N-acetyl cysteine reverses bio-behavioural changes induced by prenatal inflammation, adolescent methamphetamine exposure and combined challenges

Abstract

Rationale

Schizophrenia is associated with prenatal inflammation and/or postnatal stressors such as drug abuse, resulting in immune-redox dysfunction. Antioxidants may offer therapeutic benefits.

Objectives

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.

Methods

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.

Results

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.

Conclusions

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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Acknowledgments

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.

Funding

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.

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Authors

Contributions

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.

Corresponding author

Correspondence to Brian Herbert Harvey.

Ethics declarations

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.

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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

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Keywords

  • Psychosis
  • Prenatal infection
  • Methamphetamine
  • N-acetyl cysteine
  • Neurodevelopmental model
  • Dual-hit