α-tocopherol and α-tocopheryl phosphate interact with the cannabinoid system in the rodent hippocampus

α-Tocopherol (α-TOH), a dietary component of vitamin E, is well known for its antioxidant capacity. Nevertheless, recent studies have pointed out non-anti-radical properties including cellular and genomic actions. Decreased levels of α-tocopherol in the brain are associated with neuronal dysfunctions ranging from mood disorders to neurodegeneration. All these behavioral effects of α-tocopherol deficiency probably do not rely simply on its anti-radical properties, but could also be reminiscent of a not-yet characterized neuromodulatory action. We have thus measured the direct actions of α-tocopherol and of its natural phosphate derivative, α-tocopheryl phosphate (α-TP), on synaptic transmission in rodent hippocampus. These compounds had opposite actions on both glutamatergic and GABAergic transmission: whereas α-TOH potentiated these transmissions, α-TP inhibited them. Interestingly, these effects were both mediated by cannabinoid receptors (CB1Rs), because they were blocked by the CB1R antagonist AM251. Although α-tocopherol and α-tocopheryl phosphate did not directly bind CB1R, both α-TP and CB1R agonists inhibited forskolin-evoked Erk1/2 phosphorylation in a nonadditive manner. Furthermore, both α-tocopherol and α-tocopheryl phosphate attenuated depolarization-induced suppression of excitation and CB1R agonist-mediated hypothermia. Therefore, we identify α-tocopherol as new lipid modulator of the cannabinoid system in the rodent hippocampus, i.e., a novel "non-anti-radical" action of vitamin E, which may have some preeminent impact in neuronal disorders associated with vitamin E deficiency.