The medial prefrontal cortex is required for responding to alcohol-predictive cues but only in the absence of alcohol delivery.

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The prelimbic medial prefrontal cortex is implicated in promoting drug-seeking in relapse tests. However, drug-seeking behaviour is typically extinguished before a test and tests normally occur without drug delivery. We investigated the involvement of the prelimbic and the infralimbic cortex in responding elicited by a non-extinguished cue for alcohol that was presented without alcohol in an alcohol-associated context or a neutral context, and in responding to the same cue when it was paired with alcohol. Male, Long-Evans rats (220-240 g on arrival) were acclimated to 15% ethanol (v/v; 'alcohol') and then trained to associate a conditioned stimulus (10 s white noise; 15 trials/session) with alcohol delivery into a fluid port (0.2 mL/conditioned stimulus, 3 mL per session) for oral intake. Conditioning sessions occurred in a specific 'alcohol context' and were alternated daily with exposure to a second 'neutral' context that contained neither the conditioned stimulus nor alcohol. At test, functional prelimbic cortex inactivation using baclofen/muscimol reduced fluid port entries elicited by a non-extinguished conditioned stimulus that was presented without alcohol, but had no subsequent impact on port entries when the conditioned stimulus was paired with alcohol. Similar results were obtained following infralimbic cortex inactivation; however, infralimbic cortex inactivation also non-specifically reduced port entries in the absence of alcohol. These data indicate that the prelimbic and infralimbic cortex are involved in responding to cues for alcohol when alcohol delivery is omitted, but suggest that other brain regions are engaged in responding to such cues in the presence of alcohol.