title: Quantification of ten neuroactive steroids in plasma in Withdrawal Seizure-Prone and -Resistant mice during chronic ethanol withdrawal.
abstract: BACKGROUND
  The rapid membrane actions of neuroactive steroids, particularly via an enhancement of γ-aminobutyric acidA receptors (GABAARs), participate in the regulation of central nervous system excitability. Prior evidence suggests an inverse relationship between endogenous GABAergic neuroactive steroid levels and behavioral changes in excitability during ethanol withdrawal.
  
  
  OBJECTIVE
  Previously, we found that ethanol withdrawal significantly decreased plasma allopregnanolone (ALLO) levels, a potent GABAergic neuroactive steroid, and decreased GABAAR sensitivity to ALLO in Withdrawal Seizure-Prone (WSP) but not in Withdrawal Seizure-Resistant (WSR) mice. However, the effect of ethanol withdrawal on levels of other endogenous GABAAR-active steroids is not known.
  
  
  METHODS
  After validation of a gas chromatography-mass spectrometry method for the simultaneous quantification of ten neuroactive steroids, we analyzed plasma from control male WSP-1 and WSR-1 mice and during ethanol withdrawal.
  
  
  RESULTS
  We quantified levels of nine neuroactive steroids in WSP-1 and WSR-1 plasma; levels of pregnanolone were not detectable. Basal levels of five neuroactive steroids were higher in WSR-1 versus WSP-1 mice. Ethanol withdrawal significantly suppressed five neuroactive steroids in WSP-1 and WSR-1 mice, including ALLO.
  
  
  CONCLUSIONS
  Due to lower basal levels of some GABAAR-active steroids in WSP-1 mice, a withdrawal-induced decrease in WSP-1 mice may have a greater physiological consequence than a similar decrease in WSR-1 mice. Because WSP-1 mice also exhibit a reduction in GABAAR sensitivity to neuroactive steroids during withdrawal, it is possible that the combined decrease in neuroactive steroids and GABAAR sensitivity during ethanol withdrawal in WSP-1 mice represents a neurochemical substrate for severe ethanol withdrawal.
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Snelling
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Tanchuck-Nipper
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ford
authors.forename: Jeremiah P
authors.initials: JP
authors.lastname: Jensen
authors.forename: Debra K
authors.initials: DK
authors.lastname: Cozzoli
authors.forename: Marcia J
authors.initials: MJ
authors.lastname: Ramaker
authors.forename: Melinda
authors.initials: M
authors.lastname: Helms
authors.forename: John C
authors.initials: JC
authors.lastname: Crabbe
authors.forename: David J
authors.initials: DJ
authors.lastname: Rossi
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Finn
mesh_terms: D000818:Animals; D002492:Central Nervous System Depressants; D002908:Chronic Disease; D000431:Ethanol; D008297:Male; D051379:Mice; D018377:Neurotransmitter Agents / Q000097:blood*; D011280:Pregnanolone / Q000097:blood; D011963:Receptors, GABA-A / Q000378:metabolism; D015203:Reproducibility of Results; D012640:Seizures / Q000097:blood* / Q000235:genetics / Q000523:psychology; D013375:Substance Withdrawal Syndrome / Q000097:blood* / Q000235:genetics / Q000523:psychology
chemical_list: D002492:Central Nervous System Depressants; D018377:Neurotransmitter Agents; D011963:Receptors, GABA-A; D000431:Ethanol; D011280:Pregnanolone