N-acetyl cysteine reverses bio-behavioural changes induced by prenatal inflammation, adolescent methamphetamine exposure and combined challenges
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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.
KeywordsPsychosis Prenatal infection Methamphetamine N-acetyl cysteine Neurodevelopmental model Dual-hit
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.
Twanette Swanepoel (TS) undertook all behavioural and neurochemical studies, collected the data and prepared the figures and tables and the first draft of the manuscript. Marisa Möller (MM) advised on the setting up of all the exposure models, undertook some of the behavioural and neurochemical studies, analyzed the data, prepared the final figures and contributed towards preparation of the final manuscript. BHH initiated and designed the study, assisted in the interpretation of the results, supervised TS, provided critical revision of the manuscript and approved it for submission.
Compliance with ethical standards
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).
Conflict of interest
The authors declare that they have no conflicts of interest.
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- Brunton LL, Chabner BA, Knollman BC (2011) Goodman and Gilman's The Pharmacological Basis of Therapeutics 12th Ed. McGraw-Hill Medical, New YorkGoogle Scholar
- 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: 207-17Google Scholar
- 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 11:155CrossRefPubMedPubMedCentralGoogle Scholar
- 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.Google Scholar
- Gaskin PLR (2014) Evaluation of novel dual-hit models of ‘schizophrenia-like’ symptoms in the rat (Doctoral dissertation, University of Nottingham)Google Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedPubMedCentralGoogle Scholar
- 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: 330-48Google Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 6:178Google Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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
- 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 DiseaseGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefGoogle Scholar