A combination of Δ9-tetrahydrocannabinol and cannabidiol modulates glutamate dynamics in the hippocampus of an animal model of Alzheimer's disease
A combination of Δ<sup>9</sup>-tetrahydrocannabinol (Δ<sup>9</sup>-THC) and cannabidiol (CBD) at non-psychoactive doses was previously demonstrated to reduce cognitive decline in APP/PS1 mice, an animal model of Alzheimer's disease (AD). However, the neurobiological substrates underlying these therapeutic properties of Δ<sup>9</sup>-THC and CBD are not fully understood. Considering that dysregulation of glutamatergic activity contributes to cognitive impairment in AD, the present study evaluates the hypothesis that the combination of these two natural cannabinoids might reverse the alterations in glutamate dynamics within the hippocampus of this animal model of AD. Interestingly, our findings reveal that chronic treatment with Δ<sup>9</sup>-THC and CBD, but not with any of them alone, reduces extracellular glutamate levels and the basal excitability of the hippocampus in APP/PS1 mice. These effects are not related to significant changes in the function and structure of glutamate synapses, as no relevant changes in synaptic plasticity, glutamate signaling or in the levels of key components of these synapses were observed in cannabinoid-treated mice. Our data instead indicate that these cannabinoid effects are associated with the control of glutamate uptake and/or to the regulation of the hippocampal network. Taken together, these results support the potential therapeutic properties of combining these natural cannabinoids against the excitotoxicity that occurs in AD brains.
Authors
- Marija Radošević
- Anna Castañé (ORCID: https://orcid.org/0000-0002-2578-445X)
- Samira G. Ferreira (ORCID: https://orcid.org/0000-0001-7486-5056)
- Núria Sánchez-Fernández
- Francisco Ciruela (ORCID: https://orcid.org/0000-0003-0832-3739)
- Henrique B. Silva (ORCID: https://orcid.org/0000-0002-7234-3411)
- Jordi Bonaventura (ORCID: https://orcid.org/0000-0002-4745-0151)
- Albert Adell (ORCID: https://orcid.org/0000-0003-0570-4931)
- Xavier Gasull (ORCID: https://orcid.org/0000-0002-6154-8323)
- Sílvia Ginés (ORCID: https://orcid.org/0000-0002-9479-8185)
- João Pedro Lopes (ORCID: https://orcid.org/0000-0002-5122-1802)
- Rodrigo A. Cunha (ORCID: https://orcid.org/0000-0003-2550-6422)
- Attila Köfalvi (ORCID: https://orcid.org/0000-0001-6910-9707)
- Cátia R. Lopes (ORCID: https://orcid.org/0000-0002-9835-5146)
- Francisco Queiróz
- Verónica Brito (ORCID: https://orcid.org/0000-0002-4137-0708)
- Leticia Campa (ORCID: https://orcid.org/0000-0002-5778-5879)
- Laura Gómez-Acero (ORCID: https://orcid.org/0000-0003-2107-2129)
- Ester Aso (ORCID: https://orcid.org/0000-0003-1836-1747)
Institutions
- Institut d'Investigació Biomédica de Bellvitge (ES)
- Centro de Investigación Biomédica en Red de Salud Mental (ES)
- Instituto de Biomedicina y Biotecnología de Cantabria (ES)
- Centro de Investigación Biomédica en Red (ES)
- Institut d'Investigacions Biomèdiques de Barcelona (ES)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- University of Coimbra (PT)
Publication Details
- Journal
- Neurotherapeutics
- Published
- 2024-09-01
- DOI
- https://doi.org/10.1016/j.neurot.2024.e00439
- Citations
- 3
- Primary Topic
- Cannabis and Cannabinoid Research
- Type
- article
- Field-Weighted Citation Impact
- 1.34
Funders
- National Science Foundation
- Centres de Recerca de Catalunya
- Universitat Pompeu Fabra
- Generalitat de Catalunya
- Universitat de Barcelona
- CYTED Ciencia y Tecnología para el Desarrollo
- European Regional Development Fund
- Departament de Salut, Generalitat de Catalunya
- Agencia Estatal de Investigación
- Spanish National Plan for Scientific and Technical Research and Innovation
- European Social Fund