Schizophrenia (SCZ) is a neurodevelopmental disorder influenced by patient sex. Mechanisms underlying sex differences in SCZ remain unknown. A two-hit model of SCZ combines the exposure to perinatal infection (first-hit) with peripubertal unpredictable stress (PUS, second-hit). N-acetylcysteine (NAC) has been tested in SCZ because of the involvement of glutathione mechanisms in its neurobiology.
Aims:
We aim to investigate whether NAC administration to peripubertal rats of both sexes could prevent behavioral and neurochemical changes induced by the two-hit model.
Methods:
Wistar rats were exposed to polyinosinic:polycytidylic acid (a viral mimetic) or saline on postnatal days (PND) 5–7. On PND30–59 they received saline or NAC 220 mg/kg and between PND40–48 were subjected to PUS or left undisturbed. On PND60 behavioral and oxidative alterations were evaluated in the prefrontal cortex (PFC) and striatum. Mechanisms of hippocampal memory regulation such as immune expression of G protein-coupled estrogen receptor 1 (GPER), α7-nAChR and parvalbumin were also evaluated.
Results:
NAC prevented sensorimotor gating deficits only in females, while it prevented alterations in social interaction, working memory and locomotor activity in both sexes. Again, in rats of both sexes, NAC prevented the following neurochemical alterations: glutathione (GSH) and nitrite levels in the PFC and lipid peroxidation in the PFC and striatum. Striatal oxidative alterations in GSH and nitrite were observed in females and prevented by NAC. Two-hit induced hippocampal alterations in females, namely expression of GPER-1, α7-nAChR and parvalbumin, were prevented by NAC.
Conclusion:
Our results highlights the influences of sex in NAC preventive effects in rats exposed to a two-hit schizophrenia model.
Abdel-SalamOMEEl-ShamarkaM El-SOmaraEA (2018) Brain oxidative stress and neurodegeneration in the ketamine model of schizophrenia during antipsychotic treatment: Effects of N-acetylcysteine treatment. Reactive Oxygen Species6: 253–266.
2.
Abdul-MonimZNeillJCReynoldsGP (2007) Sub-chronic psychotomimetic phencyclidine induces deficits in reversal learning and alterations in parvalbumin-immunoreactive expression in the rat. J Psychopharmacol21: 198–205.
3.
American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders (DSM-5®). Washington, DC: American Psychiatric Publishing.
4.
ArcherJ (1973) Tests for emotionality in rats and mice: A review. Anim Behav21: 205–235.
5.
BavarsadRSHarriganMRAlexandrovAV (2014) N-acetylcysteine (NAC) in neurological disorders: Mechanisms of action and therapeutic opportunities. Brain Behav4: 108–122.
6.
BeanLAIanovLFosterTC (2014) Estrogen receptors, the hippocampus, and memory. Neuroscientist20: 534–545.
7.
BehrensMMAliSSDaoDN, et al. (2007) Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase. Science318: 1645–1647.
8.
BodnarALCortes-BurgosLACookKK, et al. (2005) Discovery and structure–activity relationship of quinuclidine benzamides as agonists of α7 nicotinic acetylcholine receptors. J Med Chem48: 905–908.
9.
BoessFGDe VryJErbC, et al. (2007) The novel α7 nicotinic acetylcholine receptor agonist N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-[2-(methoxy)phenyl]-1-benzofuran-2-carboxamide improves working and recognition memory in rodents. J Pharmacol Exp Ther321: 716–725.
10.
BorellaVCMMVSeemanCordeiroRC, et al. (2016) Gender and estrous cycle influences on behavioral and neurochemical alterations in adult rats neonatally administered ketamine. Dev Neurobiol76: 519–532.
11.
BotsakisKTheodoritsiSGrintzalisK, et al. (2016) 17β-Estradiol/N-acetylcysteine interaction enhances the neuroprotective effect on dopaminergic neurons in the weaver model of dopamine deficiency. Neuroscience320: 221–229.
12.
CabungcalJHCounotteDSLewisEM, et al. (2014) Juvenile antioxidant treatment prevents adult deficits in a developmental model of schizophrenia. Neuron83: 1073–1084.
13.
CabungcalJHSteulletPKraftsikR, et al. (2013) Early-life insults impair parvalbumin interneurons via oxidative stress: Reversal by N-acetylcysteine. Biol Psychiatry73: 574–582.
14.
CarmeliCKnyazevaMGCuénodM, et al. (2012) Glutathione precursor N-acetyl-cysteine modulates EEG synchronization in schizophrenia patients: A double-blind, randomized, placebo-controlled trial. PLoS One7: e29341.
15.
