The effect of phencyclidine-mediated blockade of NMDA receptors in the early postnatal period on glutathione and sulfur amino acid levels in the rat brain as a potential causative factor of schizophrenia-like behavior in adulthood

Abstract

Background: Phencyclidine, an NMDA receptor antagonist, is frequently used to model behavioral and neurochemical changes correlated with schizophrenia in laboratory animals. The present study aimed to examine the effects of repeated administration of phencyclidine during early postnatal development on the contents of glutathione and sulfur-containing amino acids, as well as the activity of antioxidant enzymes in the brain of 12-day-old rats, and schizophrenia-like symptoms in adulthood.

Methods: Male Sprague-Dawley pups were administered phencyclidine (10 mg/kg) or saline subcutaneously on the postnatal days p2, p6, p9 and p12. In 12-day-old pups, 4 h after the last dose of phencyclidine, the levels of glutathione, cysteine, methionine, and homocysteine, and the enzymatic activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR) were measured in the frontal cortex, hippocampus, and striatum. In 70-72-day-old rats, schizophrenia-like symptoms were assessed using behavioral tests.

Results: Biochemical data showed that perinatal phencyclidine treatment significantly reduced glutathione and cysteine levels in all brain structures studied, methionine was diminished in the striatum, and homocysteine in both the frontal cortex and striatum. GR activity was increased in the frontal cortex while SODactivity was decreased in the hippocampus. Behaviorally, perinatal phencyclidine induced long-term deficits in social and cognitive function and a decrease in locomotor activity assessed as the time of walking. Finally, perinatal treatment with phencyclidine resulted in a significant reduction in body weight gain over time.

Conclusion: Our research provides further evidence for the usefulness of the phencyclidine-induced neurodevelopmental model of schizophrenia for studying the pathogenesis of schizophrenia.

Keywords: Glutathione deficiency; Neurodevelopmental model of schizophrenia; Phencyclidine in early postnatal development; Social and cognitive deficits; Sulfur amino acid homeostasis.

Fig. 1

The effects of repeated PCP administration in the early postnatal days (p2, p6, p9, p12) on the concentrations of GSH, Cys, Met, and Hcy in the frontal cortex (A), hippocampus (B), and striatum (C) of 12-day-old pups. Data in nmole/g of tissue are presented as the mean ± SEM, n = 8 for each group. Statistical analysis was carried out with the Student’s t-test for independent samples, ***p < 0.001, **p < 0.01 and *p < 0.05 vs. the control group

Fig. 2

The effects of repeated PCP administration in the early postnatal days (p2, p6, p9, p12) on the enzymatic activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione-disulfide reductase (GR) in the frontal cortex (A), hippocampus (B), and striatum (C) of 12-day-old pups. SOD activity is expressed in the conventional unit U/mg of protein while GPx and GR activities are expressed in nmol/mg of protein/min. Further explanations are provided in the Material and Methods section. Data are shown as the mean ± SEM, n = 7–8 for each group. Statistical analysis was carried out with the Student’s t-test for independent samples, **p < 0.01 and *p < 0.05 vs. the control group

Fig. 3

The effects of repeated PCP treatment in the early postnatal days (p2, p6, p9, p12) on social behavior deficits assessed in the SIT in 70-day-old rats as the total social interaction time expressed in seconds (A) and the number of interactions (B). Data are presented as the mean ± SEM, n = 12 (6 pairs) for each group. Statistical analysis was carried out with the Student’s t-test for independent samples, ***p < 0.001 vs. the control group

Fig. 4

The effects of repeated (PCP administration in the early postnatal days (p2, p6, p9, p12) on cognitive performance assessed in the NOR test in adult rats. The effects of PCP on: (A) exploration of two objects in the T1 session, (B) exploration of a novel and familiar object in the T2 session, (C) the recognition index, and on (D) motility of rats in T1 and T2 sessions. Data are presented as the mean ± SEM, n = 12 for each group. Statistical analysis for data presented in figures A and B was performed using two-way ANOVA; asterisks indicate the significance of difference according to the Tukey post hoc test, **p < 0.01 vs. familiar object (A). Statistical analysis for data presented in figures C, D and E was carried out with the Student’s t-test for independent samples, ***p < 0.001 vs. the control group

Fig. 5

The effects of repeated PCP administration in the early postnatal days (p2, p6, p9, p12) on exploratory behavior evaluated in the OFT in adult rats as (A) the time of walking expressed in seconds, (B) the number of sector crossings, (C) the number of peeping and rearing episodes. Data is shown as the mean ± SEM, n = 12 for each group. Statistical analysis was carried out with the Student’s t-test for independent samples, ^*p < 0.05 vs. the control group