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Ethanol withdrawal-induced dysregulation of neurosteroid levels in plasma, cortex, and hippocampus in genetic animal models of high and low withdrawal.

ABSTRACT: RATIONALE:Endogenous ?-aminobutyric acidA receptor (GABAAR)-active neurosteroids (e.g., allopregnanolone) regulate central nervous system excitability and many physiological functions, so fluctuations are implicated in several neuropsychiatric disorders. Pertinently, evidence supports an inverse relationship between endogenous GABAAR-active neurosteroid levels and behavioral changes in excitability during ethanol withdrawal (WD). OBJECTIVES:The present studies determined mouse genotype differences in ten neurosteroid levels in plasma, cortex, and hippocampus over the time course of ethanol WD in the WD Seizure-Prone (WSP) and WD Seizure-Resistant (WSR) selected lines and in the DBA/2J (DBA) inbred strain. METHODS:Gas chromatography-mass spectrometry was utilized to simultaneously quantify neurosteroid levels from control-treated male WSP-1, WSR-1, and DBA mice and during 8 and 48 h of WD. RESULTS:Combined with our prior work, there was a consistent decrease in plasma allopregnanolone levels at 8 h WD in all three genotypes, an effect that persisted at 48 h WD only in DBA mice. WSR-1 and WSP-1 mice exhibited unexpected divergent changes in cortical neurosteroids at 8 h WD, with the majority of neurosteroids (including allopregnanolone) being significantly decreased in WSR-1 mice, but unaffected or significantly increased in WSP-1 mice. In DBA mice, hippocampal allopregnanolone and tetrahydrodeoxycorticosterone were significantly decreased at 8 h WD. The pattern of significant correlations between allopregnanolone and other GABAAR-active neurosteroid levels differed between controls and withdrawing mice. CONCLUSIONS:Ethanol WD dysregulated neurosteroid synthesis. Results in WSP-1 mice suggest that diminished GABAAR function is more important for their high WD phenotype than fluctuations in neurosteroid levels.

SUBMITTER: Jensen JP

PROVIDER: S-EPMC5990276 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Ethanol withdrawal-induced dysregulation of neurosteroid levels in plasma, cortex, and hippocampus in genetic animal models of high and low withdrawal.

Jensen Jeremiah P JP Nipper Michelle A MA Helms Melinda L ML Ford Matthew M MM Crabbe John C JC Rossi David J DJ Finn Deborah A DA

Psychopharmacology 20170629 18

<h4>Rationale</h4>Endogenous γ-aminobutyric acid<sub>A</sub> receptor (GABA<sub>A</sub>R)-active neurosteroids (e.g., allopregnanolone) regulate central nervous system excitability and many physiological functions, so fluctuations are implicated in several neuropsychiatric disorders. Pertinently, evidence supports an inverse relationship between endogenous GABA<sub>A</sub>R-active neurosteroid levels and behavioral changes in excitability during ethanol withdrawal (WD).<h4>Objectives</h4>The pre ...[more]

PMID: 28664280

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Project description:BackgroundThe prefrontal cortex (PFC) acts as an integrative hub for the processing of cortical and subcortical input into meaningful efferent signaling, permitting complex associative behaviors. PFC dysfunction is consistently observed with ethanol (EtOH) dependence and is a core component of the pathology of alcohol use disorders in current models of addiction. While intracortical gamma-aminobutryric acid (GABA)ergic neurotransmission is understood to be essential for maintaining coordinated network activity within the cortex, relatively little is known regarding functional GABAergic adaptations in PFC during EtOH dependence.MethodsIn the present study, male and female (> postnatal day 60) Sprague-Dawley rats were administered EtOH (5.0 g/kg; intragastric gavage) for 14 to 15 consecutive days. Twenty-four hours after the final administration, animals were sacrificed and brains extracted for electrophysiological recordings of isolated GABAA receptor-mediated currents or analysis of GABAA receptor subunit protein expression in deep-layer PFC neurons.ResultsChronic EtOH exposure significantly attenuated activity-dependent spontaneous GABAA receptor-mediated inhibitory postsynaptic current (IPSC) frequency with no effect on amplitude. Furthermore, analysis of IPSC decay kinetics revealed a significant enhancement of IPSC decay time that was associated with decrements in expression of the α1 GABAA receptor subunit, indicative of further impaired phasic inhibition. These phenomena occurred irrespective of neuron projection destination and sex. Based on previous observations by our laboratory of an epigenetic mechanism for EtOH-induced changes in cortical GABAA receptor subunit expression, the histone deacetylase inhibitor Trichostatin A was administered to water- and EtOH-exposed animals, and prevented EtOH-induced changes in spontaneous IPSC frequency, IPSC decay kinetics, and GABAA receptor subunit expression.ConclusionsTaken together, these results demonstrate that chronic EtOH exposure impairs synaptic inhibitory neurotransmission in deep-layer pyramidal neurons of the medial PFC in both male and female rats. These maladaptations occur in neurons projecting to numerous regions implicated in the sequelae of EtOH dependence, offering a mechanistic link between the manifestation of PFC dysfunction and negative affective states observed with extended consumption.

Dataset Information

Ethanol withdrawal-induced dysregulation of neurosteroid levels in plasma, cortex, and hippocampus in genetic animal models of high and low withdrawal.

Publications

Ethanol withdrawal-induced dysregulation of neurosteroid levels in plasma, cortex, and hippocampus in genetic animal models of high and low withdrawal.

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