Schizophrenia is associated with prenatal inflammation and/or postnatal stressors such as drug abuse, resulting in immune-redox dysfunction. Antioxidants may offer therapeutic benefits.
The objective of this study is to investigate N-acetyl cysteine (NAC) as a therapeutic antioxidant to reverse schizophrenia-like bio-behavioural changes in rats exposed to maternal immune activation (MIA), adolescent methamphetamine (MA) or a combination thereof.
Sprague-Dawley offspring prenatally exposed to saline/lipopolysaccharide (LPS) received saline or MA (0.2–6 mg kg−1 twice daily × 16 days) during adolescence and divided into LPS, MA and LPS + MA groups. Vehicle/NAC (150 mg kg−1 × 14 days) was administered following MA/saline exposure on postnatal day 51–64. Social interaction, novel object recognition and prepulse inhibition (PPI) of startle, as well as regional brain monoamines, lipid peroxidation, plasma reactive oxygen species (ROS) and pro- and anti-inflammatory cytokines (TNF-α; IL-10), were assessed.
NAC reversed LPS, MA and LPS + MA-induced anxiety-like social withdrawal behaviours, as well as MA and LPS + MA-induced deficits in recognition memory. PPI deficits were evident in MA, LPS and LPS + MA models, with NAC reversing that following LPS + MA. NAC reversed LPS, MA and LPS + MA-induced frontal cortical dopamine (DA) and noradrenaline (NA) elevations, LPS and LPS + MA-induced frontal cortical 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT) and striatal NA deficits as well as LPS + MA-induced frontal cortical 5-HT turnover. Decreased IL-10 in the LPS, MA and LPS + MA animals, and increased TNF-α in the LPS and MA animals, was reversed with NAC. NAC also reversed elevated lipid peroxidation and ROS in the LPS and LPS + MA animals.
Prenatal LPS, LPS + postnatal MA challenge during adolescence, and to a lesser extent MA alone, promotes schizophrenia-like bio-behavioural changes later in life that are reversed by NAC, emphasizing therapeutic potential for schizophrenia and MA-associated psychosis. The nature and timing of the dual-hit are critical.
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Akdag SJ, Nestor PG, O'Donnell BF, Niznikiewicz MA, Shenton ME, McCarley RW (2003) The startle reflex in schizophrenia: habituation and personality correlates. Schizo Res 64:165–173. https://doi.org/10.1016/S0920-9964(03)00059-8
Alsene KM, Rajbhandari AK, Bakshi VP, Ramaker MJ (2011) Discrete forebrain neuronal networks supporting noradrenergic regulation of sensorimotor gating. Neuropsychopharmacology 36:1003–1014. https://doi.org/10.1038/npp.2010.238
Antunes M, Biala G (2012) The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process 13:93–110. https://doi.org/10.1007/s10339-011-0430-z
Arsenault D, St-Amour I, Cisbani G, Rousseau LS, Cicchetti F (2014) The different effects of LPS and poly I: C prenatal immune challenges on the behavior, development and inflammatory responses in pregnant mice and their offspring. Brain Behav Immun 38:77–90. https://doi.org/10.1016/j.bbi.2013.12.016
Baharnoori M, Bhardwaj SK, Srivastava LK (2013) Effect of maternal lipopolysaccharide administration on the development of dopaminergic receptors and transporter in the rat offspring. PLoS One 8. https://doi.org/10.1371/journal.pone.0054439
Basta-Kaim A, Budziszewska B, Regulska M, Leśkiewicz M, Kubera M, Lasoń W, Fijał K, Wȩdzony K, Gołembiowska K (2011) Prenatal lipopolysaccharide treatment enhances MK-801-induced psychotomimetic effects in rats. Pharmacol Biochem Behav 98:241–249. https://doi.org/10.1016/j.pbb.2010.12.026
