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endocannabinoid system with the cannabinoid agonist HU-210 decreased NMDA-induced neuronal death exclusively in ethanol-withdrawn neurons.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by a decrease in NMDA-stimulated calcium influx after the administration of HU-210, found exclusively in ethanol-withdrawn neurons.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system with the CB1 receptor antagonist rimonabant (SR141716) during ethanol withdrawal increased death of ethanol-withdrawn neurons without any modification of NMDA-stimulated calcium influx. Moreover, chronic administration of rimonabant increased NMDA-stimulated toxicity not only in withdrawn neurons, but also in control neurons.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.
Highlights
Continued excessive ethanol consumption can lead to the development of dependence that is associated with a withdrawal syndrome when ethanol consumption is interrupted or substantially reduced
It has been described that CB1 receptor-deficient mice do not develop the changes in N-methyl-D-aspartate (NMDA) and c-amino butyric acid (GABA)A receptors observed in wild-type animals [8], suggesting that the endocannabinoid system may be implicated in the development of these glutamatergic and GABAergic neuroadaptations during chronic ethanol exposure
In the current study we show, first, that ethanol withdrawal increases both basal neuronal death and NMDA-stimulated neuronal death in primary cortical cultures, probably due to a change in the expression of NMDA receptor subunits
Summary
Continued excessive ethanol consumption can lead to the development of dependence that is associated with a withdrawal syndrome when ethanol consumption is interrupted or substantially reduced. The search of novel compounds able to protect the brain against the degenerative events associated with alcohol dependence and withdrawal is a key objective, concurring with the efforts for developing protective drugs for the treatment of acute or chronic neurodegenerative disorders In this context, there is large evidence that cannabinoid agonists exert neuroprotection in several models of neuronal injury [3]. It has been described that CB1 receptor-deficient mice do not develop the changes in N-methyl-D-aspartate (NMDA) and c-amino butyric acid (GABA)A receptors observed in wild-type animals [8], suggesting that the endocannabinoid system may be implicated in the development of these glutamatergic and GABAergic neuroadaptations during chronic ethanol exposure It would be of a great interest to examine whether the pharmacological activation or inhibition of the endocannabinoid system affects alcohol withdrawal-induced hypersensitivity to excitotoxic insults. Concordant with qRT-PCR results, GluN2A subunit levels decreased during ethanol withdrawal (figure 2B) (P,0.01), whereas GluN1 (figure 2A) and GluN2B (figure 2C) levels remained unaffected
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