Repeated ethanol exposure and withdrawal impairs human fear conditioning and depresses long-term potentiation in rat amygdala and hippocampus

Background: In rats, repeated episodes of alcohol consumption and withwdrawal (RWD) impair fear conditioning to discrete cues. Methods: Fear conditioning was measured. in human binge drinkers as the increased startle response in the presence of a CS + conditioned to aversive white noise. Secondly, the ability of tone CSs, paired with footshock, to induce c-fos expression, a marker of neuronal activity, in limbic structures subserving emotion was studied in rats. Additionally, consequences of RWD on subsequent induction of long term potentiation (LTP) in external capsule/lateral amygdala and Schaffer collateral/hippocampus CA1 pathways were studied in rat brain slices. Results: Fear conditioning was impaired in young human binge drinkers. The ability of fear-conditioned CSs to increase c-fos expression in limbic brain arc-as was reduced following RWD, as was LTP induction. Rats conditioned prior to RWD, following RWD showed generalization of conditioned/carfrom the tone CS+ to a neutral control stimulus, and a novel tone. Conclusions: Binge-like drinking impairs fear conditioning, reduces LTP, and results in inappropriate generalization of learned fear responses. We propose a mechanism whereby RWD-induced synaptic plasticity reduces capacity for future learning, while allowing unconditioned stimuli access to neuronal pathways underlying conditioned fear.