Schizophrenia and Substance Abuse: Investigating the Role of the Mesocorticolimbic Dopaminergic System

• Grant number: 25/04726-3
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: October 01, 2025
• End date: September 30, 2026
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Vanessa Costhek Abílio
• Grantee: Marcus Vinicius Soares de Lara
• Supervisor: Fabricio Hoffmann Martins do Monte
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Institution abroad: University of Texas Health Science Center at Houston (UTHealth), United States
• Associated to the scholarship: 22/00211-0 - Sodium nitroprusside action mechanisms as a preventive therapeutic strategy for Schizophrenia, BP.DR

Abstract

Schizophrenia is a severe and debilitating neuropsychiatric disorder affecting 0.3% of the population worldwide. Individuals diagnosed with schizophrenia are more vulnerable to substance use disorder (SUD), but the underlying neural mechanisms are unclear. This proposal is a part of the current doctoral project which aims to evaluate drug responses in an animal model of schizophrenia, including the evaluation of possible mechanisms involved in increased vulnerability to drugs of abuse. One central hypothesis to explain the association between these two disorders is that both schizophrenia and SUD could share pathophysiological alterations in the brain reward system, mainly in the mesocorticolimbic pathway, which consists of dopamine neurons projecting from the ventral tegmental area (VTA) to areas such as the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc). Opioids, the most prescribed postoperative analgesics in the world, are known for worsening the symptoms and increasing the risk of developing schizophrenia. However, it remains unknown whether the response to opioids in the mesocorticolimbic pathway is altered in schizophrenia, highlighting the importance of investigating neural substrates associated with the co-presentation of schizophrenia and SUD. Here, we propose the use of both sexes in an animal model of schizophrenia, which involves the sub-chronic administration of the NMDA receptor antagonist MK-801. The goal is to evaluate whether animals respond differently to morphine in the conditioned place preference and extinction tests while allowing the measurement of dopamine release in the infralimbic mPFC and NAc shell after viral vector injection and fiber probe implantation. Identifying alterations in various aspects of substance use in schizophrenia, as well as shared mechanisms between schizophrenia and SUD, is essential for enhancing the treatment and management of the conditions.