Cannabinoid receptor agonists protect cultured rat hippocampal neurons from excitotoxicity. Molecular Pharmacology 54:459462

Cannabinoid receptor agonists act presynaptically to inhibit the release of glutamate. Because other drugs with this action are known to reduce excitotoxicity, we tested several cannabimi-metics in a model of synaptically mediated neuronal death. Reduction of the extracellular Mg21 concentration to 0.1 mM evoked a repetitive pattern of intracellular Ca21 concentration ([Ca21]i) spiking that, when maintained for 24 hr, resulted in significant neuronal death. The [Ca21]i spiking and cell death in this model result from excessive activation of N-methyl-D-as-partate receptors, as indicated by the inhibition of both [Ca21]i spiking and neuronal death by the N-methyl-D-aspartate recep-tor antagonist CGS19755 (10 mM). The cannabimimetic drug Win55212–2 (100 nM) completely blocked [Ca21]i spiking and prevented neuronal death induced by low extracellular Mg21 concentrations. These effects on [Ca21]i spiking and viability were stereoselective and were prevented by the CB1 receptor antagonist SR141716 (100 nM). The partial agonist CP55940 (100 nM) also afforded significant protection from excitotoxicity. Cannabimimetic drugs did not protect cells from the direct application of glutamate (30 mM). These data suggest that can-nabimimetic drugs may slow the progression of neurodegen-erative diseases. The medicinal use of marijuana is controversial (Annas, 1997). The euphoria produced by D9-tetrahydrocannabinol, the principal psychoactive ingredient in marijuana, has led to the widespread recreational use of this drug. Therefore, the potential for abuse must be weighed against the thera-peutic benefits of cannabimimetics. These drugs have been reported to be effective in the treatment of chronic pain, glaucoma, epilepsy, and the wasting and emesis associated with acquired immunodeficiency syndrome and cancer che