Sodium nitroprusside action mechanisms as a preventive therapeutic strategy for Schizophrenia

• Grant number: 22/00211-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: October 01, 2022
• End date: September 30, 2026
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Vanessa Costhek Abílio
• Grantee: Marcus Vinicius Soares de Lara
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 14/50891-1 - INCT 2014: Translational Medicine, AP.TEM

Abstract

Schizophrenia is a neuropsychiatric disorder affecting around 1% of the global population. Its main symptoms are positive, negative, and cognitive deficits. Among negative symptoms, alterations in hedonic behavior are evidenced and may vary between social stimulus and substance reward. We hypothesize a dysregulation of the hedonic tone, in which the abuse of substances might associate with deficits in social reward. Our laboratory is evaluating such hedonic tone in the SHR strain, an animal model of Schizophrenia. At the same time, we showed that the administration during periadolescence of sodium nitroprusside (SNP), a nitric oxide donor, can prevent behavioral alterations in this animal model of Schizophrenia, evidencing its preventive potential if administered during the prodromic stage of the disorder. Thus, the aims of this project are 1) to analyze the hedonic tone regulation between social stimuli and substance use in a different model of Schizophrenia - induced by neonatal administration of a non-competitive NMDA-receptor antagonist (MK-801). We will evaluate sex differences since they are relevant to the disorder; 2) to analyze related neurochemical alterations in the GABAergic, glutamatergic, dopaminergic, and endocannabinoid systems associated with hedonic behavior in the prefrontal cortex, amygdala, and Nucleus Accumbens; 3) to evaluate the participation of the mesolimbic pathway in hedonic behavior through chemogenetic neuronal activation; 4) to evaluate the effects of an SNP treatment during periadolescence on the same alterations. Our project can help the comprehension of aspects that deeply affect the social life of patients with Schizophrenia, and also propose prevention to such aspects, like social behavior and substance abuse, since they do not respond well to currently available pharmacotherapy. (AU)