Effects of cannabidiol on basolateral amygdala hyperactivity and abnormal corticoamygdalar connectivity electrophysiological changes in the gestational methylazoxymethanol acetate model for schizophrenia

• Grant number: 22/15718-3
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Effective date (Start): May 03, 2023
• Effective date (End): May 02, 2024
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Francisco Silveira Guimaraes
• Grantee: Debora dos Santos Fabris
• Supervisor: Anthony Albert Grace
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Research place: University of Pittsburgh (Pitt), United States
• Associated to the scholarship: 19/24591-4 - Mechanisms of cannabidiol antipsychotics effects in schizophrenia model based in neurodevelopment variation, BP.DR

Abstract

Schizophrenia is a disabling developmental psychiatry disorder that involves alterations in the connectivity between various brain regions. The medial prefrontal cortex (mPFC) and amygdala have reciprocal connections that control their activities. A dysregulation in the connectivity between these brain areas is proposed to play a role in the pathophysiology of SCZ. Abnormalities in neurodevelopmental processes during early life may affect brain function, resulting in psychosis later in life, mainly during late adolescence/early adulthood. The administration of the DNA-alkylating agent methylazoxymethanol acetate (MAM) on the gestational day (GD) 17 produces in the offspring several behavioral, physiological, and anatomical brain changes that resemble those seen in schizophrenia and has been used as a model to study this disorder. MAM- treated animals show GABAergic dysfunction in the mPFC and basolateral amygdala (BLA) hyperactivity, modifying the connectivity between these two structures. A dysfunction in the mPFC could lead to BLA hyperactivity, which has been associated with circuit deficits underlying schizophrenia symptoms. Changes in the mPFC and BLA are thought to arise before the emergence of psychotic symptoms in schizophrenia. Therefore, interventions that can attenuate deficits in corticoamygdalar connectivity may prevent the emergence of a schizophrenia-like state. Findings from our Ph.D. studies indicated that cannabidiol (CBD) administered to adolescent MAM animals prevented the emergence of cognitive deficits and the increased activity of dopamine neurons in the ventral tegmental area, which are associated with psychotic symptoms in individuals with schizophrenia. Here we aim to investigate, using in vivo electrophysiology recordings, if CBD preventive effects in the MAM model could involve attenuation of the observed deficits in corticoamygdalar connectivity and increased BLA activity. (AU)