The phytocannabinoid Δ9‐tetrahydrocannabivarin modulates inhibitory neurotransmission in the cerebellum

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.