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Multi-level therapeutic actions of cannabidiol in ketamine-induced schizophrenia psychopathology in male rats

Neuropsychopharmacology (2024)Cite this article

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Abstract

Repeated administration of ketamine (KET) has been used to model schizophrenia-like symptomatology in rodents, but the psychotomimetic neurobiological and neuroanatomical underpinnings remain elusive. In parallel, the unmet need for a better treatment of schizophrenia requires the development of novel therapeutic strategies. Cannabidiol (CBD), a major non-addictive phytocannabinoid has been linked to antipsychotic effects with unclear mechanistic basis. Therefore, this study aims to clarify the neurobiological substrate of repeated KET administration model and to evaluate CBD’s antipsychotic potential and neurobiological basis. CBD-treated male rats with and without prior repeated KET administration underwent behavioral analyses, followed by multilevel analysis of different brain areas including dopaminergic and glutamatergic activity, synaptic signaling, as well as electrophysiological recordings for the assessment of corticohippocampal and corticostriatal network activity. Repeated KET model is characterized by schizophrenia-like symptomatology and alterations in glutamatergic and dopaminergic activity mainly in the PFC and the dorsomedial striatum (DMS), through a bi-directional pattern. These observations are accompanied by glutamatergic/GABAergic deviations paralleled to impaired function of parvalbumin- and cholecystokinin-positive interneurons, indicative of excitation/inhibition (E/I) imbalance. Moreover, CBD counteracted the schizophrenia-like behavioral phenotype as well as reverted prefrontal abnormalities and ventral hippocampal E/I deficits, while partially modulated dorsostriatal dysregulations. This study adds novel insights to our understanding of the KET-induced schizophrenia-related brain pathology, as well as the CBD antipsychotic action through a region-specific set of modulations in the corticohippocampal and costicostrtiatal circuitry of KET-induced profile contributing to the development of novel therapeutic strategies focused on the ECS and E/I imbalance restoration.

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Fig. 1: KET induces schizophrenia-like behavior and dysregulates dopaminergic activity; CBD ameliorates behavioral deficits while modulates dopaminergic effects.
Fig. 2: CBD modulates KET-induced glutamatergic dysregulation in a region-specific manner.
Fig. 3: CBD modulates KET-induced brain oscillatory activity alterations.
Fig. 4: The modulatory effects of CBD on ketamine-induced reduction of the parvalbumin interneuron density in the prefrontal cortex and ventral hippocampus.
Fig. 5: The modulatory effects of CBD on ketamine-induced alterations related to the ECS function in the ventral CA1.

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Data availability

Data are available upon request to the corresponding author.

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Acknowledgements

We would like to thank Dr Sofia Bellou (Network of Research Supporting Laboratories (NRSL) of the University of Ioannina and the foundation for Research & Technology-Hellas, Institute of Molecular Biology and Biotechology, Department of Biomedical Research (FORTH/IMBB-BR) foundation for Research & Technology-Hellas) for the support she provided in confocal imaging. The research work was supported by the Hellenic Foundation for Research and Innovation (HFRI) under the HFRI PhD Fellowship grant to CB (Fellowship Number: 1203), supervised by KA. An International Brain Research Organization (IBRO) short stay Grant to CB supported their stay at the Life and Health Sciences Research Institute (ICVS), University of Minho for performing electrophysiological experiments under supervision of JFO. Further funding to JFO from Bial Foundation (037/18) and”la Caixa” Foundation (LCF/PR/HR21/52410024); ICVS Scientific Microscopy Platform, member of the national infrastructure PPBI - Portuguese Platform of Bioimaging (PPBI-POCI-01-0145-FEDER-022122; by National funds, through the Foundation for Science and Technology (FCT) - project UIDB/50026/2020. Additional funding to IS from NIH subcontract RF1AG069941.

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Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110, Ioannina, Greece

    Charalampos Brakatselos, George Ntoulas, Michail-Zois Asprogerakas, Olga Tsarna, Gerasimos Nakas, Foteini Delis & Katerina Antoniou

  2. Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527, Athens, Greece

    Alexia Polissidis

  3. Department of Science and Mathematics, ACG-Research Center, Deree - American College of Greece, 15342, Athens, Greece

    Alexia Polissidis

  4. Institute of Biosciences & Applications, NCSR Demokritos, Athens, Greece

    Anastasia Vamvaka-Iakovou & Ioannis Sotiropoulos

  5. Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal

    Anastasia Vamvaka-Iakovou, Joana Silva, Joao Filipe Oliveira & Ioannis Sotiropoulos

  6. ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal

    Anastasia Vamvaka-Iakovou, Joana Silva, Joao Filipe Oliveira & Ioannis Sotiropoulos

  7. Center of Basic Research, Biological Imaging Unit, Biomedical Research Foundation Academy of Athens, 11527, Athens, Greece

    Anastasios Delis

  8. Department of Pharmacognosy and Natural Product Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, 15771, Athens, Greece

    Petros Tzimas & Leandros Skaltsounis

  9. IPCA-EST-2Ai, Polytechnic Institute of Cávado and Ave, Applied Artificial Intelligence Laboratory, Campus of IPCA, Barcelos, Portugal

    Joao Filipe Oliveira

Authors
  1. Charalampos Brakatselos
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  2. Alexia Polissidis
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  15. Katerina Antoniou
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Contributions

Conceptualization-study design: CB, KA; Funding acquisition: CB, FD, KA, Methodological design: CB, AP, JFO, KA; Investigation: CB, AP, GN, MZA, OT, AV-I, GN, AD, PT, LS, JS, FD, JFO, AD, KA; Methodology: CB, AP, GN, AD, JS, JFO, KA; Data analysis: CB, AP, JFO, KA; Data curation: CB, JFO, KA; Visualization: CB, JFO, IS, KA; manuscript preparation: CB, KA; manuscript editing: CB, AP, FD, JFO, IS, KA.

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Correspondence to Katerina Antoniou.

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Brakatselos, C., Polissidis, A., Ntoulas, G. et al. Multi-level therapeutic actions of cannabidiol in ketamine-induced schizophrenia psychopathology in male rats. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-024-01977-1

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