Original Investigation

Psychopharmacology

, Volume 231, Issue 17, pp 3401-3414

First online:

Quantification of ten neuroactive steroids in plasma in Withdrawal Seizure-Prone and -Resistant mice during chronic ethanol withdrawal

  • Christopher SnellingAffiliated withDepartment of Behavioral Neuroscience, Oregon Health and Science University
  • , Michelle A. Tanchuck-NipperAffiliated withDepartment of Behavioral Neuroscience, Oregon Health and Science University
  • , Matthew M. FordAffiliated withDepartment of Behavioral Neuroscience, Oregon Health and Science UniversityDivision of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University
  • , Jeremiah P. JensenAffiliated withDepartment of Behavioral Neuroscience, Oregon Health and Science University
  • , Debra K. CozzoliAffiliated withDepartment of Behavioral Neuroscience, Oregon Health and Science University
  • , Marcia J. RamakerAffiliated withDepartment of Behavioral Neuroscience, Oregon Health and Science University
  • , Melinda HelmsAffiliated withDepartment of Behavioral Neuroscience, Oregon Health and Science University
  • , John C. CrabbeAffiliated withDepartment of Behavioral Neuroscience, Oregon Health and Science UniversityDepartment of Veterans Affairs Medical Center, Portland Alcohol Research Center
  • , David J. RossiAffiliated withDepartment of Behavioral Neuroscience, Oregon Health and Science UniversityDepartment of Integrative Physiology and Neuroscience, Washington State University
    • , Deborah A. FinnAffiliated withDepartment of Behavioral Neuroscience, Oregon Health and Science UniversityDepartment of Veterans Affairs Medical Center, Portland Alcohol Research Center Email author 

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Abstract

Rationale

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.

Objectives

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.

Keywords

Allopregnanolone Androstanediol Tetrahydrodeoxycorticosterone Alcohol Gas chromatography Mass spectrometry DHEA Pregnenolone Male