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Cannabidiol induces antidepressant and anxiolytic‐like effects in experimental type-1 diabetic animals by multiple sites of action

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Abstract

Cannabidiol (CBD), a phytocannabinoid compound, presents antidepressant and anxiolytic-like effects in the type-1 diabetes mellitus(DM1) animal model. Although the underlying mechanism remains unknown, the type-1A serotonin receptor (5-HT1A) and cannabinoids type-1 (CB1) and type-2 (CB2) receptors seem to play a central role in mediating the beneficial effects on emotional responses. We aimed to study the involvement of these receptors on an antidepressant- and anxiolytic-like effects of CBD and on some parameters of the diabetic condition itself. After 2 weeks of the DM1 induction in male Wistar rats by streptozotocin (60 mg/kg; i.p.), animals were treated continuously for 2-weeks with the 5-HT1A receptor antagonist WAY100635 (0.1 mg/kg, i.p.), CB1 antagonist AM251 (1 mg/kg i.p.) or CB2 antagonist AM630 (1 mg/kg i.p.) before the injection of CBD (30 mg/kg, i.p.) or vehicle (VEH, i.p.) and then, they were submitted to the elevated plus-maze and forced swimming tests. Our findings show the continuous treatment with CBD improved all parameters evaluated in these diabetic animals. The previous treatment with the antagonists − 5-HT1A, CB1, or CB2 - blocked the CBD-induced antidepressant-like effect whereas only the blockade of 5-HT1A or CB1 receptors was able to inhibit the CBD-induced anxiolytic-like effect. Regarding glycemic control, only the blockade of CB2 was able to inhibit the beneficial effect of CBD in reducing the glycemia of diabetic animals. These findings indicated a therapeutic potential for CBD in the treatment of depression/anxiety associated with diabetes pointing out a complex intrinsic mechanism in which 5-HT1A, CB1, and/or CB2 receptors are differently recruited.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

YC Chaves is recipient of Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil) fellowship.

Funding

The present study was partially supported by a CNPq grants (Universal 01/2016; 408517/2016-6; CNPq/MS/SCTIE/DECIT N∘ 26/2014 – Pesquisas sobre Distúrbios Neuropsiquiátricos; 466805/2014-4). JAC is a recipient of fellowship awards from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil – 1A).

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Authors and Affiliations

  1. Department of Pharmacology, Biological Science Sector, Federal University of Paraná, Curitiba, Paraná, Brazil

    Yane Costa Chaves, Joice Maria da Cunha & Janaína Menezes Zanoveli

  2. Institute of Neurosciences and Behavior (INeC), University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil

    Karina Genaro, Joice Maria da Cunha & Janaína Menezes Zanoveli

  3. Department of Pharmaceutical Sciences, University of California, Irvine, CA, USA

    Karina Genaro

  4. Department of Neuroscience and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil

    José Alexandre Crippa

  5. National Institute of Science and Technology for Translational Medicine (INCT-TM- CNPq), Ribeirão Preto, São Paulo, Brazil

    José Alexandre Crippa

Authors
  1. Yane Costa Chaves
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  2. Karina Genaro
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  3. José Alexandre Crippa
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  4. Joice Maria da Cunha
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  5. Janaína Menezes Zanoveli
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Contributions

Janaína M Zanoveli and Joice Maria da Cunha proposed the study and wrote the manuscript.

Yane C. Chaves conducted all behavioral tests.

José A Crippa and Karina Genaro kindly donate the cannabidiol.

All the authors contributed to the data analysis and interpretation and approved the final version of the manuscript.

Corresponding author

Correspondence to Janaína Menezes Zanoveli.

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Declaration of conflicting interests

JAC is co-inventor (Mechoulam R, JC, Guimaraes FS, AZ, JH, Breuer A) of the patent “Fluorinated CBD compounds, compositions and uses thereof. Pub. No.: WO/2014/108899. International Application No.: PCT/IL2014/050023” Def. US no. Reg. 62,193,296; 29/07/2015; INPI on 19/08/2015 (BR1120150164927). The University of São Paulo has licensed the patent to Phytecs Pharm (USP Resolution No. 15.1.130002.1.1). The University of São Paulo has an agreement with Prati-Donaduzzi (Toledo, Brazil) to “develop a pharmaceutical product containing synthetic cannabidiol and prove its safety and therapeutic efficacy in the treatment of epilepsy, schizophrenia, Parkinson’s disease, and anxiety disorders.” JAC has received travel support from and was medical advisor of SCBD Centre. JAC has received a grant from University Global Partnership Network (UGPN) – “Global priorities in cannabinoid research excellence.” JAC is member of the international advisory board of The Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE), funded by the National Health and Medical Research Council through the Centre of Research Excellence).

Ethics approval

All experiments were conducted in accordance with the rules and legislation contained by the UFPR Animal Research Ethics Committee (CEUA number #1106).

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Chaves, Y.C., Genaro, K., Crippa, J.A. et al. Cannabidiol induces antidepressant and anxiolytic‐like effects in experimental type-1 diabetic animals by multiple sites of action. Metab Brain Dis 36, 639–652 (2021). https://doi.org/10.1007/s11011-020-00667-3

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