ConusPSeidmanLJFournierM, et al. (2018) N-acetylcysteine in a double-blind randomized placebo-controlled trial: Toward biomarker-guided treatment in early psychosis. Schizophr Bull44: 317–327.
16.
Dall’IgnaOPFettPGomesMW, et al. (2007) Caffeine and adenosine A(2a) receptor antagonists prevent beta-amyloid (25-35)-induced cognitive deficits in mice. Exp Neurol203: 241–245.
17.
DeanOGiorlandoFBerkM (2011a) N-acetylcysteine in psychiatry: Current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci36: 78–86.
18.
DeanOMvan den BuuseMBerkM, et al. (2011b) N-acetyl cysteine restores brain glutathione loss in combined 2-cyclohexene-1-one and d-amphetamine-treated rats: Relevance to schizophrenia and bipolar disorder. Neurosci Lett499: 149–153.
19.
den BuuseMEikelisN (2001) Estrogen increases prepulse inhibition of acoustic startle in rats. Eur J Pharmacol425: 33–41.
20.
DoKQCuenodMHenschTK (2015) Targeting oxidative stress and aberrant critical period plasticity in the developmental trajectory to schizophrenia. Schizophr Bull41: 835–846.
21.
DraperHHSquiresEJMahmoodiH, et al. (1993) A comparative evaluation of thiobarbituric acid methods for the determination of malondialdehyde in biological materials. Free Radic Biol Med15: 353–363.
22.
DunSLBrailoiuGCGaoX, et al. (2009) Expression of estrogen receptor GPR30 in the rat spinal cord and in autonomic and sensory ganglia. J Neurosci Res87: 1610–1619.
23.
DurieuxAMSCFernandesMurphyD, et al. (2015) Targeting glia with N-acetylcysteine modulates brain glutamate and behaviors relevant to neurodevelopmental disorders in C57BL/6J mice. Front Behav Neurosci9: 343.
GawrylukJWWangJFAndreazzaAC, et al. (2011) Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders. Int J Neuropsychopharmacol14: 123–130.
26.
GeyerMASwerdlowNR (2001) Measurement of startle response, prepulse inhibition, and habituation. Curr Protoc Neurosci Chapter 8: Unit 8.7.
27.
GiovanoliSEnglerHEnglerA, et al. (2013) Stress in puberty unmasks latent neuropathological consequences of prenatal immune activation in mice. Science339: 1095–1099.
28.
GiovanoliSWeberLMeyerU (2014) Single and combined effects of prenatal immune activation and peripubertal stress on parvalbumin and reelin expression in the hippocampal formation. Brain Behav Immun40: 48–54.
29.
GogosAvan den BuuseMRossellS (2009) Gender differences in prepulse inhibition (PPI) in bipolar disorder: Men have reduced PPI, women have increased PPI. Int J Neuropsychopharmacol12: 1249.
30.
GreenLCGoldmanPTannenbaumSR, et al. (1981) Nitrate synthesis in the germfree and conventional rat. Science212: 56–58.
31.
JinYWangQWangY, et al. (2017) Alpha7 nAChR agonists for cognitive deficit and negative symptoms in schizophrenia: A meta-analysis of randomized double-blind controlled trials. Shanghai Arch Psychiatry29: 191–199.
32.
KalpouzosGGarzónBSitnikovR, et al. (2017) Higher striatal iron concentration is linked to frontostriatal underactivation and poorer memory in normal aging. Cereb Cortex27: 3427–3436.
33.
KapurSMizrahiRLiM (2005) From dopamine to salience to psychosis-linking biology, pharmacology and phenomenology of psychosis. Schizophr Res79: 59–68.
34.
KerksickCWilloughbyD (2005) The antioxidant role of glutathione and N-acetyl-cysteine supplements and exercise-induced oxidative stress. J Int Soc Sports Nutr2: 38–44.
35.
KhanMM (2018) Translational significance of selective estrogen receptor modulators in psychiatric disorders. Int J Endocrinol2018: 1–12.
36.
KinkeadBSelzKAOwensMJ, et al. (2006) Algorithmically designed peptides ameliorate behavioral defects in animal model of ADHD by an allosteric mechanism. J Neurosci Methods151: 68–81.
37.
KlauserPXinLFournierM, et al. (2018) N-acetylcysteine add-on treatment leads to an improvement of fornix white matter integrity in early psychosis: A double-blind randomized placebo-controlled trial. Transl Psychiatry8: 220.
38.
KulakACuenodMDoKQ (2012) Behavioral phenotyping of glutathione-deficient mice: Relevance to schizophrenia and bipolar disorder. Behav Brain Res226: 563–570.
