Withdrawal from alcohol in withdrawal seizure-prone and -resistant mice: evidence for enkephalin resistance

Methionine enkephalin (Met-enkephalin) functions as an endogenous anticonvu lsant. Peptide transport system-1 (PTS-1) is an important regulator of Met- enkephalin levels in brain and transports the peptide from brain to blood. In outbred mice, alcohol dependence is associated with decreased PTS-1 acti vity and increased levels of Met-enkephalin. In contrast, alcohol withdrawa l is associated with recovery of PTS-1 activity, decreased levels of Met-en kephalin, and seizures. In this study, we examined the PTS-1/Met-enkephalin system in two replicates of withdrawal seizure-resistant (WSR) and withdra wal seizure-prone (WSP) mouse lines. We measured levels of preproenkephalin (PPE) mRNA and Met-enkephalin peptide in brain and the activity of PTS-1 d uring alcohol-naive, -dependent and -withdrawal states. In alcohol-naive an imals, Met-enkephalin levels were higher in WSP than in WSR mice. In alcoho l-withdrawal animals, Met-enkephalin levels remained elevated in WSP mice. whereas they increased in WSR mice. Peptide levels were unrelated to levels of PPE mRNA or activity of PTS-1. Factorial analysis showed that proneness to seizures was genetically linked to Met-enkephalin levels in alcohol-nai ve, -dependent, and -withdrawing mice but not to mRNA levels or PTS-1 activ ity. Overall, these results may be explained by resistance to enkephalin in WSP mice and suggest that the dysregulation of the PTS-1/Met-enkephalin sy stem contributes to susceptibility to seizures in WSP mice. (C) 2001 Elsevi er Science Inc. All rights reserved.