Cannabidiol modulates brain molecular alterations, gut microbiota dysbiosis and alcohol self-administration in a mouse model of fetal alcohol spectrum disorder
Year: 2025
Type: article
Abstract: Fetal Alcohol Spectrum Disorder (FASD) is a range of neurodevelopmental abnormalities caused by Perinatal Alcohol Exposure (PAE), leading to profound behavioral and molecular disturbances in the offspring. Unraveling the central and peripheral mechanisms involved, including the microbiota-gut-brain axis, is crucial to improving our understanding of the disease and developing new treatment strategies from a sex perspective. In this study, we investigated the impact of PAE on emotional behavior, brain biomarkers, and gut microbiota composition and diversity in a preclinical C57BL/6 J mouse model, as well as the extent of their vulnerability to alcohol consumption. Furthermore, we have also explored the potential modulatory effects of cannabidiol (CBD) administered chronically (30 mg/kg/day, i.p.) from weaning on PAE-induced sex-dependent emotional and brain molecular impairments, gut microbiota dysbiosis, and increased alcohol reinforcing and motivational actions. FASD model mice showed increased anxiety- and depressive-like behavior accompanied by sex-dependent changes in synaptic density, dopamine D2/D3 receptors availability, cannabinoid receptors 1 and 2 ( Cnr1/Cnr2 ), tyrosine hydroxylase ( Th ), and serotonin transporter ( Slc6a4) gene expression, and gut microbiota dysbiosis. Interestingly, CBD sex-dependently improved and/or normalized PAE-induced behavioral and molecular disturbances. In addition, females but not males exposed to the animal model of FASD showed a higher motivation to drink alcohol, which CBD abolished. Our findings provide new insights into the brain and gut microbiota sex-dependent mechanisms involved in FASD pathophysiology and further highlight the therapeutic potential of CBD to improve the management of FASD-induced emotional disturbances and alcohol addiction from a sex-oriented approach. • FASD model mice displayed emotional disturbances (anxiety- and depressive-like behaviors), which CBD alleviated. • PAE induced sex-dependent brain molecular alterations and CBD differentially modulated these changes. • PAE caused sex-dependent gut dysbiosis reflected in alpha diversity alterations and distinct clustering in beta diversity. • CBD treatment modulated microbial diversity, promoted separation in beta diversity, and enriched protective bacterial taxa. • PAE only in female mice induced higher motivation to consume alcohol and CBD treatment mitigated this behavior.
Source: Biomedicine & Pharmacotherapy
Institutions: Instituto de Salud Carlos III, Instituto de Neurociencias, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Consejo Superior de Investigaciones Científicas, Instituto de Agroquímica y Tecnología de Alimentos, University of Turku, Turku PET Centre, Åbo Akademi University
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,610
Awards: G1175115578, G1197116131, G121809054, G1341303, G1422035950, G1424512411, G170384189, G1855990336, G1888407288, G2099925525, G2262748287, G2309174360, G2400938149, G2660406951, G2672435700, G279363373, G300979063, G3220251042, G34346518, G3480869486, G3518538256, G3532166471, G3565621276, G3857581125, G425668148, G430777504, G4526231891, G4857567810, G5080475149, G5362055841, G5408403652, G5421974903, G6460844539, G7084143925, G792975244, G8696694383, G8920660035, G897484643, IDENTIFICACIÓN DE BIOMARCADORES CANNABINOIDES IN LA DEPENDENCIA ALCOHÓLICA: INVESTIGACIÓN TRASLACIONAL Y NUEVAS ESTRATEGIAS TERAPÉUTICAS. PROYECTO CANNABIAL. ESTUDIOS EN ANIMALES, G99296377
OpenAlex ID: W4416573143