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

Psychopharmacology (Berl). 2018 Jan;235(1):351-368. doi: 10.1007/s00213-017-4776-5. Epub 2017 Nov 8.

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.

Keywords: Dual-hit; Methamphetamine; N-acetyl cysteine; Neurodevelopmental model; Prenatal infection; Psychosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3,4-Dihydroxyphenylacetic Acid
  • Acetylcysteine / pharmacology*
  • Analysis of Variance
  • Animals
  • Antioxidants / pharmacology*
  • Behavior, Animal / drug effects*
  • Biogenic Monoamines / metabolism
  • Corpus Striatum / drug effects
  • Cytokines / metabolism
  • Dopamine / metabolism
  • Female
  • Form Perception / drug effects
  • Free Radical Scavengers / pharmacology*
  • Inflammation / complications
  • Lipid Peroxidation / drug effects
  • Lipopolysaccharides / toxicity
  • Male
  • Memory / drug effects
  • Methamphetamine / administration & dosage
  • Methamphetamine / toxicity*
  • Pregnancy
  • Prenatal Exposure Delayed Effects / chemically induced
  • Prepulse Inhibition / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Recognition, Psychology / drug effects
  • Reflex, Startle / drug effects
  • Schizophrenia / chemically induced
  • Schizophrenia / drug therapy*
  • Schizophrenia / metabolism
  • Serotonin
  • Social Behavior

Substances

  • Antioxidants
  • Biogenic Monoamines
  • Cytokines
  • Free Radical Scavengers
  • Lipopolysaccharides
  • Reactive Oxygen Species
  • 3,4-Dihydroxyphenylacetic Acid
  • Serotonin
  • Methamphetamine
  • Dopamine
  • Acetylcysteine