Cannabidiol modulates brain molecular alterations, gut microbiota dysbiosis and alcohol self-administration in a mouse model of fetal alcohol spectrum disorder

Biomed Pharmacother. 2025 Dec:193:118791. doi: 10.1016/j.biopha.2025.118791. Epub 2025 Nov 21.

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.

Keywords: Alcohol addiction; Brain biomarkers; Cannabidiol (CBD); Emotional behavior; Fetal alcohol spectrum disorder (FASD); Gut microbiota.

MeSH terms

  • Alcohol Drinking / psychology
  • Animals
  • Behavior, Animal / drug effects
  • Brain* / drug effects
  • Brain* / metabolism
  • Cannabidiol* / pharmacology
  • Disease Models, Animal
  • Dysbiosis* / drug therapy
  • Ethanol* / administration & dosage
  • Female
  • Fetal Alcohol Spectrum Disorders* / drug therapy
  • Fetal Alcohol Spectrum Disorders* / metabolism
  • Fetal Alcohol Spectrum Disorders* / microbiology
  • Fetal Alcohol Spectrum Disorders* / psychology
  • Gastrointestinal Microbiome* / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Pregnancy
  • Self Administration

Substances

  • Cannabidiol
  • Ethanol