Withdrawal from alcohol in withdrawal seizure-prone and -resistant mice: evidence for enkephalin resistance.
Methionine enkephalin (Met-enkephalin) functions as an endogenous anticonvulsant. 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 activity and increased levels of Met-enkephalin. In contrast, alcohol withdrawal is associated with recovery of PTS-1 activity, decreased levels of Met-enkephalin, and seizures. In this study, we examined the PTS-1/Met-enkephalin system in two replicates of withdrawal seizure-resistant (WSR) and withdrawal seizure-prone (WSP) mouse lines. We measured levels of preproenkephalin (PPE) mRNA and Met-enkephalin peptide in brain and the activity of PTS-1 during alcohol-naive, -dependent, and -withdrawal states. In alcohol-naive animals, Met-enkephalin levels were higher in WSP than in WSR mice. In alcohol-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-naive, -dependent, and -withdrawing mice but not to mRNA levels or PTS-1 activity. Overall, these results may be explained by resistance to enkephalin in WSP mice and suggest that the dysregulation of the PTS-1/Met-enkephalin system contributes to susceptibility to seizures in WSP mice.
Plotkin
S R
SR
Partners Neurology Program, Harvard Medical School, Boston, MA 02115, USA.
Banks
W A
WA
Cohn
C S
CS
Kastin
A J
AJ
D000535:Aluminum / Q000494:pharmacology; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D002492:Central Nervous System Depressants; D004076:Digoxigenin / Q000378:metabolism; D004744:Enkephalin, Methionine / Q000378:metabolism; D004745:Enkephalins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000431:Ethanol; D005260:Female; D006207:Half-Life; D009075:MSH Release-Inhibiting Hormone / Q000031:analogs & derivatives* / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009479:Neuropeptides / Q000032:analysis; D011498:Protein Precursors / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D011863:Radioimmunoassay; D012640:Seizures / Q000235:genetics / Q000503:physiopathology*; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*
D002492:Central Nervous System Depressants; D004745:Enkephalins; D009479:Neuropeptides; D011498:Protein Precursors; D012333:RNA, Messenger; D000431:Ethanol; D004744:Enkephalin, Methionine; C036930:tyrosyl-prolyl-leucyl-glycinamide; D009075:MSH Release-Inhibiting Hormone; C033660:preproenkephalin; D000535:Aluminum; D004076:Digoxigenin