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Phytocannabinoids restore seizure-induced alterations in emotional behaviour in male rats

Neuropsychopharmacology volume 50, pages 751–761 (2025)Cite this article

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Abstract

Epilepsy often presents with severe emotional comorbidities including anxiety and abnormal fear responses which impose a significant burden on, and reduce, quality of life in people living with the disease. Our lab has recently shown that kindled seizures lead to changes in emotional processing resulting from the downregulation of anandamide signalling within the amygdala. Phytocannabinoids derived from the Cannabis sativa plant have attracted a lot of interest as a new class of drugs with potential anticonvulsant effects. Among the wide number of compounds occurring in Cannabis sativa, Δ9- tetrahydrocannabinol (THC), the one responsible for its main psychoactive effects, and the nonpsychoactive cannabidiol (CBD) have been extensively examined under pre-clinical and clinical contexts to control seizures, however, neither have been assessed in the context of the management of emotional comorbidities associated with seizure activity. We used two behavioural procedures to assess anxiety- and fear-like responding in adult male Long-Evans rats: elevated plus maze and auditory fear conditioning. In agreement with previous reports, we found seizure-induced increases in anxiety- and fear-like responding. These effects were reversed by either CBD (vaporized) or THC (oral). We also found that antagonism of serotonin 1 A receptors prior to CBD exposure prevented its protective effects. Phytocannabinoids offer a novel and reliable opportunity to treat seizure induced comorbid emotional alterations.

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Fig. 1: Vaporized CBD rescued seizure-induced increase in anxiety-like behaviour the EPM via the 5-HT1A receptor.
Fig. 2: Vaporized CBD rescued seizure-induced heightened fear memory responses via the 5-HT1A receptor.
Fig. 3: Edible, but not vaporized, THC rescued the seizure-induced increase in anxiety-like behaviour on the EPM.
Fig. 4: Neither route of THC administration rescued seizure-induced impairments in fear memory dynamics.
Fig. 5: THC and CBD levels following vaporized and oral administration.

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Funding

This work was funded by the Canadian Institute of Health Research (CIHR) Grant (PJT-162204) awarded to G. Campbell Teskey. The authors would like to thank the members of the Hill Lab at the University of Calgary for their technical expertise and time for training on the use of the vaporizer chambers.

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Author notes

  1. These authors contributed equally: G. Campbell Teskey, Roberto Colangeli.

Authors and Affiliations

  1. Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada

    Renaud C. Gom, Pasindu Wickramarachchi, Antis G. George, Savannah H. M. Lightfoot, Dana Newton-Gunderson, Matthew N. Hill, G. Campbell Teskey & Roberto Colangeli

  2. Department of Cell Biology and Anatomy, University of Calgary, Calgary, Calgary, AB, Canada

    Renaud C. Gom, Pasindu Wickramarachchi, Antis G. George, Dana Newton-Gunderson, Matthew N. Hill, G. Campbell Teskey & Roberto Colangeli

  3. Mathison Centre for Mental Health Research and Education; University of Calgary, Calgary, AB, T2N 4N1, Canada

    Savannah H. M. Lightfoot & Matthew N. Hill

  4. Department of Experimental and Clinical Medicine; Università Politecnica delle Marche, 60126, Ancona, Italy

    Roberto Colangeli

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Contributions

Renaud C. Gom: involved in study conceptualization, data collection, formal analysis, writing – original draft. Pasindu Wickramarachchi: involved in data collection, formal analysis, writing – original draft. Antis G. George: involved in data analysis, writing – review and editing. Savannah H.M. Lightfoot: involved in data collection, writing – review and editing. Dana Newton-Gunderson: involved in data collection, data analysis, writing – review and editing. Matthew N. Hill: involved in material supply, writing – review and editing. G. Campbell Teskey: involved in study conceptualization, oversight of data collection, writing – review and editing, funding acquisition. Roberto Colangeli: involved in study conceptualization, oversight of data collection, writing – review and editing.

Corresponding author

Correspondence to Renaud C. Gom.

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Competing interests

Matthew Hill is an associate editor for Neuropsychopharmacology. The remaining authors have nothing to disclose.

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Gom, R.C., Wickramarachchi, P., George, A.G. et al. Phytocannabinoids restore seizure-induced alterations in emotional behaviour in male rats. Neuropsychopharmacol. 50, 751–761 (2025). https://doi.org/10.1038/s41386-024-02005-y

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