Treatment with aripiprazole and N-acetylcysteine affects anaerobic cysteine metabolism in the hippocampus and reverses schizophrenia-like behavior in the neurodevelopmental rat model of schizophrenia

FEBS J. 2023 Dec;290(24):5773-5793. doi: 10.1111/febs.16944. Epub 2023 Sep 8.


Preclinical and clinical studies have shown that the antipsychotic drug aripiprazole and the antioxidant N-acetylcysteine have unique biological properties. The aim of the study was to investigate, in a rat model of schizophrenia, the effects of chronic administration of these drugs on schizophrenia-like behaviors and anaerobic cysteine metabolism in the hippocampus (HIP). The schizophrenia-type changes were induced in Sprague-Dawley rats by repeated administration of the glutathione synthesis inhibitor l-butionine-(S,R)-sulfoximine in combination with the dopamine reuptake inhibitor GBR 12909 in the early postnatal period. Adult model rats were chronically treated with aripiprazole (0.3 mg·kg-1 , i.p.) or N-acetylcysteine (30 mg·kg-1 , orally), and their effects on schizophrenia-like behaviors were assessed using the social interaction test and novel object recognition test. In the HIP, the level of anaerobic cysteine metabolites, H2 S, and bound sulfane sulfur were determined by a fluorescence method, while the expression of H2 S-synthetizing enzymes: cystathionine β-synthase (CBS) and mercaptopyruvate sulfurtransferase (MST) by western blot. Long-term treatment with aripiprazole or N-acetylcysteine reversed social and cognitive deficits and reduced the exploratory behaviors. In the HIP of 16-day-old model pups, H2 S levels and MST protein expression were significantly decreased. In adult model rats, H2 S levels remained unchanged, bound sulfane sulfur significantly increased, and the expression of CBS and MST slightly decreased. The studied drugs significantly reduced the level of bound sulfane sulfur and the expression of tested enzymes. The reduction in bound sulfane sulfur level coincided with the attenuation of exploratory behavior, suggesting that modulation of anaerobic cysteine metabolism in the HIP may have therapeutic potential in schizophrenia.

Keywords: N-acetylcysteine; aripiprazole; neurodevelopmental model of schizophrenia; reactive sulfur species; schizophrenia-like symptoms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine* / pharmacology
  • Anaerobiosis
  • Animals
  • Aripiprazole / adverse effects
  • Cysteine / metabolism
  • Hippocampus / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Schizophrenia* / chemically induced
  • Schizophrenia* / drug therapy
  • Schizophrenia* / metabolism
  • Sulfur / metabolism


  • Acetylcysteine
  • Cysteine
  • Aripiprazole
  • sulfur-32
  • Sulfur