Low prefrontal PSA-NCAM confers risk for alcoholism-related behavior

Factors underlying vulnerability to alcoholism are largely unknown. We identified an innate endophenotype in rodents that predicted individual risk for alcohol-related behaviors that was associated with decreased expression of the neuroplasticity-related cell-adhesion molecule PSA-NCAM. Depletion of PSA-NCAM within the ventromedial prefrontal cortex was sufficient to render mice unable to extinguish alcohol seeking, indicating a causal role of naturally occurring variation. These data demonstrate a novel mechanism of aberrant prefrontal neuroplasticity that underlies enhanced propensity for inflexible addiction-related behavior.