To determine how acute ethanol intoxication may alter memory processing, we 
examined the effects of stepwise increases in ethanol on long-term potentiation 
(LTP) in rat hippocampal slices. LTP was inhibited by acute administration of 60 
mM ethanol, but was readily induced if ethanol was increased gradually to 60 mM 
over 75 min. Administration of 2-amino-5 phosphonovalerate (APV), an 
N-methyl-D-aspartate receptor (NMDAR) antagonist, during the stepwise increase 
in ethanol inhibited LTP, suggesting involvement of NMDARs in the development of 
tolerance. However, APV and nifedipine, an inhibitor of L-type calcium channels, 
failed to inhibit LTP when administered following the slow increase in ethanol. 
Ethanol-tolerant LTP was inhibited by thapsigargin, suggesting a major role for 
intracellular calcium release in this form of plasticity. The unique properties 
of ethanol-tolerant LTP suggest that memories formed during binge drinking are 
not acquired by standard synaptic mechanisms and that acute tolerance may 
involve the induction of novel mechanisms to maintain function.