title: Ethanol induced adaptations in 5-HT2c receptor signaling in the bed nucleus of the stria terminalis: implications for anxiety during ethanol withdrawal.
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 After the 5th and final exposure, mice were withdrawn for 24 h or 1 week before experiments began.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.
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Marcinkiewcz
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Cayce E
authors.initials: CE
authors.lastname: Dorrier
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Alberto J
authors.initials: AJ
authors.lastname: Lopez
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: thomas_kash@med.unc.edu.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Kash
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects / Q000502:physiology; D000437:Alcoholism / Q000378:metabolism* / Q000523:psychology; D000818:Animals; D001007:Anxiety / Q000378:metabolism* / Q000523:psychology; D000431:Ethanol / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D012686:Septal Nuclei / Q000187:drug effects / Q000378:metabolism*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013375:Substance Withdrawal Syndrome / Q000378:metabolism* / Q000523:psychology
chemical_list: D044405:Receptor, Serotonin, 5-HT2C; D058830:Serotonin 5-HT2 Receptor Antagonists; D000431:Ethanol
keywords: Anxiety; Bed nucleus of stria terminalis; Ethanol; Serotonin; Withdrawal