Skip to main content
Log in

Antipsychotic-induced oxidative stress in Rat Brain

  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

Typical and atypical antipsychotic drugs have been shown to have different clinical and behavioral profiles. Haloperidol (HAL) is a typical neuroleptic that acts primarily as a D2 dopamine receptor antagonist. It has been proposed that reactive oxygen species play a causative role in neurotoxic effects induced by HAL. We evaluated oxidative damage in rat brain induced by chronic (28 days) HAL, clozapine (CLO), olanzapine (OLZ) or aripiprazole (ARI) administration. Adult male Wistar rats received daily injections of HAL (1.5 mg/kg), CLO (25 mg/kg), OLZ (2.5, 5 or 10 mg/kg) or ARI (2, 10 or 20 mg/kg); control animals received vehicle (Tween 1% solution). Thiobarbituric acid reactive substances (TBARS) and protein carbonylation were measured in the prefrontal cortex, hippocampus, striatum and cerebral cortex. The results showed that TBARS were increased in the striatum after HAL treatment. On the other hand, TBARS were diminished in the prefrontal cortex by OLZ and ARI. Our results also showed that all drugs tested in this work decreased TBARS levels in the cerebral cortex. In hippocampus, TBARS levels were not altered by any drug. Protein carbonyl content after HAL and CLO treatment was increased in the hippocampus. Moreover, OLZ and ARI did not alter protein carbonyl content when compared to control group. ARI chronic administration (20 mg/kg) also increased mitochondrial superoxide in the prefrontal cortex and striatum. ARI did not alter mitochondrial superoxide in the hippocampus and cerebral cortex. Moreover, HAL, OLZ and CLO did not cause significant alterations in mitochondrial superoxide in rat brain. Our findings demonstrate that OLZ and ARI do not induce oxidative damage in rat brain as observed after HAL and CLO treatment.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abdul-Monim Z, GP Reynolds and JC Neill (2006) The effect of atypical and classical antipsychotics on sub-chronic PCP-induced cognitive deficits in a reversal-learning paradigm.Behav. Brain Res. 169, 263–273.

    Article  PubMed  CAS  Google Scholar 

  • Angelucci F, L Aloe, SH Gruber, M Fiore and AA Mathe (2000) Chronic antipsychotic treatment selectively alters nerve growth factor and neuropeptide Y immunoreactivity and the distribution of choline acetyl transferase in rat brain regions.Int. J. Neuropsychopharmacol. 3, 13–25.

    Article  PubMed  CAS  Google Scholar 

  • Arnaiz SL, MF Coronel and A Boveris (1999) Nitric oxide, superoxide and hydrogen peroxide production in brain mitochondria after haloperidol treatment.Nitric Oxide 3, 235–243.

    Article  PubMed  CAS  Google Scholar 

  • Assis LC, G Scaini, PB Di-Pietro, AA Castro, CM Comim, EL Streck and J Quevedo (2007) Effect of antipsychotics on creatine kinase activity in rat brain.Basic Clin. Pharmacol. Toxicol. 101, 315–319. DOI:10.1111/j. 1742-7843.2007.00128.x.

    Article  PubMed  CAS  Google Scholar 

  • Beuzen JN, N Taylor, K Wesnes and A Wood (1999) A comparison of the effects of olanzapine, haloperidol and placebo on cognitive and psychomotor functions in healthy elderly volunteers.J. Psychopharmacol. 13, 152–158.

    Article  PubMed  CAS  Google Scholar 

  • Bilder RM, RS Goldman, J Volavka, P Czobor, M Hoptman, B Sheitman, JP Lindenmayer, L Citrome, J McEvoy, M Kunz, M Chakos, TB Cooper, TL Horowitz and JA Lieberman (2002) Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder.Am. J. Psychiatry 159, 1018–1028.

    Article  PubMed  Google Scholar 

  • Buckley PF (2001) Broad therapeutic uses of atypical antipsychotic medications.Biol. Psychiatry 50, 912–924.

