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The two-hit hypothesis has been used to explain the onset mechanism of schizophrenia. It assumes that predisposition to schizophrenia is originally attributed to vulnerability in the brain which stems from genetic or early developmental factors, and that onset is triggered by exposure to later detrimental factors such as stress in adolescence or adulthood. Based on this hypothesis, the present study examined whether rats that had received neonatal repeated treatment with an N-methyl-d-aspartate (NMDA) receptor antagonist (MK-801), an animal model of schizophrenia, were vulnerable to chronic stress. Rats were treated with MK-801 (0.2 mg/kg) or saline twice daily on postnatal days 7–20, and animals in the stress subgroups were subjected to 20 days (5 days/week × 4 weeks) of forced-swim stress in adulthood. Following this, behavioral tests (prepulse inhibition, spontaneous alternation, open-field, and forced-swim tests) were carried out. The results indicate that neonatal repeated MK-801 treatment in rats inhibits an increase in immobility in the forced-swim test after they have experienced chronic forced-swim stress. This suggests that rats that have undergone chronic neonatal repeated NMDA receptor blockade could have a reduced ability to habituate or adapt to a stressful situation, and supports the hypothesis that these rats are sensitive or vulnerable to stress.Stress-vulnerability in rats neonatally treated with MK-801 was examined.Rats were subjected to chronic forced-swim stress.Neonatal MK-801 treatment reduced stress-induced immobility in the forced-swim test.Neonatal MK-801 treatment may impair adaptation or coping ability against stress.Discussing the results in terms of the two-hit hypothesis of schizophrenia.