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.
Bibliographical noteFunding Information:
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.
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.
© 2019, Springer Science+Business Media, LLC, part of Springer Nature.
- Cognitive impairment
- Gene expression