Anxiety during alcohol withdrawal involves 5-HT2C receptors and M-channels in the lateral habenula

Rao Fu, Qinghua Mei, Nimisha Shiwalkar, Wanhong Zuo, Haifeng Zhang, Danielle Gregor, Shivani Patel, Jiang Hong Ye

Research output: Contribution to journalArticle

Abstract

Anxiety disorders often co-occur with alcohol use disorders, but the mechanisms underlying this comorbidity remain elusive. Previously, we reported that rats withdrawn from chronic alcohol consumption (Post-EtOH rats) exhibited robust anxiety-like behaviors (AB), which were accompanied by neuronal hyperexcitability, and the downregulation of M-type potassium channels (M-channels) in the lateral habenula (LHb); and that serotonin (5-HT) stimulated LHb neurons via type 2C receptors (5-HT2CRs). Also, 5-HT2CR activation is known to inhibit M-current in mouse hypothalamic neurons. The present study investigated whether LHb 5-HT2CRs and M-channels contribute to AB in adult male Long-Evans rats. We used the intermittent-access to 20% ethanol two-bottle free-choice drinking paradigm to induce dependence. We measured AB with the elevated plus-maze, open-field, and marble-burying tests at 24 h withdrawal. We found that intra-LHb infusion of SB242084, a selective 5-HT2CR antagonist alleviated AB and reduced the elevated c-Fos expression in the LHb of Post-EtOH rats. By contrast, intra-LHb infusion of the selective 5-HT2CR agonist WAY161503 induced AB and increased c-Fos expression in the LHb in alcohol-naive but not Post-EtOH rats. Also, intra-LHb SB242084 significantly reduced self-administration of alcohol intake in the operant chambers. Furthermore, both 5-HT2CR protein levels and 5-HIAA/5-HT ratio was increased in the LHb of Post-EtOH rats. Finally, intra-LHb SB242084 increased LHb KCNQ2/3 membrane protein expression in Post-EtOH rats. Collectively, these results suggest that enhanced LHb 5-HT2CR signaling that interacted with M-channels triggers AB in Post-EtOH rats and that 5-HT2CRs may be a promising target for treating comorbid anxiety disorders in alcoholics.

Original languageEnglish (US)
Article number107863
JournalNeuropharmacology
Volume163
DOIs
StatePublished - Feb 2020

Fingerprint

Receptor, Serotonin, 5-HT2C
Habenula
Potassium Channels
Anxiety
Alcohols
Serotonin
Neurons
Anxiety Disorders
Long Evans Rats
Hydroxyindoleacetic Acid
Self Administration
Calcium Carbonate
Alcoholics
Alcohol Drinking
Drinking
Comorbidity

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Cellular and Molecular Neuroscience

Keywords

  • Alcohol-self administration
  • Elevated plus-maze
  • Marble burying test
  • Open filed test
  • cFos

Cite this

Fu, Rao ; Mei, Qinghua ; Shiwalkar, Nimisha ; Zuo, Wanhong ; Zhang, Haifeng ; Gregor, Danielle ; Patel, Shivani ; Ye, Jiang Hong. / Anxiety during alcohol withdrawal involves 5-HT2C receptors and M-channels in the lateral habenula. In: Neuropharmacology. 2020 ; