Neonatal D-fenfluramine treatment promotes long-term behavioral changes in adult mice

Author(s)

Laureano-Melo, Roberto ; Dos-Santos, Raoni Conceicao ; da Conceicao, Rodrigo Rodrigues ; de Souza, Janaina Sena ; Almeida, Claudio da Silva ; Reis, Luis Carlos ; Marinho, Bruno Guimaraes ; Giannocco, Gisele ; Ahmed, Ragab Gaber ; Cortes, Wellington da Silva

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE; v. N/A, p. 13-pg., 2022-06-29.

Abstract

Serotonin exerts a significant role in the mammalian central nervous system embryogenesis and brain ontogeny. Therefore, we investigate the effect of neonatal treatment of d-fenfluramine (d-FEN), a serotonin (5-HT) releaser, on the behavioral expression of adult male Swiss mice. For this purpose, we divided pregnant female Swiss mice into two groups (n = 6 each and similar to 35 g). Their off-spring were treated with d-FEN (3 mg/kg, s.c.) from postnatal days (PND) 5 to 20. At PND 21, one male puppy of each litter was euthanized; the midbrain and the hippocampus were dissected for RNA analysis. At PND 70, the male off-spring underwent a behavioral assessment in the open field, elevated plus-maze, light-dark box, tail suspension, and rotarod test. The programmed animals had a decrease in 5HT1a, serotonin transporter (SERT), and brain-derived neurotrophic factor (BDNF) expression in the mesencephalic raphe region. Alternatively, there was a reduction only in the tryptophan hydroxylase (TPH2) and BDNF expression in the hippocampus. In the light-dark box test, offspring of the treated group had higher latency to light and less time on the light side than the control. Also, it was observed less time of immobility in the tail suspension test. We also observed low motor skill learning in the rotarod test. These findings suggest that programming with d-FEN during the neonatal period alters a mesencephalic and hippocampal serotonergic system, promoting anxiety, antidepressant behavior, low coordination, and motor learning in adults. (AU)

• FAPESP's process: 17/23169-1 - Thyroid hormones action on 3xTg-AD (APPswe, PS1m146v, tauP301L) Alzheimer's Disease mice model
• Grantee: Gisele Giannocco
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/22763-0 - Ancient DNA, bioengineering and brain "organoids": study of thyroid hormone homeostasis and Alzheimer's Disease markers in NOVA1 gene CRISPR edited stem cells
• Grantee: Janaína Sena de Souza
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• FAPESP's process: 17/07053-3 - Effect of thyroid hormone on the brain of 3xTg-AD mice, model of Alzheimer's Disease, on glucose and cholesterol metabolism
• Grantee: Janaína Sena de Souza
• Support Opportunities: Scholarships in Brazil - Post-Doctoral