Beloosesky R, Weiner Z, Ginsberg Y, Ross MG (2012) Maternal N-acetyl-cysteine (NAC) protects the rat fetal brain from inflammatory cytokine responses to lipopolysaccharide (LPS). J Matern Fetal Neonatal Med 25:1324–1328. https://doi.org/10.3109/14767058.2011.632793
Berk M, Copolov D, Dean O, Bush AI, Lu K, Schapkaitz I, Anderson-Hunt M, Jeavons S, Judd F, Katz F, Katz P, Ording-Jespersen S, Little J, Conus P, Cuenod M, Do KQ (2008) N-acetyl cysteine as a glutathione precursor for schizophrenia—a double-blind, randomized, placebo-controlled trial. Biol Psychiatry 64:361–368. https://doi.org/10.1016/j.biopsych.2008.03.004
Bitanihirwe BKY, Woo TUW (2011) Oxidative stress in schizophrenia: an integrated approach. Neurosci Biobehav Rev 35:878–893
Boksa P (2010) Effects of prenatal infection on brain development and behavior: a review of findings from animal models. Brain Behav Immun 24:881–897. https://doi.org/10.1016/j.bbi.2010.03.005
Borrell J, Vela JM, Arévalo-Martin A, Molina-Holgado E, Guaza C (2002) Prenatal immune challenge disrupts sensorimotor gating in adult rats: implications for the etiopathogenesis of schizophrenia. Neuropsychopharmacology 26:204–215. https://doi.org/10.1038/S0893-133X(01)00360-8
Brand SJ, Möller M, Harvey BH (2015) A review of biomarkers in mood and psychotic disorders: a dissection of clinical vs. preclinical correlates. Curr Neuropharmacol 13:324–368
Brecht M, Herbeck D (2014) Time to relapse following treatment for methamphetamine use: a long-term perspective on patterns and predictors. Drug Alcohol Depend 139:18–25
Brown AS, Derkits EJ (2010) Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry 167:261–280
Brown JM, Yamamoto BK (2003) Effects of amphetamines on mitochondrial function: role of free radicals and oxidative stress. Pharmacol Ther 99:45–53. https://doi.org/10.1016/S0163-7258(03)00052-4
Brunton LL, Chabner BA, Knollman BC (2011) Goodman and Gilman's The Pharmacological Basis of Therapeutics 12th Ed. McGraw-Hill Medical, New York
Calcagnetti DJ, Schechter MD (1992) Place conditioning reveals the rewarding aspect of social interaction in juvenile rats. Physiol Behav 51:667–672
Chen CK, Lin SK, Sham PC, Ball D, Loh EW, Hsiao CC, Chiang YL, Ree SC, Lee CH, Murray RM (2003) Pre-morbid characteristics and co-morbidity of methamphetamine users with and without psychosis. Psychol Med 33:1407–1414. https://doi.org/10.1017/S0033291703008353
Chen CK, Lin SK, Sham PC, Ball D, Loh e-W, Murray RM (2005) Morbid risk for psychiatric disorder among the relatives of methamphetamine users with and without psychosis. Am J Med Genet Neuropsychiatr Genet 136 B:87–91
Crumeyrolle-Arias M, Jaglin M, Bruneau A, Vancassel S, Cardona A, Daugé V, Naudon L, Rabot S (2014) Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats. Psychoneuroendocrinology 42: 207-17
Dantzer R, O'Connor JC, Lawson MA, Kelley KW (2011) Inflammation-associated depression: from serotonin to kynurenine. Psychoneuroendocrinology 36:426–436. https://doi.org/10.1016/j.psyneuen.2010.09.012
Darke S, Kaye S, McKetin R, Duflou J (2008) Major physical and psychological harms of methamphetamine use. Drug Alcohol Rev 27:253–262. https://doi.org/10.1080/09595230801923702
Davis J, Moylan S, Harvey BH, Maes M, Berk M (2014) Neuroprogression in schizophrenia: pathways underpinning clinical staging and therapeutic corollaries. Aust NZ J Psychiatry 48:512–529. https://doi.org/10.1177/0004867414533012
Davis J, Eyre H, Jacka FN, Dodd S, Dean O, McEwen S, Debnath M, McGrath J, Maes M, Amminger P, McGorry PD, Pantelis C, Berk M (2016) A review of vulnerability and risks for schizophrenia: beyond the two hit hypothesis. Neurosci Biobehav Rev 65:185–194
