Abstract
Treatment of negative symptoms and cognitive disorders in patients with schizophrenia is still a serious clinical problem. The aim of our study was to compare the efficacy of chronic administration of the atypical antipsychotic drug aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl] butoxy}-3,4-dihydro-2(1H)-quinolinone; ARI) and the well-known antioxidant N-acetylcysteine (NAC) both in alleviating schizophrenia-like social and cognitive deficits and in reducing the decreases in the levels of the brain-derived neurotrophic factor (BDNF) in the prefrontal cortex (PFC) and hippocampus (HIP) of adult Sprague-Dawley rats, that have been induced by chronic administration of the model compound L-buthionine-(S, R)-sulfoximine (BSO) during the early postnatal development (p5–p16). ARI was administered at doses of 0.1 and 0.3 mg/kg while NAC at doses of 10 and 30 mg/kg, alone or in combination. Administration of higher doses of ARI or NAC alone, or co-treatment with lower, ineffective doses of these drugs significantly improved social and cognitive performance as assessed in behavioral tests. Both doses of NAC and 0.3 mg/kg of ARI increased the expression of BDNF mRNA in the PFC, while all doses of these drugs and their combinations enhanced the levels of BDNF protein in this brain structure. In the HIP, only 0,3 mg/kg ARI increased the levels of both BDNF mRNA and its protein. These data show that in the rat BSO-induced neurodevelopmental model of schizophrenia, ARI and NAC differently modulated BDNF levels in the PFC and HIP.
Highlights
Among the heterogeneous group of psychotic disorders [1], schizophrenia is distinguished by a wide range of psychopathological features, such as positive symptoms, negative symptoms and cognitive dysfunction [2–5].Pharmacological treatment of schizophrenia became available thanks to the development of chlorpromazine, and since antipsychotic drugs, have been widely used until today
The aim of the current study was to compare the therapeutic efficacy of the atypical antipsychotic drug aripiprazole, 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl] butoxy}3,4-dihydro-2(1H)-quinolinone (ARI) and the antioxidant N-acetylcysteine (NAC) highly recommended for the treatment of schizophrenia [58,59], administered alone or in combination, in reversing the social and cognitive deficits caused by chronic BSO given during early postnatal days (p5–p16)
A one-way analysis of variance (ANOVA) for the planned comparisons performed for the total time spent in social interactions (F(9,50) = 26.990, p < 0.00001) showed that repeated administration of BSO to neonatal rats on the postnatal days p5–p16, resulted in a significant reduction in the total time spent in social interactions after these rats reached adulthood (p90)
Summary
Pharmacological treatment of schizophrenia became available thanks to the development of chlorpromazine, and since antipsychotic drugs, have been widely used until today These drugs are effective against positive symptoms, including hallucinations and delusions, but have no or little beneficial effect on the negative or cognitive symptoms [5,6]. The effects of antipsychotics are associated with significant side effects and not all patients respond positively to their application Given that both negative and cognitive symptoms remain largely untouched by current antipsychotic drugs, treating schizophrenia still constitutes a serious clinical problem and challenges researches to seek more effective therapies [7]. To achieve these goals, a thorough understanding of the biological basis of schizophrenia is essential
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