Effects of cannabidiol in post-stroke mood disorders in neonatal rats

María Villa; María Martínez-Vega; Laura Silva; Itziar Muneta-Arrate; Ana Gómez-Soria; Carolina Muguruza; Aarón Del Pozo; María de Hoz-Rivera; Angela Romero; Luis F Callado; Maria José Casarejos; José Martínez-Orgado

doi:10.1038/s41390-024-03077-8

Effects of cannabidiol in post-stroke mood disorders in neonatal rats

Pediatr Res. 2024 Feb 15. doi: 10.1038/s41390-024-03077-8. Online ahead of print.

Authors

Affiliations

¹ Biomedical Research Foundation, Hospital Clínico San Calos-IdISSC, Madrid, Spain.
² Department of Pharmacology, University of the Basque Country, UPV/EHU, Bizkaia, Spain.
³ Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Bizkaia, Spain.
⁴ Servicio de Neurobiología-Investigación, Hospital Ramón y Cajal, Madrid, Spain.
⁵ Biocruces-Bizkaia Health Research Institute, Barakaldo, Bizkaia, Spain.
⁶ Biomedical Research Foundation, Hospital Clínico San Calos-IdISSC, Madrid, Spain. jose.martinezo@salud.madrid.org.
⁷ Department of Neonatology, Hospital Clínico San Calos-IdISSC, Madrid, Spain. jose.martinezo@salud.madrid.org.

PMID: 38360979
DOI: 10.1038/s41390-024-03077-8

Abstract

Background: Neonatal rats can manifest post-stroke mood disorders (PSMD) following middle cerebral artery occlusion (MCAO). We investigated whether cannabidiol (CBD) neuroprotection, previously demonstrated in neonatal rats after MCAO, includes prevention of PSMD development.

Methods: Seven-day-old Wistar rats (P7) underwent MCAO and received either vehicle or 5 mg/kg CBD treatment. Brain damage was quantified by MRI, and neurobehavioral and histological (TUNEL) studies were performed at P14 and P37. PSMD were assessed using the tail suspension test, forced swimming test, and open field tests. The dopaminergic system was evaluated by quantifying dopaminergic neurons (TH+) in the Ventral Tegmental Area (VTA), measuring brain dopamine (DA) concentration and DA transporter expression, and assessing the expression and function D2 receptors (D2R) through [35S]GTPγS binding. Animals without MCAO served as controls.

Results: CBD reduced MCAO-induced brain damage and improved motor performance. At P14, MCAO induced depressive-like behavior, characterized by reduced TH+ cell population and DA levels, which CBD did not prevent. However, CBD ameliorated hyperactivity observed at P37, preventing increased DA concentration by restoring D2R function.

Conclusions: These findings confirm the development of PSMD following MCAO in neonatal rats and highlight CBD as a neuroprotective agent capable of long-term functional normalization of the dopaminergic system post-MCAO.

Impact: MCAO in neonatal rats led to post-stroke mood disorders consisting in a depression-like picture in the medium term evolving towards long-term hyperactivity, associated with an alteration of the dopaminergic system. The administration of CBD after MCAO did not prevent the development of depressive-like behavior, but reduced long-term hyperactivity, normalizing dopamine receptor function. These data point to the importance of considering the development of depression-like symptoms after neonatal stroke, a well-known complication after stroke in adults. Our work confirms the interest of CBD as a possible treatment for neonatal stroke.