Abstract
Schizophrenia is causally associated with early-life environmental stress, implicating oxidative stress in its pathophysiology. N-acetyl cysteine (NAC), a glutathione precursor and antioxidant, is emerging as a useful agent in the adjunctive treatment of schizophrenia and other psychiatric illnesses. However, its actions on brain monoamine metabolism are unknown. Social isolation rearing (SIR) in rats presents with face, predictive and construct validity for schizophrenia. This study evaluated the dose-dependent effects of NAC (50, 150 and 250 mg/kg/day × 14 days) on SIR- vs. socially reared induced changes in cortico-striatal levels of dopamine (DA), serotonin (5-HT) noradrenaline (NA) and their associated metabolites. SIR induced significant deficits in frontal cortical DA and its metabolites, 3,4-dihydroxyphenylacetic acid (Dopac) and homovanillic acid (HVA), reduced 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and reduced levels of the NA metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG). In addition, significant elevations in frontal cortical NA and striatal DA, Dopac, HVA, 5-HT, 5-HIAA, NA and MHPG were also observed in SIR rats. NAC at 150 and 250 mg/kg reversed all cortico-striatal DA, Dopac, HVA, 5-HT, 5-HIAA and striatal NA alterations in SIR animals, with 250 mg/kg of NAC also reversing alterations in cortico-striatal MHPG. In conclusion, SIR profoundly alters cortico-striatal DA, 5-HT and NA pathways that parallel observations in schizophrenia, while these changes are dose-dependently reversed or abrogated by sub-chronic NAC treatment. A modulatory action on cortico-striatal monoamines may explain NACs’ therapeutic use in schizophrenia and possibly other psychiatric disorders, where redox dysfunction or oxidative stress is a causal factor.
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References
Aghajanian GK, Marek GJ (2000) Serotonin model of schizophrenia: emerging role of glutamate mechanisms. Brain Res Rev 31:302–312
Arent CO, Réus GZ, Abelaira HM, Ribeiro KF, Steckert AV, Mina F et al (2012) Synergist effects of n-acetylcysteine and deferoxamine treatment on behavioral and oxidative parameters induced by chronic mild stress in rats. Neurochem Int 61:1072–80
Avshalumov MV, Rice ME (2003) Activation ofATP-sensitive K + (K(ATP)) channels by H2O2 underlies glutamate-dependent inhibition of striatal dopamine release. Proc. Natl Acad Sci USA 100:11729–11734
Berk M, Copolov DL, Dean O, Lu K, Jeavons S, Schapkaitz I, Anderson-Hunt M, Bush AI (2008a) N-Acetyl cysteine for depressive symptoms in bipolar disorder—a double-blind randomized placebo-controlled trial. Biol Psychiatry 64:468–475
Berk M, Copolov DL, Dean O, Lu K, Jeavons S, Schapkaitz I, Anderson-Hunt M, Judd F, Katz F, Katz P et al (2008b) N-Acetyl cysteine as a glutathione precursor for schizophrenia—a double-blind, randomized, placebo-controlled trial. Biol Psychiatry 64:361–368
Berk M, Dean O, Cotton SM, Gama CS, Kapczinski F, Fernandes BS, Kohlmann K, Jeavons S, Hewitt K, Allwang C, Cobb H, Bush AI, Dodd S, Malhi GS (2011) The efficacy of n-acetylcysteine as an adjunctive treatment in bipolar depression: an open label trial. J Affect Disord 135:389–394
Berk M, Malhi GS, Gray LJ, Dean OM (2013) The promise of N-acetylcysteine in neuropsychiatry. Trends Pharmacol Sci 34:167–177
Bernstein HG, Keilhoff G, Steiner J, Dobrowolny H, Bogerts B (2011) Nitric oxide and schizophrenia: present knowledge and emerging concepts of therapy. CNS Neurol Disord Drug Targets 10:792–807
Blier P, El Mansari M (2007) The importance of serotonin and noradrenaline in anxiety. Int J Psychiatry Clin Pract 11:16–23
Brenes JC, Fornaguera J (2009) The effect of chronic fluoxetine on social isolation-induced changes on sucrose consumption, immobility behavior, and on serotonin and dopamine function in hippocampus and ventral striatum. Behav Brain Res 198:199–205
Cabungcal JH, Steullet P, Kraftsik R, Cuenod M, Do KQ (2012) Early-life insults impair parvalbumin interneurons via oxidative stress: Reversal by N-acetylcysteine. Biol Psychiatry 73:574–82
Carlsson A, Waters N, Holm-Waters S, Tedroff J, Nilsson M, Carlsson ML (2001) Interactions between monoamines, glutomate, and GABA in schizophrenia: New evidence. Ann Rev Pharmacol Toxicol 41:237–260
Chorpita BF, Barlow DH (1998) The development of anxiety: the role of control in the early environment. Psychol Bull 124:3–21
Dantzer R, O’Connor JC, Lawson MA, Kelley KW (2011) Inflammation-associated depression: from serotonin to kynurenine. Psychoneuroendocrinology 36:426–436
Dean OM, van den Buuse M, Bush AI (2009) A role for glutathione in the pathophysiology of bipolar disorder and schizophrenia? Animal models and relevance to clinical practice. Curr Med Chem 16:2965–76
Dean OM, Giorlando F, Berk M (2011) N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci 36:78–86
Dodd S, Dean O, Copolov DL, Malhi GS, Berk M (2008) N-acetylcysteine for antioxidant therapy: Pharmacology and clinical utility. Expert Opin Biol Ther 8:1955–1962
Galynker II, Cai J, Ongseng F, Finestone H, Dutta E, Serseni D (1998) Hypofrontality and negative symptoms in major depressive disorder. J Nucl Med 39:608–612
Garcia-Cazorla A, Duarte S, Serrano M, Nascimento A, Ormazabal A, Carrilho I et al (2008) Mitochondrial diseases mimicking neurotransmitter defects. Mitochondrion 8:273–278
Garvey MJ, Tuason VB (1996) Low levels of MHPG in depressive spectrum patients. J Affect Disord 37:103–108
Gawryluk JW, Wang J, Andreazza AC, Shao L, Yatham LM, Young LT (2011) Prefrontal cortex glutathione S-transferase levels in patients with bipolar disorder, major depression and schizophrenia. Int J Neuropsychopharmacol 14:1069–1074
Grant JE, Odlaug BL, Kim SW (2009) N-acetylcysteine, a glutamate modulator, in the treatment of trichotillomania: a double-blind, placebo-controlled study. Arch Gen Psychiatry 66:756–763
Guillin O, Abi-Dargham A, Laruelle M (2007) Neurobiology of dopamine in schizophrenia. Int Rev Neurobiol 78:1–39
Haroutunian V, Dracheva S, Davis KL (2003) Neurobiology of glutamatergic abnormalities in schizophrenia. Clin Neurosci Res 3:67–76
Harsing LG, Prauda I, Barkoczy J, Matyus P, Juranyi Z (2004) A 5-HT7 heteroreceptor-mediated inhibition of [3H]serotonin release in raphe nuclei slices of the rat: evidence for a serotonergic-glutamatergic interaction. Neurochem Res 29:1487–1497
Harvey BH, Stein DJ, Emsley RA (1999) The new generation antipsychotics: integrating the neuropathology and pharmacology of schizophrenia. S Afr Med J 89:661–672
Harvey BH, Brand L, Jeeva Z, Stein DJ (2006) Cortical/hippocampal monoamines, HPA-axis changes and aversive behavior following stress and restress in an animal model of post-traumatic stress disorder. Physiol Behav 87:881–90
Heresco-Levy U, Ermilov M, Shimoni J, Shapira B, Silipo G, Javitt DC (2002) Placebo-controlled trial of D-cycloserine added to conventional neuroleptics, olanzapine, or risperidone in schizophrenia. Am J Psychiatry 159:480–482
Hovattaa J, Juhila J, Donner J (2010) Oxidative stress in anxiety and comorbid disorders. Neurosci Res 68:261–275
Howes OD, Kapur S (2009) The Dopamine Hypothesis of Schizophrenia: Version III - The Final Common Pathway. Schizophr Bull 35:549–562
Jaffe E, De Frias V, Ibarra C (1991) Changes in basal and stimulated release of endogenous serotonin from different nuclei of rats subjected to two models of depression. Neurosci Lett 62:157–160
Joyce JN, Shane A, Lexow N, Winokur A, Casanova MF, Kleinman JE (1993) Serotonin uptake sites and serotonin receptors are altered in the limbic system of schizophrenics. Neuropsychopharmacology 8:315–36
Kerksick C, Willoughby D (2005) The Antioxidant Role of Glutathione and N-Acetyl-Cysteine Supplements and Exercise-Induced Oxidative Stress. J Int Soc Sports Nutr 2:38–44
Krivoy A, Fischel T, Weizman A (2008) The possible involvement of metabotropic glutamate receptors in schizophrenia. Euro Neuropsychopharmacol 18:395–405
Krügel U, Kittner H, Illes P (2001) Mechanisms of adenosine 50-triphosphate-induced dopamine release in the rat nucleus accumbens in vivo. Synapse 39:222–232
Kuloglu M, Ustundag B, Atmaca M, Canatan H, Tezcan AE, Cinkilinc N (2002) Lipid peroxidation and antioxidant enzyme levels in patients with schizophrenia and bipolar disorder. Cell Biochem Func 20:171–175
Kunz M, Gama CS, Andreazza AC, Salvador M, Ceresér KM, Gomes FA, Belmonte-de-Abreu PS, Berk M, Kapczinski F (2008) Elevated serum superoxide dismutase and thiobarbituric acid reactive substances in different phases of bipolar disorder and in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 32:1677–1681
Lewis D, González-Burgos G (2008) Neuroplasticity of neocortical circuits in schizophrenia. Neuropsychopharmacology 33:141–165
Lieberman JA (1993) Understanding the mechanism of action of atypical antipsychotic drugs: a review of compounds in use and development. Brit J Psychiatry 163:7–18
Lysaker PH, Salyers MP (2007) Anxiety symptoms in schizophrenia spectrum disorders: associations with social function, positive and negative symptoms, hope and trauma history. Acta Psychiatr Scand 116:290–298
Magalhaes PV, Dean O, Bush AI, Copolov DL, Malhi GS, Kohlmann K, Jeavons S, Schapkaitz I, Anderson-Hunt M, Berk M (2011) N-acetylcysteine for major depressive episodes in bipolar disorder. Rev Bras Psiquiatr 33:374–378
Matheson SL, Shepherd AM, Laurens KR, Carr VJ (2011) A systematic metareview grading the evidence for non-genetic risk factors and putative antecedents of schizophrenia. Schizophr Res 133:133–142
McNamee EN, Griffin EW, Ryan KM, Ryan KJ, Heffernan S, Harkin A, Connor TJ (2010) Noradrenaline acting at beta-adrenoceptors induces expression of IL-1beta and its negative regulators IL-1ra and IL-1RII, and drives an overall anti-inflammatory phenotype in rat cortex. Neuropharmacology 59:37–48
Meltzer HY, Li Z, Kaneda Y, Ichikawa J (2003) Serotonin receptors: their key role in drugs to treat schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 27:1159–1172
Meyer U, Feldon J (2009) Prenatal exposure to infection: a primary mechanism for abnormal dopaminergic development in schizophrenia. Psychopharmacol 206:587–60
Meyer-Lindenberg A, Miletich RS, Kohn PD, Esposito G, Carson RE, Quarantelli M, Weinberger DR, Berman KF (2002) Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci 5:267–71
Milusheva E, Sperlágh B, Shikova L, Baranyi M, Tretter L, Adám-Vizi V, Vizi ES (2003) Non-synaptic release of [3H]noradrenaline in response to oxidative stress combined with mitochondrial dysfunction in rat hippocampal slices. Neurosci 120:771–781
Miyamoto S, Duncan GE, Marx CE, Lieberman JA (2005) Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry 10:79–104
Möller M, Du Preez JL, Emsley R, Harvey BH (2011) Isolation rearing-induced deficits in sensorimotor gating and social interaction in rats are related to cortico-striatal oxidative stress, and reversed by sub-chronic clozapine administration. Eur Neuropsychopharmacol 21:471–483
Möller M, Du Preez JL, Emsley R, Harvey BH (2012) Social isolation rearing in rats alters plasma tryptophan metabolism and is reversed by sub-chronic clozapine treatment. Neuropharmacology 62:2499–2506
Möller M, Du Preez JL, Viljoen FP, Berk M, Emsley R, Harvey BH (2013) Social isolation rearing induces mitochondrial, immunological, neurochemical and behavioural deficits in rats, and is reversed by clozapine or N-acetyl cysteine. Brain Behav Immun 30:156–67
Mukherjee S, Mahadik SP, Scheffer R, Correntie E, Kelkar H (1996) Impaired antioxidant defence at the onset of psychosis. Schizophr Res 19:19–26
Musazzi L, Racagni G, Popoli M (2011) Stress, glucocorticoids and glutamate release: effects of antidepressant drugs. Neurochem Int 59:138–49
Ng F, Berk M, Dean O, Bush AI (2008) Oxidative stress in psychiatric disorders: evidence base and therapeutic implications. Int J Neuropsychopharmacol 11:851–876
Okuno A, Fukuwatari T, Shibata K (2011) High tryptophan diet reduces extracellular dopamine release via kynurenic acid production in rat striatum. J Neurochem 118:796–805
O’Sullivan JB, Ryan KM, Curtin NM, Harkin A, Connor TJ (2009) Noradrenaline reuptake inhibitors limit neuroinflammation in rat cortex following a systemic inflammatory challenge: implications for depression and neurodegeneration. Int J Neuropsychopharmacol 12:687–99
Pervanidou P (2008) Biology of post-traumatic stress disorder in childhood and adolescence. J Neuroendocrinol 20:632–638
Powell SB, Geyer MA, Preece MA, Pitcher LK, Reynolds GP, Swerdlow NR (2003) Dopamine depletion of the nucleus accumbens reverses isolation-induced deficits in prepulse inhibition in rats. Neurosci 119:233–40
Prabakaran S, Swatton J, Ryan MM, Huffaker SJ, Huang JT, Griffin JL et al (2004) Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress. Mol Psychiatry 9:684–697
Radonjić NV, Knezević ID, Vilimanovich U (2010) Decreased glutathione levels and altered antioxidant defense in an animal model of schizophrenia: long-term effects of perinatal phencyclidine administration. Neuropharmacology 58:739–45
Rilke O, Will K, Jähkel M, Oehler J (2001) Behavioral and neurochemical effects of anpirtoline and citalopram in isolated and group housed mice. Prog Neuro- Psychopharmacol Biol Psychiatry 25:1125–1144
Rollema H, Lu Y, Schmidt AW, Sprouse JS, Zorn SH (2000) 5-HT(1A) receptor activation contributes to ziprasidone-induced dopamine release in the rat prefrontal cortex. Biol Psychiatry 48:229–237
Schiavone S, Sorce S, Dubois-Dauphin M, Jaquet V, Colaianna M, Zotti M, Cuomo V, Trabace L, Krause KH (2009) Involvement of Nox2 in the development of behavioral and pathologic alterations in isolated rats. Biol Psychiatry 66:384–392
Schiavone S, Jaquet V, Sorce S, Dubois-Dauphin M, Hultqvist M, Bäckdahl L et al (2012) NADPH oxidase elevations in pyramidal neurons drive psychosocial stress-induced neuropathology. Transl Psychiatry 2:e111
Schwartz TL, Sachdeva S, Stahl SM (2012) Glutamate neurocircuitry: theoretical underpinnings in Schizophrenia. Front Pharmacol 3:195
Singh S, Greene RM, Pisano MM (2010) Arsenate-induced apoptosis in murine embryonic maxillary mesenchymal cells via mitochondrial-mediated oxidative injury. Birth Defects Res A Clin Mol Teratol 88:25–34
Smaga I, Pomierny B, Krzyżanowska W, Pomierny-Chamioło L, Miszkiel J, Niedzielska E, Ogórka A, Filip M (2012) N-acetylcysteine possesses antidepressant-like activity through reduction of oxidative stress: Behavioral and biochemical analyses in rats. Prog Neuro-Psychopharmacol Biol Psychiatry 39:280–287
Smythies J (1999) Redox mechanisms at the glutamate synapse and their significance: a review. Eur J Pharmacol 370:1–7
Sorce S, Schiavone S, Tucci P, Colaianna M, Jaquet V, Cuomo V et al (2010) The NADPH oxidase NOX2 controls glutamate release: a novel mechanism involved in psychosis-like ketamine responses. J Neurosci 30:11317–11325
Stahl SM (2007) Beyond the dopamine hypothesis to the NMDA glutamate receptor hypofunction hypothesis of schizophrenia. CNS Spectr 12:265–268
Sumiyoshi T, Stockmeier C, Overholser J, Dilley G, Meltzer H (1996) Serotonin-1A receptors are increased in postmortem prefrontal cortex in schizophrenia. Brain Res 708:209–214
Swanson LW (2004) Brain maps: structure of the rat brain. Elsevier Academic Press
Ting JT, Feng G (2008) Glutamatergic synaptic dysfunction and obsessive-compulsive disorder. Curr Chem Genomics 2:62–75
Toua C, Brand L, Möller M, Emsley RA, Harvey BH (2010) The effects of sub-chronic clozapine and haloperidol administration on isolation rearing induced changes in frontal cortical N-methyl-D-aspartate and D1 receptor binding in rats. Neurosci 165:492–499
Trabace L, Zotti M, Colaianna M, Mg M, Schiavone S, Tucci P, Harvey BH, Wegener G, Cuomo V (2012) Neurochemical differences in two rat strains exposed to social isolation rearing. Acta Neuropsychiatrica 24:286–295
Wang J, Shao L, Sun X, Young LT (2009) Increased oxidative stress in the striatum of subjects with bipolar disorder and schizophrenia. Biopolar Disord 11:523–529
Wu G, Fang Y, Yang S, Lupton JR, Turner ND (2004) Glutathione Metabolism and Its Implications for Health. J Nutr 134:489–492
Yamamoto K, Hornykiewicz O (2004) Proposal for a noradrenaline hypothesis of schizophrenia. Prog NeuroPsychopharmacol Biol Psychiatry 28:913–922
Zumárraga M, Dávila R, Basterreche N, Arrue A, Goienetxea B, Zamalloa MI, Erkoreka L, Bustamante S, Inchausti L, González-Torres MA, Guimón J (2010) Catechol O-methyltransferase and monoamine oxidase A genotypes, and plasma catecholamine metabolites in bipolar and schizophrenic patients. Neurochem Int 56:774–779
Acknowledgments
The authors declare that this work has been funded by the South African Medical Research Council (BHH). The funder has no other role in this study. The authors would like to thank Mr. Cor Bester, Me. Antoinette Fick and Mr. Petri Bronkhorst for their assistance in the breeding and welfare of the animals.
Conflict of interest
The authors declare that over the past 3 years. Brian Harvey has participated in speakers/advisory boards and received honoraria from Organon, Pfizer and Servier, and has received research funding from Lundbeck. The authors declare that, except for income from the primary employer and research funding to BHH from the South African Medical Research Council, and the above-mentioned exceptions, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional services, and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. Michael Berk has received Grant/Research Support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, MBF, NHMRC, Beyond Blue, Rotary Health, Geelong Medical Research Foundation, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Organon, Novartis, Mayne Pharma and Servier, has been a speaker for Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck, Merck, Pfizer, Sanofi Synthelabo, Servier, Solvay and Wyeth, and served as a consultant to Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck Merck and Servier. Dr Berk is a co-inventor of two provisional patents regarding the use of NAC and related compounds for psychiatric indications, which, while assigned to the Flory Institute of Neuroscience and Mental Health, could lead to personal remuneration upon a commercialization event.
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Möller, M., Du Preez, J.L., Viljoen, F.P. et al. N-acetyl cysteine reverses social isolation rearing induced changes in cortico-striatal monoamines in rats. Metab Brain Dis 28, 687–696 (2013). https://doi.org/10.1007/s11011-013-9433-z
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DOI: https://doi.org/10.1007/s11011-013-9433-z