Cannabis sativa has been associated with contradictory effects upon seizure states despite its medicinal use by numerous people with epilepsy. We have recently shown that the phytocannabinoid cannabidiol (CBD) reduces seizure severity and lethality in the well-established in vivo model of pentylenetetrazole-induced generalised seizures, suggesting that earlier, small-scale clinical trials examining CBD effects in people with epilepsy warrant renewed attention. Here, we report the effects of pure CBD (1, 10 and 100mg/kg) in two other established rodent seizure models, the acute pilocarpine model of temporal lobe seizure and the penicillin model of partial seizure. Seizure activity was video recorded and scored offline using model-specific seizure severity scales. In the pilocarpine model CBD (all doses) significantly reduced the percentage of animals experiencing the most severe seizures. In the penicillin model, CBD (≥ 10 mg/kg) significantly decreased the percentage mortality as a result of seizures; CBD (all doses) also decreased the percentage of animals experiencing the most severe tonic-clonic seizures. These results extend the anti-convulsant profile of CBD; when combined with a reported absence of psychoactive effects, this evidence strongly supports CBD as a therapeutic candidate for a diverse range of human epilepsies.

-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 D 9 -THCV application ( ‡20 lM) significantly reduced burst complex incidence and the amplitude and frequency of paroxysmal depolarizing shifts (PDSs). Furthermore, slices pretreated with 10 lM D 9 -THCV prior to induction of epileptiform activity exhibited significantly reduced burst complex incidence and PDS peak amplitude. In radioligand-binding experiments, -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.

Background and purpose: The phytocannabinoid D 9 -tetrahydrocannabivarin (D 9 -THCV) has been reported to exhibit a diverse pharmacology; here, we investigate functional effects of D 9 -THCV, extracted from Cannabis sativa, using electrophysiological techniques to define its mechanism of action in the CNS. Experimental approach: Effects of D 9 -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 D 9 -THCV, and also by the CB 1 receptor antagonist AM251; D 9 -THCV or AM251 acted to increase mIPSC frequency beyond basal values. When applied alone, D 9 -THCV, AM251 or rimonabant increased mIPSC frequency. Pre-incubation with D 9 -THCV blocked WIN55-induced inhibition. In MEA recordings, WIN55 increased PC spike firing rate; D 9 -THCV and AM251 acted in the opposite direction to decrease spike firing. The effects of D 9 -THCV and WIN55 were attenuated by the GABA A receptor antagonist bicuculline methiodide. Conclusions and implications:We show for the first time that D 9 -THCV acts as a functional CB 1 receptor antagonist in the CNS to modulate inhibitory neurotransmission at IN-PC synapses and spontaneous PC output. D 9 -THCV-and AM251-induced increases in mIPSC frequency beyond basal levels were consistent with basal CB 1 receptor activity. WIN55-induced increases in PC spike firing rate were consistent with synaptic disinhibition; whilst D 9 -THCV-and AM251-induced decreases in spike firing suggest a mechanism of PC inhibition.

No abstract

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.