39.
KumariVAasenISharmaT (2004) Sex differences in prepulse inhibition deficits in chronic schizophrenia. Schizophr Res69: 219–235.
40.
LantéFMeunierJGuiramandJ, et al. (2008) Late N-acetylcysteine treatment prevents the deficits induced in the offspring of dams exposed to an immune stress during gestation. Hippocampus18: 602–609.
41.
LevinED (2012) Alpha7-Nicotinic receptors and cognition. Curr Drug Targets13: 602–606.
42.
LewisDACurleyAAGlausierJR, et al. (2012) Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci35: 57–67.
43.
LiHLuQXiaoE, et al. (2014) Methamphetamine enhances the development of schizophrenia in first-degree relatives of patients with schizophrenia. Can J Psychiatry59: 107–113.
44.
LiRMaXWangG, et al. (2016) Why sex differences in schizophrenia?J Transl Neurosci1: 37–42.
45.
LinHHsuFCBaumannBH, et al. (2014) Cortical parvalbumin GABAergic deficits with α7 nicotinic acetylcholine receptor deletion: Implications for schizophrenia. Mol Cell Neurosci61: 163–175.
46.
LiuSBHanJZhangN, et al. (2011) Neuroprotective effects of oestrogen against oxidative toxicity through activation of G-protein-coupled receptor 30 receptor. Clin Exp Pharmacol Physiol38: 577–585.
47.
LuDQuYShiF, et al. (2016) Activation of G protein-coupled estrogen receptor 1 (GPER-1) ameliorates blood-brain barrier permeability after global cerebral ischemia in ovariectomized rats. Biochem Biophys Res Commun477: 209–214.
48.
MacrìSBiamonteFRomanoE, et al. (2010) Perseverative responding and neuroanatomical alterations in adult heterozygous reeler mice are mitigated by neonatal estrogen administration. Psychoneuroendocrinology35: 1374–1387.
49.
MauriceTLockhartBPPrivatA (1996) Amnesia induced in mice by centrally administered beta-amyloid peptides involves cholinergic dysfunction. Brain Res706: 181–193.
50.
MinariniAFerrariSGallettiM, et al. (2017) N-acetylcysteine in the treatment of psychiatric disorders: Current status and future prospects. Expert Opin Drug Metab Toxicol13: 279–292.
51.
MonteASMelloBSFBorellaVCM, et al. (2017) Two-hit model of schizophrenia induced by neonatal immune activation and peripubertal stress in rats: Study of sex differences and brain oxidative alterations. Behav Brain Res331: 30–37.
52.
NgFBerkMDeanO, et al. (2008) Oxidative stress in psychiatric disorders: Evidence base and therapeutic implications. Int J Neuropsychopharmacol11: 851–876.
53.
NuciforaLGTanakaTHayesLN, et al. (2017) Reduction of plasma glutathione in psychosis associated with schizophrenia and bipolar disorder in translational psychiatry. Transl Psychiatry7: e1215.
54.
PaylorRNguyenMCrawleyJN, et al. (1998) Alpha7 nicotinic receptor subunits are not necessary for hippocampal-dependent learning or sensorimotor gating: A behavioral characterization of acra7-deficient mice. Learn Mem5: 302–316.
55.
PerlsteinWMCarterCSNollDC, et al. (2001) Relation of prefrontal cortex dysfunction to working memory and symptoms in schizophrenia. Am J Psychiatry158: 1105–1113.
56.
PhensyADuzdabanianHEBrewerS, et al. (2017) Antioxidant treatment with N-acetyl cysteine prevents the development of cognitive and social behavioral deficits that result from perinatal ketamine treatment. Front Behav Neurosci11: 106.
57.
ProssnitzERBartonM (2011) The G-protein-coupled estrogen receptor GPER in health and disease. Nat Rev Endocrinol7: 715–726.
58.
RadenovicLSelakovicV (2005) Differential effects of NMDA and AMPA/kainate receptor antagonists on nitric oxide production in rat brain following intrahippocampal injection. Brain Res Bull67: 133–41.
59.
RadyushkinKHammerschmidtKBoretiusS, et al. (2009) Neuroligin-3-deficient mice: Model of a monogenic heritable form of autism with an olfactory deficit. Genes Brain Behav8: 416–425.
60.
RalphRJPaulusMPGeyerMA (2001) Strain-specific effects of amphetamine on prepulse inhibition and patterns of locomotor behavior in mice. J Pharmacol Exp Ther298: 148–155.
61.
RatnayakeUQuinnTLaRosaDA, et al. (2014) Prenatal exposure to the viral mimetic poly I: C alters fetal brain cytokine expression and postnatal Behaviour. Dev Neurosci36: 83–94.
