Addiction to ethanol is a significant problem in our society and is a leading cause of morbidity and mortality in the population. Major changes in neurochemistry, such as in the brain levels of the opiate peptide methionine enkephalin Met-En k , have been associated with exposure to ethanol. It is our long term goal to elucidate the mechanisms and significance of these changes in Met-Enk and to design therapeutic interventions directed at their reversal. The level of Met-Enk in the brain has been linked to ethanol ingestion and withdrawal seizures while treatment with enkephalins, their analogs, or blockers of their enzymatic degradation can decrease ethanol drinking and prevent ethanol withdrawal seizures. The level of Met-Enk in the brain is determined by a balance of synthesis, release, degradation, and transport across the blood-brain barrier BB by PTS-1, which carries Met-Enk from the brain to the blood. Our work has confirmed that PTS-1 is a major regulator of the level of Met-Enk in the brain of ethanol-naive mice and that during physical dependence to and withdrawal from ethanol the control of the level of Met-Enk in the brain is post-translational and mediated at least partially by PTS-1. In the requested funding period, we will determine the relative importance during physical dependence to and withdrawal from ethanol of PTS-1 to that of other post-translational mechanisms that affect Met-Enk levels in the brain.