    Article  PubMed  CAS  Google Scholar 

  • Cadet JL and JB Lohr (1989) Possible involvement of free radicals in neuroleptic-induced movement disorders. Evidence from treatment of tardive dyskinesia with vitamin E.Ann. NYAcad. Sci. 570, 176–185.

    Article  CAS  Google Scholar 

  • Carlson CD, PA Cavazzoni, PH Berg, H Wei, CM Beasley and JM Kane (2003) An integrated analysis of acute treatmentemergent extrapyramidal syndrome in patients with schizophrenia during olanzapine clinical trials: comparisons with placebo, haloperidol, risperidone, or clozapine.J. Clin. Psychiatry 64, 898–906.

    Article  PubMed  CAS  Google Scholar 

  • Dal-Pizzol F, F Kamt, MMR Vianna, N Schroder, J Quevedo, MS Benfato, JC Moreira and R Walz (2000) Lipid peroxida tion in hippocampus early and late after status epilepticus induced by pilocarpine or kainic acid in Wistar rats.Neurosci.Lett. 291, 179–182.

    Article  PubMed  CAS  Google Scholar 

  • Dal-Pizzol F, F Klamt, MS Benfato, EA Bernard and JC Moreira (2001) Retinol supplementation induces oxidative stress and modulates antioxidant enzyme activities in rat Sertoli cells.Free Radic. Res. 34, 395–404.

    Article  PubMed  CAS  Google Scholar 

  • De Grey AD (2005) Reactive oxygen species production in the mitochondrial matrix: implications for the mechanism of mitochondrial mutation accumulation.Rejuvenation Res. 8, 13–17.

    Article  PubMed  Google Scholar 

  • Desco M, JD Gispert, S Reig, J Sanz, J Pascau, F Sarramea, C Benito, A Santos, T Palomo and V Molina (2003) Cerebral metabolic patterns in chronic and recent-onset schizophrenia.Psychiatry Res. 122, 125–135.

    Article  PubMed  Google Scholar 

  • Deutch AY, B Moghaddam, RB Innis, JH Krystal, GK Aghajanian, BS Bunney and DS Charney (1991) Mechanisms of action of atypical antipsychotic drugs: Implications for novel therapeutic strategies for schizophrenia.Schizophr. Res. 4, 121–156.

    Article  PubMed  CAS  Google Scholar 

  • Dixon LB, AF Lehman and J Levine (1995) Conventional antipsychotic medications for schizophrenia.Schizophr. Bull. 21, 567–577.

    PubMed  CAS  Google Scholar 

  • Draper HH and M Hadley (1990) Malondialdehyde determination as index of lipid peroxidation.Meth. Enzymol. 186, 421–431.

    Article  PubMed  CAS  Google Scholar 

  • Farde L, FA Wiesel, AL Nordstrom and G Sedvall (1989) D1 and D2-receptor occupancy during treatment with conventional and atypical neuroleptics.Psychopharmacology 99, Suppl. S28-S31.

    Article  PubMed  Google Scholar 

  • Gentile S (2007) Extrapyramidal adverse events associated with atypical antipsychotic treatment of bipolar disorder. J.Clin. Psychopharmacol. 27, 35–45.

    Article  CAS  Google Scholar 

  • Halliwell B (1992) Reactive oxygen species and the central nervous system.J. Neurochem. 59, 1609–1623.

    Article  PubMed  CAS  Google Scholar 

  • Jordan S, V Koprivica, R Chen, K Tottori, T Kikuchi and CA Altar (2002) The antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT1a receptor.Eur. J. Pharmacol. 441, 137–140.

    Article  PubMed  CAS  Google Scholar 

  • Kapur S and G Remington (2001) Atypical antipsychotics: new directions and new challenges in the treatment of schizophrenia.Annu. Rev. Med. 52, 503–517.

