Cannabidiol-induced modulation of behavioral, cellular and gene expression changes in an animal model of FASD

ANI GASPARYAN; NAVARRO, DANIELA; FRANCISCO NAVARRETE RUEDAS; AMAYA AM AUSTRICH-OLIVARES; ACOSTA, GABRIELA BEATRIZ; JORGE MANZANARES ROBLES

San Diego

Congreso; Society for Neuroscience; 2022

Cannabidiol-induced modulation of behavioral, cellular and gene expression changes in an animal model of FASDAni Gasparyan a,b,c, Daniela Navarro a,b,c, Francisco Navarrete a,b,c, Amaya Austrich-Olivares, Gabriela Acosta d, Jorge Manzanares a,b,c,*a.Instituto de Neurociencias, Universidad Miguel Hernández- CSIC, San Juan de Alicante, Alicante, Españab.Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), Red de Investigación en Atención Primaria de Addicciones (RIAPAd), Instituto de Salud Carlos III, MICINN y FEDER, Madrid, Españac.Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante, Españad.Instituto de Neurociencias Cognitiva y Traslacional (INCYT), Concejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Instituto de Neurología Cognitiva (INECO), Universidad Favaloro.*Corresponding author: jmanzanares@umh.es, Instituto de Neurociencias, Av Ramón y Cajal s/n, 03550, San Juan de Alicante, Alicante, España. +34 965 91 92 52Fetal alcohol spectrum disorder (FASD) includes various neuropsychiatric disturbances related to gestational and lactational ethanol exposure. Available treatments are minimal and do not modulate ethanol-induced damage. Developing animal models simulating FASD could be essential for understanding the underlying brain alterations and searching for efficient therapeutic approaches. Thus, the main goal of this study was 1) to develop a new animal model of FASD with associated long-lasting emotional, cognitive, cellular and molecular changes in males and females exposed to ethanol during gestation and lactation, and 2) to analyze early and chronic CBD administration effects on these ethanol-induced disturbances in males and females. For this purpose, C57BL/6J female mice were exposed to an ethanol voluntary consumption paradigm (28 days), selecting only those with higher ethanol consumption and preference to cross them with males. After gestation confirmation, oral ethanol gavage administration at a dose of 3 g/kg/12h (p.o.) started at gestational day 7 until the pup’s weaning at postnatal day 21. On the weaning day, pups were separated by sex and CBD administration began (30 mg/kg/day, i.p.). After 4-6 weeks of treatment, behavioral, relative gene expression and immunohistochemical protein changes were analyzed. Rodents exposed to the animal model of FASD showed higher anxiety and depressive-like behaviors in the light-dark box, novelty-suppressed feeding and tail suspension tests, and a higher emotional reactivity in the acoustic startle response evaluation. In addition, cognitive impairment was observed in the novel object recognition and step-down inhibitory avoidance tests. These behaviors were accompanied by alterations on the stress axis and cannabinoid receptor gene expressions. In addition, an essential reduction of different neuronal markers in the hippocampus was observed by immunohistochemical analyzes. Interestingly, CBD not only normalized FASD model-induced emotional and cognitive disturbances but also gene expression changes with sex-dependent differences. The administration of CBD normalized the number of neurons, BDNF-positive cells, neurofilaments and glutamatergic terminals in the hippocampus. These results suggest that the repeated administration of CBD modulated the long lasting behavioral and the gene and protein alterations induced by the FASD model. These results stimulate the possibility to perform clinical trials to evaluate the effects of CBD in children affected with Alcohol spectrum disorders.