Δ9-Tetrahydrocannabivarin suppresses in vitro epileptiform and in vivo seizure activity in adult rats

Authors

  • Andrew J. Hill,

    1. School of Pharmacy, University of Reading, Whiteknights, Reading, Berkshire, United Kingdom
    2. School of Psychology and Clinical Language Sciences, University of Reading, Earley Gate, Whiteknights, Reading, Berkshire, United Kingdom
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    • These authors contributed equally to this study.

  • Samantha E. Weston,

    1. School of Pharmacy, University of Reading, Whiteknights, Reading, Berkshire, United Kingdom
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    • These authors contributed equally to this study.

  • Nicholas A. Jones,

    1. School of Pharmacy, University of Reading, Whiteknights, Reading, Berkshire, United Kingdom
    2. School of Psychology and Clinical Language Sciences, University of Reading, Earley Gate, Whiteknights, Reading, Berkshire, United Kingdom
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  • Imogen Smith,

    1. School of Pharmacy, University of Reading, Whiteknights, Reading, Berkshire, United Kingdom
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  • Sarah A. Bevan,

    1. School of Pharmacy, University of Reading, Whiteknights, Reading, Berkshire, United Kingdom
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  • Elizabeth M. Williamson,

    1. School of Pharmacy, University of Reading, Whiteknights, Reading, Berkshire, United Kingdom
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  • Gary J. Stephens,

    1. School of Pharmacy, University of Reading, Whiteknights, Reading, Berkshire, United Kingdom
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  • Claire M. Williams,

    1. School of Psychology and Clinical Language Sciences, University of Reading, Earley Gate, Whiteknights, Reading, Berkshire, United Kingdom
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  • Benjamin J. Whalley

    1. School of Pharmacy, University of Reading, Whiteknights, Reading, Berkshire, United Kingdom
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Address correspondence to Dr Benjamin J. Whalley, School of Pharmacy, University of Reading, Whiteknights, Reading, Berks, United Kingdom E-mail: b.j.whalley@reading.ac.uk

Summary

Purpose:  We assessed the anticonvulsant potential of the phytocannabinoid Δ9-tetrahydrocannabivarin (Δ9-THCV) by investigating its effects in an in vitro piriform cortex (PC) brain slice model of epileptiform activity, on cannabinoid CB1 receptor radioligand-binding assays and in a generalized seizure model in rats.

Methods:  Δ9-THCV was applied before (10 μmΔ9-THCV) or during (10–50 μmΔ9-THCV) epileptiform activity induced by Mg2+-free extracellular media in adult rat PC slices and measured using multielectrode array (MEA) extracellular electrophysiologic techniques. The actions of Δ9-THCV on CB1 receptors were examined using [3H]SR141716A competition binding and [35S]GTPγS assays in rat cortical membranes. Effects of Δ9-THCV (0.025–2.5 mg/kg) on pentylenetetrazole (PTZ)–induced seizures in adult rats were also assessed.

Results:  After induction of stable spontaneous epileptiform activity, acute Δ9-THCV application (≥20 μm) significantly reduced burst complex incidence and the amplitude and frequency of paroxysmal depolarizing shifts (PDSs). Furthermore, slices pretreated with 10 μmΔ9-THCV prior to induction of epileptiform activity exhibited significantly reduced burst complex incidence and PDS peak amplitude. In radioligand-binding experiments, Δ9-THCV acted as a CB1 receptor ligand, displacing 0.5 nm [3H]SR141716A with a Ki∼290 nm, but exerted no agonist stimulation of [35S]GTPγS binding. In PTZ-induced seizures in vivo, 0.25 mg/kg Δ9-THCV significantly reduced seizure incidence.

Discussion:  These data demonstrate that Δ9-THCV exerts antiepileptiform and anticonvulsant properties, actions that are consistent with a CB1 receptor–mediated mechanism and suggest possible therapeutic application in the treatment of pathophysiologic hyperexcitability states.

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