    Article  PubMed  CAS  Google Scholar 

  • Kern RS, MF Green, BA Cornblatt, JR Owen, RD McQuade, WH Carson, M Ali and R Marcus (2006) The neurocognitive effects of aripiprazole: an open-label comparison with olanzapine.Psychopharmacology (Berl.) 187, 312–320.

    Article  CAS  Google Scholar 

  • Levine RL, D Garland and CN Oliver (1990) Determination of carbonyl content in oxidatively modified proteins.Meth. Enzymol. 186, 464–478.

    Article  PubMed  CAS  Google Scholar 

  • Lohr JB, JL Cadet, MA Lohr, L Larson, E Wasli, L Wade, R Hylton, C Vidoni, DV Jeste and RJ Wyatt (1988) Vitamin E in the treatment of tardive dyskinesia: the possible involvement of free radical mechanisms.Schizophr. Bull. 14, 291–296.

    PubMed  CAS  Google Scholar 

  • Lohr JB, R Kuczenski, HS Bracha, M Moir and DV Jeste (1990) Increased indices of free radical activity in the cerebrospinal fluid of patients with tardive dyskinesia.Biol. Psychiatry 28, 535–539.

    Article  PubMed  CAS  Google Scholar 

  • Lowry OH, NJ Rosebrough, AL Farr and RJ Randall (1951) Protein measurement with the Folin phenol reagent.J. Biol. Chem. 193, 265–267.

    PubMed  CAS  Google Scholar 

  • Mahadik SP, H Laev, A Korenovsky and SE Karpiak (1988) Haloperidol alters rat CNS cholinergic system: enzymatic and morphological analyses.Biol. Psychiatry 24, 199–217.

    Article  PubMed  CAS  Google Scholar 

  • Mahadik SP and S Mukherjee (1996) Free radical pathology and antioxidant defense in schizophrenia: a review.Schizophr. Res. 19, 1–17.

    Article  PubMed  CAS  Google Scholar 

  • Mahadik SP, S Mukherjee, R Scheffer, EE Correnti and JS Mahadik (1996) Elevated plasma lipid peroxides at the onset of non-affective psychosis.Biol. Psychiatry 43, 674–679.

    Article  Google Scholar 

  • Marchbanks RM, M Ryan and IN Day (2003) A mitochondrial DNA sequence variant associated with schizophrenia and oxidative stress.Schizophr. Res. 65, 33–38.

    Article  PubMed  CAS  Google Scholar 

  • McQuade RD, KD Burris, S Jordan,et al. (2002) Aripiprazole: a dopamine-serotonin system stabilizer.Int. J. Neuropsychopharmacol. 5, S176. (Abstr.)

    Google Scholar 

  • Munakata K, K Iwamoto and M Bundo (2005) Mitochondrial DNA 3243A>G mutation and increased expression of LARS2 gene in the brains of patients with bipolar disorder and schizophrenia.Biol. Psychiatry 57, 525–532.

    Article  PubMed  CAS  Google Scholar 

  • Parikh V, MM Khan and SP Mahadik (2003) Differential effects of antipsychotics on expression of antioxidant enzymes and membrane lipid peroxidation in rat brain.J. Psychiatr. Res. 37, 43–51.

    Article  PubMed  Google Scholar 

  • Parikh V, AV Terry and MM Khan (2004) Modulation of nerve growth factor and choline acetyltransferase expression in rat hippocampus after chronic exposure to haloperidol, risperidone, and olanzapine.Psychopharmacology (Berl.) 172, 365–374.

    Article  CAS  Google Scholar 

  • Peet M, J Laugharne and N Rangarajan (1993) Tardive dyskinesia, lipid peroxidation, and sustained amelioration with vitamin E treatment.Int. Clin. Psychopharmacol. 8, 151–153.

    Article  PubMed  CAS  Google Scholar 

  • Poderoso JJ, MC Carreras and C Lisdero (1996) Nitric oxide inhibits electron transfer and increases superoxide radical production in rat heart mitochondria and submitochondrial particles.Arch. Biochem. Biophys. 328, 85–92.

