Genotype Differences in Sensitivity to the Anticonvulsant Effect of the Synthetic Neurosteroid Ganaxolone during Chronic Ethanol Withdrawal

Michelle A. Nipper, Jeremiah P. Jensen, Melinda L. Helms, Matthew Ford, John Jr Crabbe, David J. Rossi, Deborah (Deb) Finn

Research output: Contribution to journalArticle

Abstract

Sensitivity to anticonvulsant effects of the γ-aminobutyric acidA receptor-active neurosteroid allopregnanolone (ALLO) during ethanol withdrawal varies across genotypes, with high sensitivity in genotypes with mild withdrawal and low sensitivity in genotypes with high withdrawal. The present studies determined whether the resistance to ALLO during withdrawal in mouse genotypes with high handling-induced convulsions (HICs) during withdrawal could be overcome with use of ganaxolone (GAN), the metabolically stable derivative of ALLO. In separate studies, male and female Withdrawal Seizure-Prone (WSP-1) and DBA/2J (D2) mice were exposed to air (controls) or 72-h ethanol vapor and then were scored for HICs during withdrawal (hourly for the first 12 h, then at hours 24 and 25). After the HIC scoring at hours 5 and 9, mice were injected with 10 mg/kg GAN or vehicle. Area under the HIC curve (AUC) for hours 5–12 was analyzed. In control WSP-1 mice, GAN significantly reduced AUC by 52% (males) and 63% (females), with effects that were absent or substantially reduced during withdrawal. In contrast, GAN significantly reduced AUC in both control and ethanol-withdrawing male and female D2 mice. AUC was decreased by 81% (males) and 70% (females) in controls and by 35% (males) and 21% (females) during withdrawal. The significant anticonvulsant effect of GAN during withdrawal in D2 but not WSP-1 mice suggests that different mechanisms may contribute to ALLO insensitivity during withdrawal in these two genotypes. Importantly, the results in D2 mice suggest that GAN may be a useful treatment for ethanol withdrawal-induced seizures.

Original languageEnglish (US)
Pages (from-to)127-137
Number of pages11
JournalNeuroscience
Volume397
DOIs
StatePublished - Jan 15 2019

Fingerprint

Anticonvulsants
Pregnanolone
Neurotransmitter Agents
Seizures
Ethanol
Genotype
Inbred DBA Mouse
Area Under Curve
ganaxolone
Air

Keywords

  • alcohol
  • allopregnanolone
  • DBA/2J mice
  • GABA receptors
  • sex
  • Withdrawal Seizure-Prone mice

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Genotype Differences in Sensitivity to the Anticonvulsant Effect of the Synthetic Neurosteroid Ganaxolone during Chronic Ethanol Withdrawal. / Nipper, Michelle A.; Jensen, Jeremiah P.; Helms, Melinda L.; Ford, Matthew; Crabbe, John Jr; Rossi, David J.; Finn, Deborah (Deb).

In: Neuroscience, Vol. 397, 15.01.2019, p. 127-137.

Research output: Contribution to journalArticle

@article{75b7a2cc2e89459cb34ff192a3a118b6,
title = "Genotype Differences in Sensitivity to the Anticonvulsant Effect of the Synthetic Neurosteroid Ganaxolone during Chronic Ethanol Withdrawal",
abstract = "Sensitivity to anticonvulsant effects of the γ-aminobutyric acidA receptor-active neurosteroid allopregnanolone (ALLO) during ethanol withdrawal varies across genotypes, with high sensitivity in genotypes with mild withdrawal and low sensitivity in genotypes with high withdrawal. The present studies determined whether the resistance to ALLO during withdrawal in mouse genotypes with high handling-induced convulsions (HICs) during withdrawal could be overcome with use of ganaxolone (GAN), the metabolically stable derivative of ALLO. In separate studies, male and female Withdrawal Seizure-Prone (WSP-1) and DBA/2J (D2) mice were exposed to air (controls) or 72-h ethanol vapor and then were scored for HICs during withdrawal (hourly for the first 12 h, then at hours 24 and 25). After the HIC scoring at hours 5 and 9, mice were injected with 10 mg/kg GAN or vehicle. Area under the HIC curve (AUC) for hours 5–12 was analyzed. In control WSP-1 mice, GAN significantly reduced AUC by 52{\%} (males) and 63{\%} (females), with effects that were absent or substantially reduced during withdrawal. In contrast, GAN significantly reduced AUC in both control and ethanol-withdrawing male and female D2 mice. AUC was decreased by 81{\%} (males) and 70{\%} (females) in controls and by 35{\%} (males) and 21{\%} (females) during withdrawal. The significant anticonvulsant effect of GAN during withdrawal in D2 but not WSP-1 mice suggests that different mechanisms may contribute to ALLO insensitivity during withdrawal in these two genotypes. Importantly, the results in D2 mice suggest that GAN may be a useful treatment for ethanol withdrawal-induced seizures.",
keywords = "alcohol, allopregnanolone, DBA/2J mice, GABA receptors, sex, Withdrawal Seizure-Prone mice",
author = "Nipper, {Michelle A.} and Jensen, {Jeremiah P.} and Helms, {Melinda L.} and Matthew Ford and Crabbe, {John Jr} and Rossi, {David J.} and Finn, {Deborah (Deb)}",
year = "2019",
month = "1",
day = "15",
doi = "10.1016/j.neuroscience.2018.11.045",
language = "English (US)",
volume = "397",
pages = "127--137",
journal = "Neuroscience",
issn = "0306-4522",
publisher = "Elsevier Limited",

