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Background and purpose: The phytocannabinoid Δ9‐tetrahydrocannabivarin (Δ9‐THCV) has been reported to exhibit a diverse pharmacology; here, we investigate functional effects of Δ9‐THCV, extracted from Cannabis sativa, using electrophysiological techniques to define its mechanism of action in the CNS. Experimental approach: Effects of Δ9‐THCV and synthetic cannabinoid agents on inhibitory neurotransmission at interneurone‐Purkinje cell (IN‐PC) synapses were correlated with effects on spontaneous PC output using single‐cell and multi‐electrode array (MEA) electrophysiological recordings respectively, in mouse cerebellar brain slices in vitro. Key results: The cannabinoid receptor agonist WIN 55,212‐2 (WIN55) decreased miniature inhibitory postsynaptic current (mIPSC) frequency at IN‐PC synapses. WIN55‐induced inhibition was reversed by Δ9‐THCV, and also by the CB1 receptor antagonist AM251; Δ9‐THCV or AM251 acted to increase mIPSC frequency beyond basal values. When applied alone, Δ9‐THCV, AM251 or rimonabant increased mIPSC frequency. Pre‐incubation with Δ9‐THCV blocked WIN55‐induced inhibition. In MEA recordings, WIN55 increased PC spike firing rate; Δ9‐THCV and AM251 acted in the opposite direction to decrease spike firing. The effects of Δ9‐THCV and WIN55 were attenuated by the GABAA receptor antagonist bicuculline methiodide. Conclusions and implications: We show for the first time that Δ9‐THCV acts as a functional CB1 receptor antagonist in the CNS to modulate inhibitory neurotransmission at IN‐PC synapses and spontaneous PC output. Δ9‐THCV‐ and AM251‐induced increases in mIPSC frequency beyond basal levels were consistent with basal CB1 receptor activity. WIN55‐induced increases in PC spike firing rate were consistent with synaptic disinhibition; whilst Δ9‐THCV‐ and AM251‐induced decreases in spike firing suggest a mechanism of PC inhibition.

Phytocannabinoids in Cannabis sativa have diverse pharmacological targets extending beyond cannabinoid receptors and several exert notable anticonvulsant effects. For the first time, we investigated the anticonvulsant profile of the phytocannabinoid cannabidivarin (CBDV) in vitro and in in vivo seizure models.The effect of CBDV (1-100 μM) on epileptiform local field potentials (LFPs) induced in rat hippocampal brain slices by 4-aminopyridine (4-AP) application or Mg(2+) -free conditions was assessed by in vitro multi-electrode array recordings. Additionally, the anticonvulsant profile of CBDV (50-200 mg·kg(-1) ) in vivo was investigated in four rodent seizure models: maximal electroshock (mES) and audiogenic seizures in mice, and pentylenetetrazole (PTZ) and pilocarpine-induced seizures in rats. The effects of CBDV in combination with commonly used antiepileptic drugs on rat seizures were investigated. Finally, the motor side effect profile of CBDV was investigated using static beam and grip strength assays.CBDV significantly attenuated status epilepticus-like epileptiform LFPs induced by 4-AP and Mg(2+) -free conditions. CBDV had significant anticonvulsant effects on the mES (≥100 mg·kg(-1) ), audiogenic (≥50 mg·kg(-1) ) and PTZ-induced seizures (≥100 mg·kg(-1) ). CBDV (200 mg·kg(-1) ) alone had no effect against pilocarpine-induced seizures, but significantly attenuated these seizures when administered with valproate or phenobarbital at this dose. CBDV had no effect on motor function.These results indicate that CBDV is an effective anticonvulsant in a broad range of seizure models. Also it did not significantly affect normal motor function and, therefore, merits further investigation as a novel anti-epileptic in chronic epilepsy models.This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.167.issue-8.

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