The phytocannabinoid Delta(9)-tetrahydrocannabivarin modulates inhibitory neurotransmission in the cerebellum

Br J Pharmacol. 2008 May;154(1):204-15. doi: 10.1038/bjp.2008.57. Epub 2008 Mar 3.


Background and purpose: The phytocannabinoid Delta(9)-tetrahydrocannabivarin (Delta(9)-THCV) has been reported to exhibit a diverse pharmacology; here, we investigate functional effects of Delta(9)-THCV, extracted from Cannabis sativa, using electrophysiological techniques to define its mechanism of action in the CNS.

Experimental approach: Effects of Delta(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 Delta(9)-THCV, and also by the CB(1) receptor antagonist AM251; Delta(9)-THCV or AM251 acted to increase mIPSC frequency beyond basal values. When applied alone, Delta(9)-THCV, AM251 or rimonabant increased mIPSC frequency. Pre-incubation with Delta(9)-THCV blocked WIN55-induced inhibition. In MEA recordings, WIN55 increased PC spike firing rate; Delta(9)-THCV and AM251 acted in the opposite direction to decrease spike firing. The effects of Delta(9)-THCV and WIN55 were attenuated by the GABA(A) receptor antagonist bicuculline methiodide.

Conclusions and implications: We show for the first time that Delta(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. Delta(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 Delta(9)-THCV- and AM251-induced decreases in spike firing suggest a mechanism of PC inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzoxazines / pharmacology
  • Bicuculline / pharmacology
  • Cannabinoids / pharmacology
  • Cerebellum / drug effects*
  • Dronabinol / analogs & derivatives*
  • Dronabinol / antagonists & inhibitors
  • Dronabinol / pharmacology
  • Electrophysiology
  • Excitatory Postsynaptic Potentials / drug effects
  • GABA Antagonists / pharmacology
  • In Vitro Techniques
  • Male
  • Mice
  • Morpholines / pharmacology
  • Naphthalenes / pharmacology
  • Patch-Clamp Techniques
  • Piperidines / pharmacology
  • Purkinje Cells / drug effects
  • Pyrazoles / pharmacology
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors
  • Rimonabant
  • Synapses / drug effects
  • Synaptic Transmission / drug effects*
  • gamma-Aminobutyric Acid / physiology*


  • Benzoxazines
  • Cannabinoids
  • GABA Antagonists
  • Morpholines
  • Naphthalenes
  • Piperidines
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • tetrahydrocannabivarin 9
  • AM 251
  • gamma-Aminobutyric Acid
  • Win 55212-2
  • Dronabinol
  • Rimonabant
  • Bicuculline