Ethanol induced adaptations in 5-HT2c receptor signaling in the bed nucleus of the stria terminalis: implications for anxiety during ethanol withdrawal

Catherine A Marcinkiewcz; Cayce E Dorrier; Alberto J Lopez; Thomas L Kash

doi:10.1016/j.neuropharm.2014.09.003

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Ethanol induced adaptations in 5-HT2c receptor signaling in the bed nucleus of the stria terminalis: implications for anxiety during ethanol withdrawal

Journal article

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Ethanol induced adaptations in 5-HT2c receptor signaling in the bed nucleus of the stria terminalis: implications for anxiety during ethanol withdrawal

Catherine A Marcinkiewcz, Cayce E Dorrier, Alberto J Lopez and Thomas L Kash

Neuropharmacology, Vol.89, pp.157-167

02/2015

DOI: 10.1016/j.neuropharm.2014.09.003

PMCID: PMC4469779

PMID: 25229718

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https://www.ncbi.nlm.nih.gov/pmc/articles/4469779View

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Abstract

One of the hallmarks of alcohol dependence is the presence of a withdrawal syndrome during abstinence, which manifests as physical craving for alcohol accompanied by subjective feelings of anxiety. Using a model of chronic intermittent ethanol (CIE) vapor in mice, we investigated the role of serotonin2c receptor (5HT2c-R) signaling in the BNST as a neural substrate underlying ethanol-induced anxiety during withdrawal. Mice were subjected to a 5-day CIE regimen of 16 h of ethanol vapor exposure followed by an 8 h "withdrawal" period between exposures. After the 5th and final exposure, mice were withdrawn for 24 h or 1 week before experiments began. Anxiety-like behavior was assessed in the social approach, light dark, and open field tests with mice showing deficits in social, but not general anxiety-like behavior that was alleviated by pretreatment with the 5HT2c-R antagonist SB 242,084 (3 mg/kg, i.p.) 24 h and 1 week post-CIE. Using immunohistochemistry and whole cell patch clamp electrophysiology, we also found that CIE increased FOS-IR and enhanced neuronal excitability in the ventral BNST (vBNST) 24 h into withdrawal in a 5HT2c-R dependent manner. This enhanced excitability persisted for 1 week post-CIE. We also found that mCPP, a 5HT2c/b agonist, induced a more robust depolarization in cells of the vBNST in CIE mice, confirming that 5HT2c-R signaling is upregulated in the vBNST following CIE. Taken together, these results suggest that CIE upregulates 5HT2c-R signaling in the vBNST, leading to increased excitability. This enhanced excitability of the vBNST may drive increased anxiety-like behavior during ethanol withdrawal.

Septal Nuclei - drug effects

Receptor, Serotonin, 5-HT2C - metabolism

Adaptation, Physiological - drug effects

Anxiety - psychology

Adaptation, Physiological - physiology

Ethanol - administration & dosage

Male

Serotonin 5-HT2 Receptor Antagonists - pharmacology

Septal Nuclei - metabolism

Animals

Substance Withdrawal Syndrome - metabolism

Signal Transduction - drug effects

Alcoholism - metabolism

Mice, Inbred DBA

Signal Transduction - physiology

Mice

Alcoholism - psychology

Anxiety - metabolism

Substance Withdrawal Syndrome - psychology

Details

Title: Subtitle: Ethanol induced adaptations in 5-HT2c receptor signaling in the bed nucleus of the stria terminalis: implications for anxiety during ethanol withdrawal
Creators: Catherine A Marcinkiewcz - Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Cayce E Dorrier - Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Alberto J Lopez - Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Thomas L Kash - Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: thomas_kash@med.unc.edu
Resource Type: Journal article
Publication Details: Neuropharmacology, Vol.89, pp.157-167
DOI: 10.1016/j.neuropharm.2014.09.003
PMID: 25229718
PMCID: PMC4469779
NLM abbreviation: Neuropharmacology
ISSN: 0028-3908
eISSN: 1873-7064
Publisher: England
Grant note: R01 AA019454 / NIAAA NIH HHS 5T32AA007573-14 / NIAAA NIH HHS F32 AA021319 / NIAAA NIH HHS T32 AA007573 / NIAAA NIH HHS R01AA019454NIAAA / NIAAA NIH HHS P60 AA011605 / NIAAA NIH HHS
Language: English
Date published: 02/2015
Academic Unit: Iowa Neuroscience Institute; Neuroscience and Pharmacology
Record Identifier: 9984040338702771

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