    Article  PubMed  CAS  Google Scholar 

  • Polydoro M, N Schröder and MN Lima, F Caldana, DC Laranja, E Bromberg, R Roesler, J Quevedo, JC Moreira and F Dal-Pizzol (2004) Haloperidol- and clozapine-induced oxidative stress in the rat brain.Pharmacol. Biochem. Behav. 78, 751–756.

    Article  PubMed  CAS  Google Scholar 

  • Reddy R and JK Yao (1996) Free radical pathology in schizophrenia: a review.Prostaglandins Leukot. Essent. Fatty Acids 55, 33–43.

    Article  PubMed  CAS  Google Scholar 

  • Reinke A, MR Martins, MS Lima, JC Moreira, F Dal-Pizzol and J Quevedo (2004) Haloperidol and clozapine, but not olanzapine, induces oxidative stress in rat brain.Neurosci. Lett. 372, 157–160.

    Article  PubMed  CAS  Google Scholar 

  • Rosengarten H and D Quartermain (2002) The effect of chronic treatment with typical and atypical antipsychotics on working memory and jaw movements in three- and eighteenmonth-old rats.Prog. Neuropsychopharmacol. Biol. Psychiatry 26, 1047–1054.

    Article  PubMed  CAS  Google Scholar 

  • Seeman P, T Lee, M Chau-Wong and K Wong (1976) Antipsychotic drug doses and neuroleptic/dopamine receptors.Nature 261, 717–719.

    Article  PubMed  CAS  Google Scholar 

  • Sharma T and D Mockler (1998) The cognitive efficacy of atypical antipsychotics in schizophrenia.J. Clin. Psychopharmacol. 18, 12–19.

    Article  Google Scholar 

  • Streck EL, GT Rezin, LM Barbosa, LC Assis, E Grandi and J Quevedo (2007) Effect of antipsychotics on succinate dehydrogenase and cytochrome oxidase activities in rat brain.Naunyn Schmiedebergs Arch. Pharmacol. 376(1-2), 127–133. DOI:10.1007/s00210-007-0178-2

    Article  PubMed  CAS  Google Scholar 

  • Terry AV, WD Hill, V Parikh, DR Evans, JL Waller and SP Mahadik (2002) Differential effects of chronic haloperidol and olanzapine exposure on brain cholinergic markers and spatial learning in rats.Psychopharmacology 164, 360–368.

    Article  PubMed  CAS  Google Scholar 

  • Terry AV, WD Hill, V Parikh, JL Waller, DR Evans and SP Mahadik (2003) Differential effects of haloperidol, risperidone and clozapine exposure on cholinergic markers and spatial learning performance in rats.Neuropsychopharmacology 28, 300–309.

    Article  PubMed  CAS  Google Scholar 

  • Terry AV and SP Mahadik (2007) Time-dependent cognitive deficits associated with first and second generation antipsychotics: cholinergic dysregulation as a potential mechanism.J. Pharmacol. Exp. Ther. 320, 961–968.

    Article  PubMed  CAS  Google Scholar 

  • Tollefson GD, CM Beasley Jr, RN Tamura, PV Tran and JH Potvin (1997) Blind, controlled, long-term study of the comparative incidence of treatment-emergent tardive dyskinesia with olanzapine or haloperidol.Am. J. Psychiatry 154, 1248–1254.

    PubMed  CAS  Google Scholar 

  • Velligan DI, J Newcomer, J Pultz, J Csernansky, AL Hoff, R Mahurin and AL Miller (2002) Does cognitive function improve with quetiapine in comparison to haloperidol?Schizophr. Res. 53, 239–248.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to JoÃo Quevedo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Martins, M.R., Petronilho, F.C., Gomes, K.M. et al. Antipsychotic-induced oxidative stress in Rat Brain. neurotox res 13, 63–69 (2008). https://doi.org/10.1007/BF03033368

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03033368

Keywords

Navigation