Autism and the dopaminergic system: analysis of sex differences, molecular and behavioral aspects

Author(s)

Luana Carvalho Cezar

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina Veterinária e Zootecnia (FMVZ/SBD)
• Defense date: 2022-11-04

Examining board members

Luciano Freitas Felicio; Maria Martha Bernardi; Jackson Cioni Bittencourt; Thiago Berti Kirsten; Helenice de Souza Spinosa

• Advisor: Luciano Freitas Felicio

Abstract

Autism is a complex developmental disorder characterized by several behavioral impairments. In rodents, prenatal exposure to VPA (400 mg/kg in GD12,5) induces similar symptoms found in the human condition of autism spectrum disorder. Previous studies suggest the autistic-like phenotype is related to functional changes on the dopaminergic system. Pharmacological challenge is a potential strategy capable of accessing neurotransmitter activity in the CNS, especially the methylphenidate that selectively increases dopamine release in striatal and cortical circuits. Prolonged administration of methylphenidate can change brain structures involving dopamine, translating this neuroplasticity into behavioral changes. This work evaluated behavioral and molecular aspects of rats exposed to prenatal VPA and the effects of acute (GD 32) treatment of methylphenidate (5 mg/kg) and chronic (GD 21 - 32) in the hypothesis of dopamine in autism. The results reveals: (1) VPA-induced autistic behavioral phenotype in GD 12.5 in male Wistar; (2) sexual dimorphic differences between males and females on behavioral and neurochemical changes induced by exposure to VPA; (3) behavioral improvements induced by acute or chronic methylphenidate treatment in rats exposed to prenatal VPA; (4) deficient dopamine signaling in different brain areas on adult rats; (5) and VPA prenatal exposure induces anxiety-like behavior, anhedonia and self-grooming behavior in both sexes. These data suggests that the autistic like model induced by VPA provides evidence to corroborate the hypothesis of dopamine in autism, but also, a clinical translational principle in the development of possible treatment routes for the disorder in humans. (AU)

• FAPESP's process: 17/04642-8 - Autism and dopaminergic system: sexual differences, molecular and behavioral analyzes
• Grantee: Luana Carvalho Cezar
• Support Opportunities: Scholarships in Brazil - Doctorate