De Laurentiis A, Pisera D, Caruso C, Candolfi M, Mohn C, Rettori V, Seilicovich A (2002) Lipopolysaccharide-and tumor necrosis factor-α-induced changes in prolactin secretion and dopaminergic activity in the hypothalamic-pituitary axis. Neuroimmunomodulation 10:30–39
Debnath M, Venkatasubramanian G, Berk M (2015) Fetal programming of schizophrenia: select mechanisms. Neurosci Biobehav Rev 49:90–104. https://doi.org/10.1016/j.neubiorev.2014.12.003
Depino A (2015) Early prenatal exposure to LPS results in anxiety-and depression-related behaviors in adulthood. Neuroscience 299:56–65
Dinel A, Joffre C, Trifilieff P, Aubert A, Foury A, Le Ruyet P, Layé S (2014) Inflammation early in life is a vulnerability factor for emotional behavior at adolescence and for lipopolysaccharide-induced spatial memory and neurogenesis alteration at adulthood. J Neuroinflammation 11:155
Ferreira FF, Biojone C, Joca SRL, Guimarães FS (2008) Antidepressant-like effects of N-acetyl-L-cysteine in rats. Behav Pharmacol 19:747–750
File SE, Hyde JR (1978) Can social interaction be used to measure anxiety? Br J Pharmacol 62:19–24
File SE, Lippa AS, Beer B, Lippa MT (2005) Animal tests of anxiety. Current protocols in pharmacology / editorial board, S J Enna (editor-in-chief) et al ] Chapter 5:Unit 5.38.
Fleckenstein AE, Wilkins DG, Gibb JW, Hanson GR (1997) Interaction between hyperthermia and oxygen radical formation in the 5-hydroxytryptaminergic response to a single methamphetamine administration. J Pharmacol Exp Ther 283:281–285
Gaskin PLR (2014) Evaluation of novel dual-hit models of ‘schizophrenia-like’ symptoms in the rat (Doctoral dissertation, University of Nottingham)
Gaskin P, Alexander S, Fone K (2014) Neonatal phencyclidine administration and post-weaning social isolation as a dual-hit model of ‘schizophrenia-like’ behaviour in the rat. Psychopharmacol 231:2533–2545
Gemmel M, Rayen I, Lotus T, van Donkelaar E, Steinbusch HW, De Lacalle S, Kokras N, Dalla C, Pawluski JL (2016) Developmental fluoxetine and prenatal stress effects on serotonin, dopamine, and synaptophysin density in the PFC and hippocampus of offspring at weaning. Dev Psychobiol 58:315–327. https://doi.org/10.1002/dev.21372
Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR (2001) Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology 156:117
Gilabert-Juan J, Belles M, Saez AR, Carceller H, Zamarbide-Fores S, Moltó MD, Nacher J (2013) A “double hit” murine model for schizophrenia shows alterations in the structure and neurochemistry of the medial prefrontal cortex and the hippocampus. Neurobiol Dis 59:126–140. https://doi.org/10.1016/j.nbd.2013.07.008
Gonçalves J, Baptista S, Martins T, Milhazes N, Borges F, Ribeiro CF, Malva JO, Silva AP (2010) Methamphetamine-induced neuroinflammation and neuronal dysfunction in the mice hippocampus: preventive effect of indomethacin. Eur J Neurosci 31:315–326
Grace CE, Schaefer TL, Herring NR, Graham DL, Skelton MR, Gudelsky GA, Williams MT, Vorhees CV (2010) Effect of a neurotoxic dose regimen of (+)-methamphetamine on behavior, plasma corticosterone, and brain monoamines in adult C57BL/6 mice. Neurotoxicol Teratol 32:346–355 https://doi.org.nwulib.nwu.ac.za/10.1016/j.ntt.2010.01.006
Graciarena M, Depino AM, Pitossi FJ (2010) Prenatal inflammation impairs adult neurogenesis and memory related behavior through persistent hippocampal TGFß1 downregulation. Brain Behav Immun 24:1301–1309
