Pharmacological Activation/Inhibition of the Cannabinoid System Affects Alcohol Withdrawal-Induced Neuronal Hypersensitivity to Excitotoxic Insults

Abstract : Cessation of chronic ethanol consumption can increase the sensitivity of the brain to excitotoxic damages. Cannabinoids have been proposed as neuroprotectants in different models of neuronal injury, but their effect have never been investigated in a context of excitotoxicity after alcohol cessation. Here we examined the effects of the pharmacological activation/inhibition of the endocannabinoid system in an in vitro model of chronic ethanol exposure and withdrawal followed by an excitotoxic challenge. Ethanol withdrawal increased N-methyl-D-aspartate (NMDA)-evoked neuronal death, probably by altering the ratio between GluN2A and GluN2B NMDA receptor subunits. The stimulation of the endocannabinoid system with the cannabinoid agonist HU-210 decreased NMDA-induced neuronal death exclusively in ethanol-withdrawn neurons. This neuroprotection could be explained by a decrease in NMDA-stimulated calcium influx after the administration of HU-210, found exclusively in ethanol-withdrawn neurons. By contrast, the inhibition of the cannabinoid system with the CB1 receptor antagonist rimonabant (SR141716) during ethanol withdrawal increased death of ethanol-withdrawn neurons without any modification of NMDA-stimulated calcium influx. Moreover, chronic administration of rimonabant increased NMDA-stimulated toxicity not only in withdrawn neurons, but also in control neurons. In summary, we show for the first time that the stimulation of the endocannabinoid system is protective against the hyperexcitability developed during alcohol withdrawal. By contrast, the blockade of the endocannabinoid system is highly counterproductive during alcohol withdrawal.
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PLoS ONE, Public Library of Science, 2011, 6 (8), 〈10.1371/journal.pone.0023690〉
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Marina Rubio, Hélène Villain, Fabian Docagne, Benoit Roussel, José Antonio Ramos, et al.. Pharmacological Activation/Inhibition of the Cannabinoid System Affects Alcohol Withdrawal-Induced Neuronal Hypersensitivity to Excitotoxic Insults. PLoS ONE, Public Library of Science, 2011, 6 (8), 〈10.1371/journal.pone.0023690〉. 〈inserm-01296814〉

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