Caffeine is a central nervous system stimulant that produces its primary effects via antagonism of the A(1) and A(2A) adenosine receptor subtypes. Previous work demonstrated a sex difference in neurotoxicity produced by specific adenosine A(1) receptor antagonism during ethanol withdrawal (EWD) in vitro that was attributable to effects downstream of A(1) 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.