Sex Differences in the Neurotoxic Effects of Adenosine A1 Receptor Antagonism During Ethanol Withdrawal: Reversal With an A1 Receptor Agonist or an NMDA Receptor AntagonistAlcoholism: Clinical and Experimental Research OnlineEarly Articles 14 May 2008
Neuronal adaptations that occur during chronic ethanol (EtOH) exposure have been observed to sensitize the brain to excitotoxic insult during withdrawal. The adenosine receptor system warrants further examination in this regard, as recent evidence has implicated adenosine receptor involvement in the behavioral effects of both EtOH exposure and withdrawal.
Twenty-four hour exposure to DPCPX in EtOH-naïve slice cultures did not produced neurotoxicity in any region of slice cultures. Though withdrawal from 10 day EtOH exposure produced no toxicity in either male or female slice cultures, exposure to DPCPX during 24 hours of EtOH withdrawal produced a marked increase in PI uptake in all hippocampal culture subregions in female cultures (to 
160% of control values). A significant effect for sex was observed in the CA1 region such that toxicity in females cultures exposed to the A1 antagonist during withdrawal was greater than that observed in male cultures. These effects of DPCPX in EtOH withdrawn female and male slices were prevented by co-exposure to either the A1 agonist CCPA or the NMDA receptor antagonist APV for 24 hours. No differences in the abundance of A1 receptors were observed in male and female EtOH-naïve or EtOH pretreated cultures.
The current findings suggest that the female hippocampus possesses an innate sensitivity to effects of EtOH exposure and withdrawal on neuronal excitability that is independent of hormonal influences. Further, this sex difference is not related to effects of EtOH exposure on A1 receptor abundance, but likely reflects increased NMDA receptor-mediated signaling downstream of A1 inhibition in females.
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