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Evaluation of the effects of nitric oxide synthase inhibitors on animal models for the study of schizophrenia based on pharmacologic and neurodevelopment hypothesis


Schizophrenia is a neuropsychiatric disease characterized by many symptoms including deficits in attention, working memory and executive functions. Among the neurochemicals related to schizophrenia it has been considered the involvement of nitric oxide (NO), an atypical neurotransmitter closely related to dopamine (DA) and glutamate (GLU) neurotransmissions. Among the animal models used for the study of schizophrenia, there are the pharmacologic ones based on the hypotheses of dopaminergic hyperfunction and glutamatergic hypofunction and those based on the theory of neurodevelopmental disruption. The latter allowed the elaboration of an animal model of neurogenesis interruption during the gestation, consisting on giving a mitotoxin named methylazoxymethanol acetate (MAM) at the gestational day 17, leading to morphophysiological and neurochemical changes on the offspring, as dopaminergic hyperfunction and behavior deficits when the offspring reaches adulthood, like disruption on prepulse inhibition test (PPI), on social interaction and potentiation of hyperactivity in response to psychostimulants. PPI consists in a sensorimotor model of high predictive value, since dopaminergic agonists and glutamatergic antagonists that cause psychotic symptoms in humans produce deficits in this test both in humans and in animals. Considering accumbens nucleus (NAcc) a fundamental brain structure in schizophrenia and on sensorimotor modulation, the present project has two main aims: i) investigate if NO modulates DA and GLU neurotransmissions in the NAcc through the behavior tests of PPI and hyperlocomotion in the arena and by histoenzymologic and immunohistochemical analyses and ii) evaluate the gene expression of NMDA receptors of GLU (subunits NR1 and NR2B), D1 and D2 of DA and of the NO synthase (NOS) enzyme in rats treated with MAM and investigate the effect of NOS inhibitors in these animals on the behavior tests of PPI, hyperlocomotion and social interaction. (AU)

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(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
RODRIGUES, SAMANTA; SALUM, CRISTIANE; FERREIRA, TATIANA L.. Dorsal striatum D1-expressing neurons are involved with sensorimotor gating on prepulse inhibition test. JOURNAL OF PSYCHOPHARMACOLOGY, v. 31, n. 4, p. 505-513, . (11/09548-3, 11/17024-4)
LOPES-ROCHA, ANA; BEZERRA, THIAGO OHNO; ZANOTTO, ROBERTA; LAGES NASCIMENTO, INDA; RODRIGUES, ANGELA; SALUM, CRISTIANE. The Antioxidant N-Acetyl-L-Cysteine Restores the Behavioral Deficits in a Neurodevelopmental Model of Schizophrenia Through a Mechanism That Involves Nitric Oxide. FRONTIERS IN PHARMACOLOGY, v. 13, p. 15-pg., . (11/09548-3, 18/22142-5, 18/22079-1)

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