}

TY - JOUR

T1 - Genotype Differences in Sensitivity to the Anticonvulsant Effect of the Synthetic Neurosteroid Ganaxolone during Chronic Ethanol Withdrawal

AU - Nipper, Michelle A.

AU - Jensen, Jeremiah P.

AU - Helms, Melinda L.

AU - Ford, Matthew

AU - Crabbe, John Jr

AU - Rossi, David J.

AU - Finn, Deborah (Deb)

PY - 2019/1/15

Y1 - 2019/1/15

N2 - Sensitivity to anticonvulsant effects of the γ-aminobutyric acidA receptor-active neurosteroid allopregnanolone (ALLO) during ethanol withdrawal varies across genotypes, with high sensitivity in genotypes with mild withdrawal and low sensitivity in genotypes with high withdrawal. The present studies determined whether the resistance to ALLO during withdrawal in mouse genotypes with high handling-induced convulsions (HICs) during withdrawal could be overcome with use of ganaxolone (GAN), the metabolically stable derivative of ALLO. In separate studies, male and female Withdrawal Seizure-Prone (WSP-1) and DBA/2J (D2) mice were exposed to air (controls) or 72-h ethanol vapor and then were scored for HICs during withdrawal (hourly for the first 12 h, then at hours 24 and 25). After the HIC scoring at hours 5 and 9, mice were injected with 10 mg/kg GAN or vehicle. Area under the HIC curve (AUC) for hours 5–12 was analyzed. In control WSP-1 mice, GAN significantly reduced AUC by 52% (males) and 63% (females), with effects that were absent or substantially reduced during withdrawal. In contrast, GAN significantly reduced AUC in both control and ethanol-withdrawing male and female D2 mice. AUC was decreased by 81% (males) and 70% (females) in controls and by 35% (males) and 21% (females) during withdrawal. The significant anticonvulsant effect of GAN during withdrawal in D2 but not WSP-1 mice suggests that different mechanisms may contribute to ALLO insensitivity during withdrawal in these two genotypes. Importantly, the results in D2 mice suggest that GAN may be a useful treatment for ethanol withdrawal-induced seizures.

AB - Sensitivity to anticonvulsant effects of the γ-aminobutyric acidA receptor-active neurosteroid allopregnanolone (ALLO) during ethanol withdrawal varies across genotypes, with high sensitivity in genotypes with mild withdrawal and low sensitivity in genotypes with high withdrawal. The present studies determined whether the resistance to ALLO during withdrawal in mouse genotypes with high handling-induced convulsions (HICs) during withdrawal could be overcome with use of ganaxolone (GAN), the metabolically stable derivative of ALLO. In separate studies, male and female Withdrawal Seizure-Prone (WSP-1) and DBA/2J (D2) mice were exposed to air (controls) or 72-h ethanol vapor and then were scored for HICs during withdrawal (hourly for the first 12 h, then at hours 24 and 25). After the HIC scoring at hours 5 and 9, mice were injected with 10 mg/kg GAN or vehicle. Area under the HIC curve (AUC) for hours 5–12 was analyzed. In control WSP-1 mice, GAN significantly reduced AUC by 52% (males) and 63% (females), with effects that were absent or substantially reduced during withdrawal. In contrast, GAN significantly reduced AUC in both control and ethanol-withdrawing male and female D2 mice. AUC was decreased by 81% (males) and 70% (females) in controls and by 35% (males) and 21% (females) during withdrawal. The significant anticonvulsant effect of GAN during withdrawal in D2 but not WSP-1 mice suggests that different mechanisms may contribute to ALLO insensitivity during withdrawal in these two genotypes. Importantly, the results in D2 mice suggest that GAN may be a useful treatment for ethanol withdrawal-induced seizures.

KW - alcohol

KW - allopregnanolone

KW - DBA/2J mice

KW - GABA receptors

KW - sex

KW - Withdrawal Seizure-Prone mice

UR - http://www.scopus.com/inward/record.url?scp=85058385556&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85058385556&partnerID=8YFLogxK

U2 - 10.1016/j.neuroscience.2018.11.045

DO - 10.1016/j.neuroscience.2018.11.045

M3 - Article

VL - 397

SP - 127

EP - 137

JO - Neuroscience

JF - Neuroscience

SN - 0306-4522

ER -