62.
Reagan-ShawSNihalMAhmadN (2008) Dose translation from animal to human studies revisited. FASEB J22: 659–661.
63.
RedrobeJPNielsenEØChristensenJK, et al. (2009) Alpha7 nicotinic acetylcholine receptor activation ameliorates scopolamine-induced behavioural changes in a modified continuous Y-maze task in mice. Eur J Pharmacol602: 58–65.
64.
RibeiroBMMdo CarmoMRSRSFreire, et al. (2013) Evidences for a progressive microglial activation and increase in iNOS expression in rats submitted to a neurodevelopmental model of schizophrenia: Reversal by clozapine. Schizophr Res151: 12–19.
65.
RossNRPorterLL (2002) Effects of dopamine and estrogen upon cortical neurons that express parvalbumin in vitro. Brain Res Dev Brain Res137: 23–34.
66.
RubinRDWatsonPDDuffMC, et al. (2014) The role of the hippocampus in flexible cognition and social behavior. Front Hum Neurosci8: 742.
67.
SadockB (2016) Compêndio de Psiquiatria - 11ed: Ciência do Comportamento e Psiquiatria Clínica - Benjamin J. Sadock, Virginia A. Sadock, Pedro Ruiz - Google Livros. 11a ed. Porto Alegre, Brazil: Artmed.
68.
SchiavoneSSorceSDubois-DauphinM, et al. (2009) Involvement of NOX2 in the development of behavioral and pathologic alterations in isolated rats. Biol Psychiatry66: 384–392.
69.
SeemanM V (2004) Gender differences in the prescribing of antipsychotic drugs. Am J Psychiatry161: 1324–1333.
70.
SeemanM V (2018) Does gender influence outcome in schizophrenia?Psychiatr Q90: 173–184.
71.
SempleBDBlomgrenKGimlinK, et al. (2013) Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species. Prog Neurobiol106–107: 1–16.
72.
ShunguDC (2012) N-acetylcysteine for the treatment of glutathione deficiency and oxidative stress in schizophrenia. Biol Psychiatry71: 937–938.
73.
SotonyiPQian GaoQBechmannI, et al. (2010) Estrogen promotes parvalbumin expression in arcuate nucleus POMC neurons. Reprod Sci17: 1077–1080.
74.
SparyEJChapmanSESinfieldJK, et al. (2013) Novel G protein-coupled oestrogen receptor GPR30 shows changes in mRNA expression in the rat brain over the oestrous cycle. Neurosignals21: 14–27.
75.
SwerdlowNRHanlonFMHenningL, et al. (2001) Regulation of sensorimotor gating in rats by hippocampal NMDA: Anatomical localization. Brain Res898: 195–203.
76.
TosicMOttJBarralS, et al. (2006) Schizophrenia and oxidative stress: Glutamate cysteine ligase modifier as a susceptibility gene. Am J Hum Genet79: 586–592.
77.
van OsJKenisGRuttenBPF (2010) The environment and schizophrenia. Nature468: 203–212.
78.
VicensPRibesDHerediaL, et al. (2013) Effects of an alpha7 nicotinic receptor agonist and stress on spatial memory in an animal model of Alzheimer’s disease. Biomed Res Int2013: 952719.
79.
WibleCGAndersonJShentonME, et al. (2001) Prefrontal cortex, negative symptoms, and schizophrenia: An MRI study. Psychiatry Res108: 65–78.
80.
WuYCDuXvan den BuuseM, et al. (2014) Sex differences in the adolescent developmental trajectory of parvalbumin interneurons in the hippocampus: A role for estradiol. Psychoneuroendocrinology45: 167–178.
81.
WuYCHillRAGogosA, et al. (2013) Sex differences and the role of estrogen in animal models of schizophrenia: Interaction with BDNF. Neuroscience239: 67–83.
82.
YaoJKLeonardSReddyR (2006) Altered glutathione redox state in schizophrenia. Dis Markers22: 83–93.
83.
YoungJWPowellSBRisbroughV, et al. (2009) Using the MATRICS to guide development of a preclinical cognitive test battery for research in schizophrenia. Pharmacol Ther122: 150–202.
84.
ZhangXLiQWongN, et al. (2015) Behaviour and prefrontal protein differences in C57BL/6N and 129 X1/SvJ mice. Brain Res Bull116: 16–24.
85.
ZlatkovićJTodorovićNBoškovićM, et al. (2014) Different susceptibility of prefrontal cortex and hippocampus to oxidative stress following chronic social isolation stress. Mol Cell Biochem393: 43–57.
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