Cannabinoid type 2 receptor inhibition enhances the antidepressant and proneurogenic effects of physical exercise after chronic stress
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Abstract
Chronic stress is a major risk factor for neuropsychiatric conditions such as depression. Adult hippocampal neurogenesis (AHN) has emerged as a promising target to counteract stress-related disorders given the ability of newborn neurons to facilitate endogenous plasticity. Recent data sheds light on the interaction between cannabinoids and neurotrophic factors underlying the regulation of AHN, with important effects on cognitive plasticity and emotional flexibility. Since physical exercise (PE) is known to enhance neurotrophic factor levels, we hypothesised that PE could engage with cannabinoids to influence AHN and that this would result in beneficial effects under stressful conditions. We therefore investigated the actions of modulating cannabinoid type 2 receptors (CB2R), which are devoid of psychotropic effects, in combination with PE in chronically stressed animals. We found that CB2R inhibition, but not CB2R activation, in combination with PE significantly ameliorated stress-evoked emotional changes and cognitive deficits. Importantly, this combined strategy critically shaped stress-induced changes in AHN dynamics, leading to a significant increase in the rates of cell proliferation and differentiation of newborn neurons, overall reduction in neuroinflammation, and increased hippocampal levels of BDNF. Together, these results show that CB2Rs are crucial regulators of the beneficial effects of PE in countering the effects of chronic stress. Our work emphasises the importance of understanding the mechanisms behind the actions of cannabinoids and PE and provides a framework for future therapeutic strategies to treat stress-related disorders that capitalise on lifestyle interventions complemented with endocannabinoid pharmacomodulation.
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- Authors
- Rodrigues, R. S., Moreira, J. B., Mateus, J. M., Barateiro, A., Paulo, S. L., Vaz, S. H., Lourenço, D. M., Ribeiro, F. F., Soares, R., Loureiro-Campos, E., Bielefeld, P., Sebastião, A. M., Fernandes, A., Pinto, L., Fitzsimons, C. P., & Xapelli, S.
- Affiliations
- University of Lisbon (PT)
- University of Amsterdam (NL)
- University of Minho (PT)
- Corresponding author
- Xapelli, S.
- ORCID
- Venue
- Translational Psychiatry
- Published
- 2024-03-30
- Volume
- 14
- Issue
- 1
- Pages
- 170-170
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC10981758
- OpenAlex
- W4393334203
- Cited by
- 12
- References
- 107
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 1
- FWCI
- 3.39
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Translational Psychiatry (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by)
- UvA-DARE (University of Amsterdam) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Oskar-Bordeaux (Universite de Bordeaux) (submittedVersion, cc-by)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
- Funders
- International Society for Neurochemistry (ISN Career Development Grant)
- International Brain Research Organization (IBRO Early Career Award)
- European Commission (H2020-WIDESPREAD-05-2020-Twinning (EpiEpinet, no. 952455), ERA-NET-NEURON)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- cannabinoid type 2 receptor, physical activity, chronic stress, adult hippocampal neurogenesis, depression, brain-derived neurotrophic factor, neuroinflammation, neurotrophic factors, stress-related disorders, cognitive impairment, emotional flexibility
- MeSH terms
- Animals, Antidepressive Agents, Cannabinoids, Hippocampus, Exercise, Receptors, Cannabinoid, Neurogenesis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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