emotional stimuli in euthymic bipolar disorder: no associations with psychotropic medication load. Bipolar Disord 2008;10:916927.
61.Hroudova, J, Fisar, Z.Activities of respiratory chain complexes and citrate synthase influenced by pharmacologically different antidepressants and mood stabilizers. Neuroendocrinology Lett 2010;31:336342.
62.Burke, WJ, Cj, Kratochvil. Stereoisomers in psychiatry: the case of escitalopra. Prim Care Companion J Clin Psychiatry 2002;4:2024.
63.Mitchell, PJ, Hogg, S. Beavioural effects of escitalopram predict potent antidepressant activity. Presented at the 7th World Congress of Biological Psychiatry, July 1–6. Berlin, Germany, 2001.
64.Sanchez, C, Hogg, S. The antidepressant effect of citalopram resides in the S-enantiomer (Lu 26-054). Presented at the 55th annual meeting of the Society of Biological Psychiatry, May 11–13. Chicago, IL, 2000.
65.Mitchell, P, Hogg, S. Escitalopram: rapid antidepressant activity in rats. Presented at the 7th World Congress of Biological Psychiatry, July 1–6. Berlin, Germany, 2001.
66.Pathak, RU, Davey, GP.Complex I and energy theresholds in the brain. Biochim Biophys Acta 2008;1777:777782.
67.Barja, G, Herrero, AJ.Localization at complex I and mechanism of the higher free radical production of brain nonsynaptic mitochondria in the short-lived rat than in the longevous pigeon. J Bioenerg Biomembr 1998;30:235–224.
68.Sherer, TB, Betarbet, R, Jh, Kim, Greenamyre, JT.Selective microglial activation in the rat rotenone model of Parkinson's disease. Neurosci Lett 2003;341:8790.
69.Degli, EM.Inhibitors of NADH-ubiquinone reductase: an overview. Biochim Biophys Acta 1998;1364:222235.
70.Miyoshi, H.Structure-activity relationships of some complex I inhibitors. Biochim Biophys Acta 1998;1364: 236244.
71.Don, AS, Hogg, PJ.Mitochondria as cancer drug targets. Trends Mol Med 2004;10:372378.
72.Scatena, R, Bottoni, P, Botta, G, Martorana, GE, Giardina, B.The role of mitochondria in pharmacotoxicology: a reevaluation of an old, newly emerging topic. Am J Physiol Cell Physiol 2007;293:C12C21.


Differential effects of escitalopram administration on metabolic parameters of cortical and subcortical brain regions of Wistar rats

  • Cinara L. Gonçalves (a1) (a2), Gislaine T. Rezin (a1) (a2), Gabriela K. Ferreira (a1) (a2), Isabela C. Jeremias (a1) (a2), Mariane R. Cardoso (a1) (a2), Milena Carvalho-Silva (a1) (a2), Alexandra I. Zugno (a2) (a3), João Quevedo (a2) (a3) and Emilio L. Streck (a1) (a2)...


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed