Blocking μ-opioid receptors attenuates reinstatement of responding to an alcohol-predictive conditioned stimulus through actions in the ventral hippocampus.

The µ-opioid system is involved in the reinstatement of responding that is immediately evoked by alcohol-predictive cues. The extent of its involvement in reinstatement observed in a new model that evaluates the delayed effects of re-exposure to alcohol, however, is unclear. The current study investigated the role of µ-opioid receptors (MORs) in the delayed reinstatement of an extinguished, Pavlovian conditioned response that was evoked 24 h after alcohol re-exposure. Female and male Long-Evans rats received Pavlovian conditioning in which a conditioned stimulus (CS) was paired with the delivery of an appetitive unconditioned stimulus (US; Experiments 1, 2, 4: 15% v/v alcohol; Experiment 3: 10% w/v sucrose) that was delivered into a fluid port for oral intake. During subsequent extinction sessions, the CS was presented as before but without the US. Next, the US was delivered but without the CS. A reinstatement test was conducted 24 h later, during which the CS was presented in the absence of the US. Silencing MORs via systemic naltrexone (0.3 or 1.0 mg/kg) attenuated reinstatement of port entries elicited by an alcohol-CS, but not those elicited by a sucrose-CS. Finally, blocking MORs in the ventral hippocampus via bilateral microinfusion of D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP; 2.5 or 5.0 µg/hemisphere) prevented reinstatement of port alcohol-CS port entries. These data show that MORs are involved in the delayed reinstatement of a Pavlovian conditioned response in an alcohol-specific manner. Importantly, these data illustrate, for the first time, that MORs in the ventral hippocampus are necessary for responding to an alcohol-predictive cue.