Grant KM, LeVan TD, Wells SM, Gendelman HE, Li M, Stoltenberg SF, Carlo G, Bevins RA (2012) Methamphetamine-associated psychosis. J NeuroImmune Pharmacol 7:113–139. https://doi.org/10.1007/s11481-011-9288-1
Granholm AC, Zaman V, Godbee J, Smith M, Ramadan R, Umphlet C, Randall P, Bhat NR, Rohrer B, Middaugh LD, Boger HA (2011) Prenatal LPS increases inflammation in the substantia nigra of Gdnf heterozygous mice. Brain Pathol 21: 330-48
Grima G, Benz B, Parpura V, Cuénod M, Do KQ (2003) Dopamine-induced oxidative stress in neurons with glutathione deficit: implication for schizophrenia. Schizophr Res 62:213–224. https://doi.org/10.1016/S0920-9964(02)00405-X
Harvey L, Boksa P (2012) A stereological comparison of GAD67 and reelin expression in the hippocampal stratum oriens of offspring from two mouse models of maternal inflammation during pregnancy. Neuropharmacology 62:1767–1776. https://doi.org/10.1016/j.neuropharm.2011.11.022
Harvey L, Boksa P (2014) Additive effects of maternal iron deficiency and prenatal immune activation on adult behaviors in rat offspring. Brain Behav Immun 40:27–37 https://doi.org.nwulib.nwu.ac.za/10.1016/j.bbi.2014.06.005
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 87:881–890. https://doi.org/10.1016/j.physbeh.2006.01.033
Hastings TG (1995) Enzymatic oxidation of dopamine: the role of prostaglandin H synthase. J Neurochem 64:919–924
Hayashi I, Morishita Y, Imai K, Nakamura M, Nakachi K, Hayashi T (2007) High-throughput spectrophotometric assay of reactive oxygen species in serum. Mut Res Genet Toxicol Environ Mutagen 631:55–61. https://doi.org/10.1016/j.mrgentox.2007.04.006
Hornung JP (2003) The human raphe nuclei and the serotonergic system. J Chem Neuroanat 26:331–343
Howes OD, Kapur S (2014) A neurobiological hypothesis for the classification of schizophrenia: type A (hyperdopaminergic) and type B (normodopaminergic). Br J Psychiatry 205:1–3. https://doi.org/10.1192/bjp.bp.113.138578.
Howes OD, McCutcheon R, Owen MJ, Murray RM (2017) The role of genes, stress, and dopamine in the development of schizophrenia. Biol Psychiatry 81:9–20. https://doi.org/10.1016/j.biopsych.2016.07.014
Huckans M, Fuller BE, Chalker AL, Adams M, Loftis JM (2015) Plasma Inflammatory Factors Are Associated with Anxiety, Depression, and Cognitive Problems in Adults with and without Methamphetamine Dependence: An Exploratory Protein Array Study. Front Psychiatry 6:178
Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG (2010) Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 8:e1000412
Lanté F, Guiramand J, De Ferreira M-J, Cambonie G, Aimar R, Cohen-Solal C, Vignes M, Barbanel G, Meunier J, Maurice T (2008) Late N-acetylcysteine treatment prevents the deficits induced in the offspring of dams exposed to an immune stress during gestation. Hippocampus 18:602–609. https://doi.org/10.1002/hipo.20421
Laruelle M (2014) Schizophrenia: from dopaminergic to glutamatergic interventions. Curr Opin Pharmacol 14:97–102. https://doi.org/10.1016/j.coph.2014.01.001
Lieberman JA (1999) Is schizophrenia a neurodegenerative disorder? A clinical and neurobiological perspective. Biol Psychiatry 46:729–739
Limón-Pacheco J, Gonsebatt ME (2009) The role of antioxidants and antioxidant-related enzymes in protective responses to environmentally induced oxidative stress. Mutat Res Genet Toxicol Environ Mutagen 674:137–147
Loftis JM, Choi D, Hoffman W, Huckans MS (2011) Methamphetamine causes persistent immune dysregulation: a cross-species, translational report. Neurotox Res 20:59–68. https://doi.org/10.1007/s12640-010-9223-x
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
Martínez-Cengotitabengoa M, Mac-Dowell KS, Leza JC, Micó JA, Fernandez M, Echevarría E, Sanjuan J, Elorza J, González-Pinto A (2012) Cognitive impairment is related to oxidative stress and chemokine levels in first psychotic episodes. Schizophr Res 137:66–72. https://doi.org/10.1016/j.schres.2012.03.004
McDonnell-Dowling K, Kelly JP (2017) The role of oxidative stress in methamphetamine-induced toxicity and sources of variation in the design of animal studies. Curr Neuropharmacol 15:300–314. https://doi.org/10.2174/1570159X14666160428110329
McGrath JJ, Feron FP, Burne TH, Mackay-Sim A, Eyles DW (2003) The neurodevelopmental hypothesis of schizophrenia: a review of recent developments. Ann Med 35:86–93
Meyer U (2013) Developmental neuroinflammation and schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry 42:20–34
Meyer U, Schwendener S, Feldon J, Yee BK (2006) Prenatal and postnatal maternal contributions in the infection model of schizophrenia. Exp Brain Res 173:243–257. https://doi.org/10.1007/s00221-006-0419-5
Meyer U, Feldon J, Yee BK (2009) A review of the fetal brain cytokine imbalance hypothesis of schizophrenia. Schizophr Bull 35:959–972. https://doi.org/10.1093/schbul/sbn022
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 5:267–271. https://doi.org/10.1038/nn804
Millan MJ (2003) The neurobiology and control of anxious states. Prog Neurobiol 70:83–244
Möller M, Harvey BH, Du Preez JL, Emsley R (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. https://doi.org/10.1016/j.euroneuro.2010.09.006
Möller M, Du Preez JL, Viljoen FP, Berk M, Emsley R, Harvey BH (2013a) Social isolation rearing induces mitochondrial, immunological, neurochemical and behavioural deficits in rats, and is reversed by clozapine or N-acetyl cysteine. Brain Behav Immun 30:156–167 https://doi.org.nwulib.nwu.ac.za/10.1016/j.bbi.2012.12.011
Möller M, Du Preez JL, Viljoen FP, Berk M, Harvey BH (2013b) N-acetyl cysteine reverses social isolation rearing induced changes in cortico-striatal monoamines in rats. Metab Brain Dis 28:687–696
Möller M, Swanepoel T, Harvey BH (2015) Neurodevelopmental animal models reveal the convergent role of neurotransmitter systems, inflammation, and oxidative stress as biomarkers of schizophrenia: implications for novel drug development. ACS Chem Neurosci 6:987–1016. https://doi.org/10.1021/cn5003368
Montoya A, Bruins R, Katzman MA, Blier P (2016) The noradrenergic paradox: implications in the management of depression and anxiety. Neuropsychiatr Dis Treat 12:541
Mousavi SG, Sharbafchi MR, Peykanpour M, Sichani NK, Maracy M (2015) The efficacy of N-acetylcysteine in the treatment of methamphetamine dependence: a double-blind controlled, crossover study. Arch Iran Med 18:28
Mouton M, Harvey BH, Cockeran M, Brink CB (2016) The long-term effects of methamphetamine exposure during pre-adolescence on depressive-like behaviour in a genetic animal model of depression. Met Brain Dis 31:63–74. https://doi.org/10.1007/s11011-015-9765-y
Murray RM, Lewis SW (1987) Is schizophrenia a neurodevelopmental disorder? Br Med J 295:681–682
Nishijima K, Kashiwa A, Hashimoto A, Iwama H, Umino A, Nishikawa T (1996) Differential effects of phencyclidine and methamphetamine on dopamine metabolism in rat frontal cortex and striatum as revealed by in vivo dialysis. Synapse 22:304–312
Ohyama K, Sano T, Toyoda H (2004) Predominant contribution of IFN-β expression to apoptosis induction in human uterine cervical fibroblast cells by influenza-virus infection. Biol Pharm Bull 27:1750–1757. https://doi.org/10.1248/bpb.27.1750
Panenka WJ, Procyshyn RM, MacEwan GW, Flynn SW, Honer WG, Barr AM, Lecomte T (2012) Methamphetamine use: a comprehensive review of molecular, preclinical and clinical findings. Drug Alcohol Depend. https://doi.org/10.1016/j.drugalcdep.2012.11.016
Paxinos G, Watson CR, Emson PC (1980) AChE-stained horizontal sections of the rat brain in stereotaxic coordinates. J Neurosci Methods 3:129–149
Pelletier M, Achim AM, Montoya A, Lal S, Lepage M (2005) Cognitive and clinical moderators of recognition memory in schizophrenia: a meta-analysis. Schizophr Res 74:233–252
Rajagopal L, W Massey B, Huang M, Oyamada Y, Y Meltzer H (2014) The novel object recognition test in rodents in relation to cognitive impairment in schizophrenia. Curr Pharm Des 20:5104–5114
Rajasekaran A, Venkatasubramanian G, Berk M, Debnath M (2015) Review: mitochondrial dysfunction in schizophrenia: pathways, mechanisms and implications. Neurosci Biobehav Rev 48:10–21. https://doi.org/10.1016/j.neubiorev.2014.11.005.
Rico JLR, Ferraz DB, Ramalho-Pinto F, Morato S (2010) Research report: neonatal exposure to LPS leads to heightened exploratory activity in adolescent rats. Behav Brain Res 215:102–109. https://doi.org/10.1016/j.bbr.2010.07.001.
Rogers J, De Santis S, See R (2008) Extended methamphetamine self-administration enhances reinstatement of drug seeking and impairs novel object recognition in rats. Psychopharmacology 199:615
Ross CA, Margolis RL, Reading SAJ, Pletnikov M, Coyle JT (2006) Review: neurobiology of schizophrenia. Neuron 52:139–153. https://doi.org/10.1016/j.neuron.2006.09.015
Santos P, Herrmann AP, Benvenutti R, Noetzold G, Giongo F, Gama CS, Piato AL, Elisabetsky E (2017) Anxiolytic properties of N-acetylcysteine in mice. Behav Brain Res 317:461–469
Sara SJ (2009) The locus coeruleus and noradrenergic modulation of cognition. Nat Rev Neurosci 10:211–223. https://doi.org/10.1038/nrn2573
Semple BD, Blomgren K, Gimlin K, Ferriero DM, Noble-Haeusslein LJ (2013) Brain development in rodents and humans: identifying benchmarks of maturation and vulnerability to injury across species. Prog Neurobiol 106:1–16
Shivalingappa PC, Jin H, Anantharam V, Kanthasamy A, Kanthasamy A (2012) N-acetyl cysteine protects against methamphetamine-induced dopaminergic neurodegeneration via modulation of redox status and autophagy in dopaminergic cells. Parkinson’s Disease
Strauss L, Brink CB, Möller M, Stein DJ, Harvey BH (2014) Late-life effects of chronic methamphetamine exposure during puberty on behaviour and corticostriatal mono-amines in social isolation-reared rats. Dev Neurosci 36:18–28
Tanaka M, Yoshida M, Emoto H, Ishii H (2000) Noradrenaline systems in the hypothalamus, amygdala and locus coeruleus are involved in the provocation of anxiety: basic studies. Eur J Pharmacol 405:397–406. https://doi.org/10.1016/S0014-2999(00)00569-0
Tandon R, Nasrallah HA, Keshavan MS (2009) Schizophrenia, “just the facts” 4. Clinical features and conceptualization. Schizophr Res 110:1–23. https://doi.org/10.1016/j.schres.2009.03.005
Temmingh H, Stein DJ (2015) Anxiety in patients with schizophrenia: epidemiology and management. CNS drugs 29:819–832
Toua C, Brand L, Möller M, Harvey BH, Emsley RA (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. Neuroscience 165:492–499. https://doi.org/10.1016/j.neuroscience.2009.10.039
Uys M, Shahid M, Sallinen J, Dreyer W, Cockeran M, Harvey BH (2016) The α2C-adrenoceptor antagonist, ORM-10921, has antipsychotic-like effects in social isolation reared rats and bolsters the response to haloperidol. Prog Neuro-Psychopharmacol Biol Psychiatry 71:108–116
Uys M, Shahid M, Harvey BH (2017) Therapeutic potential of selectively targeting the α2C-adrenoceptor in cognition, depression, and schizophrenia—new developments and future perspective. Front Psychiatry 8:144. https://doi.org/10.3389/fpsyt.2017.00144
Velakoulis D, Wood SJ, McGorry PD, Pantelis C (2000) Evidence for progression of brain structural abnormalities in schizophrenia: beyond the neurodevelopmental model. Aust N Z J Psychiatry 34:S113–S126
Weinberger DR (1987) Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 44:660–669
Wischhof L, Irrsack E, Osorio C, Koch M (2015) Prenatal LPS-exposure—a neurodevelopmental rat model of schizophrenia—differentially affects cognitive functions, myelination and parvalbumin expression in male and female offspring. Prog Neuro-Psychopharmacol Biol Psychiatry 57:17–30 https://doi.org.nwulib.nwu.ac.za/10.1016/j.pnpbp.2014.10.004
Wongwitdecha N, Marsden CA (1996) Social isolation increases aggressive behaviour and alters the effects of diazepam in the rat social interaction test. Behav Brain Res 75:27–32. https://doi.org/10.1016/0166-4328(96)00181-7
Yamamoto K, Hornykiewicz O (2004) Review article: proposal for a noradrenaline hypothesis of schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry 28:913–922. https://doi.org/10.1016/j.pnpbp.2004.05.033.
Yamamoto BK, Moszczynska A, Gudelsky GA (2010) Amphetamine toxicities: classical and emerging mechanisms. Ann N Y Acad Sci 1187:101–121
Zhang M, He L, Wan C, Zhao Z (2010) A meta-analysis of oxidative stress markers in schizophrenia. Sci China Life Sci 53:112–124. https://doi.org/10.1007/s11427-010-0013-8
Zhu Y, Carvey PM, Ling Z (2007) Altered glutathione homeostasis in animals prenatally exposed to lipopolysaccharide. Neurochem Int 50:671–680. https://doi.org/10.1016/j.neuint.2006.12.013
The authors wish to thank Antoinette Fick (GLP manager, Vivarium, North-West University), Marike Cockeran (North-West University Statistical Consultation Service), Dan J Stein (University of Cape Town) and Michael Berk and Olivia Dean (Deakin University, Australia) for their initial input into the study. We also acknowledge Walter Dreyer and Francois Viljoen, respectively, for their assistance during the ELISA and HPLC analyses.
This work was supported by the South African Medical Research Council (MRC) (BHH), the National Research Foundation (NRF) (BHH; grant number 77323) and Deakin University, Geelong, Australia (BHH). The grant-holder acknowledges that opinions, findings and conclusions or recommendations expressed in any publication generated by NRF supported research are those of the authors and that the NRF accepts no liability whatsoever in this regard.
All experiments were approved by the AnimCare animal research ethics committee (NHREC reg. number AREC-130913-015) at NWU. Animals were maintained and procedures performed in accordance with the code of ethics in research, training and testing of drugs in South Africa and complied with national legislation (ethics approval number: NWU-00147-14-A5).
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The authors declare that they have no conflicts of interest.
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Swanepoel, T., Möller, M. & Harvey, B.H. N-acetyl cysteine reverses bio-behavioural changes induced by prenatal inflammation, adolescent methamphetamine exposure and combined challenges. Psychopharmacology 235, 351–368 (2018). https://doi.org/10.1007/s00213-017-4776-5
- Prenatal infection
- N-acetyl cysteine
- Neurodevelopmental model