Sex Differences in Caffeine Neurotoxicity Following Chronic Ethanol Exposure and WithdrawalAlcohol and Alcoholism Advance Access published online on September 16, 2009
Caffeine is a central nervous system stimulant that produces its primary effects via antagonism of the A1 and A2A adenosine receptor subtypes. Previous work demonstrated a sex difference in neurotoxicity produced by specific adenosine A1 receptor antagonism during ethanol withdrawal (EWD) in vitro that was attributable to effects downstream of A1 receptors at NMDA receptors.
The current studies were designed to examine the effect of non-specific adenosine receptor antagonism with caffeine during ethanol withdrawal on hippocampal toxicity in cultures derived from male and female rats.
Twenty-four-hour exposure to caffeine during EWD produced significant toxicity in the pyramidal cell layer of the CA3 region in male and female cultures, though toxicity in the granule cell layer of the DG and pyramidal cell layer of the CA1 region was observed only in female cultures. Greater sensitivity of the female slice cultures to toxicity upon caffeine exposure after prolonged ethanol exposure is consistent with previous studies of effects of a specific A1 receptor antagonism during EWD on toxicity and indicate that this effect is independent of the hormonal milieu.
Together, these data suggest that the A1 receptor subtype is predominant in mediating caffeine's neurotoxic effects during EWD. These findings demonstrate the importance of considering gender/sex when examining neuroadaptive changes in response to ethanol exposure and withdrawal.
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