Δ⁹-Tetrahydrocannabinol induces the apoptotic pathway in cultured cortical neurones via activation of the CB₁ receptor

Δ⁹-Tetrahydrocannabinol, the principal psychoactive component of marijuana, exerts a variety of effects on the CNS, including impaired cognitive function and neurobehavioural deficits. The mechanisms underlying these neuronal responses to tetrahydrocannabinol are unclear but may involve alterations in neuronal viability. Tetrahydrocannabinol has been shown to influence neuronal survival but the role of the cannabinoid receptors in the regulation of neuronal viability has not been fully clarified. In this study we demonstrate that tetrahydrocannabinol promotes the release of cytochrome c, activates caspase-3, promotes cleavage of the DNA repair enzyme poly-ADP ribose polymerase and induces DNA fragmentation in cultured cortical neurones. These effects of tetrahydrocannabinol were completely abrogated by the CB₁ receptor antagonist AM-251. The findings of this study demonstrate that tetrahydrocannabinol induces apoptosis in cortical neurones in a manner involving the CB₁ subtype of cannabinoid receptor.