Tetrahydrocannabinol-induced apoptosis of cultured cortical neurones is associated with cytochrome c release and caspase-3 activation

Neuropharmacology. 2001 Apr;40(5):702-9. doi: 10.1016/s0028-3908(00)00210-0.


Delta(9)-tetrahydrocannabinol (THC), the principal psychoactive component of marijuana, is associated with impaired cognition and altered cortical function. THC transduces its central effects via activation of the G-protein linked cannabinoid receptor CB1. In this study we report that THC induces morphological degenerative changes in cultured cortical neurones, such as membrane blebbing and formation of apoptotic bodies, that are consistent with the apoptotic pathway of cell death. The THC-induced apoptosis was blocked by the CB1 receptor antagonist AM251 and pertussis toxin (PTX), suggesting that this effect of THC involves receptor-mediated activation of the G-protein subtypes G(i) or G(o). THC also promoted translocation of mitochondrial cytochrome c to the cytosol and increased the activity of the cysteine protease caspase-3, in a PTX-sensitive manner. The results from this study suggest that coupling of THC to a PTX-sensitive G-protein promotes cytochrome c release, caspase-3 activation and subsequent degeneration of cultured cortical neurones. This apoptotic pathway may underlie the compromised neuronal function that is associated with marijuana usage.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Blotting, Western
  • Caspase 1 / metabolism
  • Caspase 3
  • Caspases / metabolism*
  • Cerebral Cortex / cytology*
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / enzymology*
  • Cytochrome c Group / metabolism*
  • Dronabinol / antagonists & inhibitors
  • Dronabinol / toxicity*
  • Enzyme Activation / drug effects*
  • GTP-Binding Proteins / biosynthesis
  • GTP-Binding Proteins / genetics
  • In Situ Nick-End Labeling
  • Kinetics
  • Male
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Nerve Degeneration
  • Neurons / drug effects*
  • Neurons / enzymology*
  • Pertussis Toxin
  • Rats
  • Rats, Wistar
  • Virulence Factors, Bordetella / pharmacology


  • Cytochrome c Group
  • Virulence Factors, Bordetella
  • Dronabinol
  • Pertussis Toxin
  • Casp3 protein, rat
  • Caspase 3
  • Caspases
  • Caspase 1
  • GTP-Binding Proteins