Alcohol disrupts long-term potentiation at hippocampus-medium spiny neuron synapses in the medial shell of the nucleus accumbens.

Chronic alcohol exposure is a major driver of alcohol use disorders (AUD), in part through its ability to induce maladaptive plasticity within neural circuits that regulate reward, motivation, and affect. Excitatory projections from the hippocampus (Hipp) to the nucleus accumbens (NAc) play a pivotal role in regulating reward-related behaviors, and this pathway serves as a key locus for establishing associations between rewarding stimuli and related contextual information. Regulation of the strength of Hipp-NAc synapses is critical for supporting these behaviors, and impairments in Hipp-NAc plasticity are associated with anhedonia and disrupted reward learning. Here, we demonstrate that acute ethanol application to ex vivo brain slices prevents long-term potentiation (LTP) at Hipp-NAc synapses without altering presynaptic release probability. Furthermore, chronic intermittent exposure to ethanol abolishes LTP at these synapses, an effect we observed during early abstinence indicating that ethanol-induced disruptions in Hipp-NAc plasticity outlasts exposure periods. Together, our findings demonstrate that ethanol rapidly alters Hipp-NAc plasticity, and its effects are still evident in early abstinence. Given the behavioral relevance of these synapses, this work has important implications for the mechanisms underlying ethanol-dependent effects on reward processing and negative affective states associated with AUD.