Escalating ethanol intake is associated with altered corticostriatal BDNF expression.

Alcoholism is a chronically relapsing condition, indicative of long-term neuronal adaptations maintaining the disease even after prolonged abstinence. Previously, we identified brain-derived neurotrophic factor (BDNF) in the dorsal striatum as the central mediator of a homeostatic mechanism which is activated by acute alcohol (ethanol) exposure and functions to decrease the sensitivity of rodents to ethanol-related behaviors. We hypothesized that extensive exposure to ethanol would result in dysregulation of this BDNF-mediated protective mechanism, accompanied by heightened ethanol intake. In this study, we demonstrate that while a single bout of ethanol intake increases BDNF mRNA expression in the dorsal striatum, this effect is no longer observed after 6 weeks of daily ethanol access. Additionally, 6 weeks of ethanol consumption decreases BDNF in the cortex, a main source of BDNF for the striatum. Importantly, these ethanol-induced changes in BDNF levels are not ameliorated by 2 weeks' abstinence. Together, these data suggest that the BDNF pathway, which is activated following a single bout of ethanol drinking, breaks down by the end of 6 weeks of access and does not recover its protective function after a 2-week deprivation period. These results suggest that the persistence of altered BDNF signaling may contribute to the inflexibility of addictive behaviors.