Cannabinoids, electrophysiology, and retrograde messengers: challenges for the next 5 years

Most of the behavioral effects of cannabis and its active ingredients, the cannabinoids (delta9THC being the most abundant of these), appear to be mediated by cannabinoid receptors. Endogenous cannabinoids (endocannabinoids) are lipid mediators that activate these same cannabinoid receptors. Elegant work from several laboratories over the past 5 years has established that endocannabinoids, possibly acting as retrograde messengers, mediate several forms of neuronal plasticity. Endocannabinoid-mediated neuronal plasticity is common, apparently occurring at all neurons that express cannabinoid receptors. Thus, it is likely that delta9THC produces its effects by interacting with endocannabinoid-mediated neuronal plasticity, though whether it does so cooperatively or antagonistically remains an open question. In this review we will briefly discuss the work establishing endocannabinoids as mediators of neuronal plasticity and then present evidence that a major effect of delta9THC may be to antagonize the actions of endocannabinoids.