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Cannabidiol Improves Cognitive Impairment and Reverses Cortical Transcriptional Changes Induced by Ketamine, in Schizophrenia-Like Model in Rats

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Abstract

Cannabidiol (CBD), a non-psychotropic cannabinoid, demonstrates antipsychotic-like and procognitive activities in humans and in animal models of schizophrenia. The mechanisms of these beneficial effects of CBD are unknown. Here, we examined behavioral effects of CBD in a pharmacological model of schizophrenia-like cognitive deficits induced by repeated ketamine (KET) administration. In parallel, we assessed transcriptional changes behind CBD activities in the prefrontal cortex (PFC), the main brain area linked to schizophrenia-like pathologies. Male Sprague-Dawley rats were injected for 10 days with KET followed by 6 days of CBD. The cognitive performance was evaluated in the novel object recognition test followed by PFC dissections for next-generation sequencing (RNA-Seq) analysis and bioinformatics. We observed that KET-induced learning deficits were rescued by CBD (7.5 mg/kg). Similarly, CBD reversed transcriptional changes induced by KET. The majority of the genes affected by KET and KET-CBD were allocated to astroglial and microglial cells and associated with immune-like processes mediating synaptogenesis and neuronal plasticity. These genes include C1qc, C1qa, C1qb, C2, and C3 complement cascade elements, Irf8 factor and Gpr84, Gpr34, Cx3cr1, P2ry12, and P2ry6 receptors. The main pathway regulators predicted to be involved included TGFβ1 and IFNγ. In addition, CBD itself upregulated oxytocin mRNA in the PFC. The present data suggest that KET induces cognitive deficits and transcriptional changes in the PFC and that both effects are sensitive to a reversal by CBD treatment.

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Acknowledgments

The RNA-Seq and bioinformatics analyzes were performed in The Crown Genomics Institute and in The Mantoux Bioinformatics Institute, respectively, of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel. Particularly, we thank Dr Sima Benjamini for technical assistance with RNA sample handling and performing RNA-Seq, and to Michael Gershovis for the core bioinformatics analysis.

Funding

This work was supported by the Dr Miriam and Sheldon G. Adelson Medical Research Foundation and by the statutory funds of the Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.

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Authors and Affiliations

  1. The Dr Miriam and Sheldon G. Adelson Center for the Biology of Addictive Diseases, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Ewa Kozela, Ana Juknat & Zvi Vogel

  2. Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel

    Ewa Kozela, Ana Juknat & Zvi Vogel

  3. Department of Behavioral Neuroscience & Drug Development, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland

    Martyna Krawczyk, Tomasz Kos & Piotr Popik

Authors
  1. Ewa Kozela
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  2. Martyna Krawczyk
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  3. Tomasz Kos
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  4. Ana Juknat
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  5. Zvi Vogel
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  6. Piotr Popik
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Contributions

T.K., M.K., and P.P. designed, performed, and analyzed the behavioral experiments. E.K. performed the mRNA extractions, the qPCR analysis of gene expression, the IPA analysis and wrote the article. E.K., T.K., M.K., A.J., Z.V., and P.P. contributed to discussions of article content, and to reviewing and editing the manuscript before submission.

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Correspondence to Ewa Kozela.

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Main findings:

1. Cannabidiol rescues learning deficits in schizophrenia-like conditions induced by ketamine administration.

2. Cannabidiol reverses transcriptional changes induced by ketamine in the rat prefrontal cortex.

3. Cannabidiol and ketamine treatments affect the transcription of genes allocated to astroglial and microglial cells and mediating neuronal plasticity.

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Kozela, E., Krawczyk, M., Kos, T. et al. Cannabidiol Improves Cognitive Impairment and Reverses Cortical Transcriptional Changes Induced by Ketamine, in Schizophrenia-Like Model in Rats. Mol Neurobiol 57, 1733–1747 (2020). https://doi.org/10.1007/s12035-019-01831-2

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  • DOI: https://doi.org/10.1007/s12035-019-01831-2

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