Abstract
Growing body of evidence points to dysregulation of redox status in the brain as an important factor in the pathogenesis of schizophrenia. The aim of our study was to evaluate the effects of l-buthionine-(S,R)-sulfoximine (BSO), a glutathione (GSH) synthesis inhibitor, and 1-[2-Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride (GBR 12909), a dopamine reuptake inhibitor, given alone or in combination, to Sprague–Dawley pups during early postnatal development (p5–p16), on the time course of the onset of schizophrenia-like behaviors, and on the expression of brain-derived neurotrophic factor (BDNF) mRNA and its protein in the prefrontal cortex (PFC) and hippocampus (HIP) during adulthood. BSO administered alone decreased the levels of BDNF mRNA and its protein both in the PFC and HIP. Treatment with the combination of BSO + GBR 12909 also decreased BDNF mRNA and its protein in the PFC, but in the HIP, only the level of BDNF protein was decreased. Schizophrenia-like behaviors in rats were assessed at three time points of adolescence (p30, p42–p44, p60–p62) and in early adulthood (p90–p92) using the social interaction test, novel object recognition test, and open field test. Social and cognitive deficits first appeared in the middle adolescence stage and continued to occur into adulthood, both in rats treated with BSO alone or with the BSO + GBR 12909 combination. Behavior corresponding to positive symptoms in humans occurred in the middle adolescence period, only in rats treated with BSO + GBR 12909. Only in the latter group, amphetamine exacerbated the existing positive symptoms in adulthood. Our data show that rats receiving the BSO + GBR 12909 combination in the early postnatal life reproduced virtually all symptoms observed in patients with schizophrenia and, therefore, can be considered a valuable neurodevelopmental model of this disease.
Highlights
12909 showed the increased exploratory behavior assessed in the open field test (OFT) as the time of walking, the number of sector crossings as well as the number of peeping and rearing episodes that are considered to be equivalent to positive symptoms in patients with schizophrenia
Unlike the groups treated with BSO alone or with the BSO + GBR 12909 combination, rats receiving GBR 12909 alone in early postnatal life showed no deficits in social behavior, as measured by the total interaction time and the number of interactions, both during adolescence and early adulthood
To validate the rat model of schizophrenia presented here in screening drugs that can be used in the therapy, we recently showed that chronic per os administration of the antioxidant N-acetylcysteine at a dose of 30 mg/kg to adult rats treated with BSO resulted in the reversal of social and cognitive deficits assessed by the social interaction test (SIT) and novel object recognition test (NOR) tests
Summary
Positive symptoms are the most striking feature of the disease, but cognitive deficits, typically present before the onset of psychosis [5], are critical determinants of patients’ quality of life and their daily functioning [6,7,8]. It is believed that the aberrant neurodevelopmental processes are induced by multiple interactions between the genetic and environmental factors [9] that occur during embryonic or early postnatal development. Detrimental effects of these interactions result in the emergence of cognitive deficits and other symptoms of schizophrenia in adolescence and/or early adulthood [3,10,11,12,13]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
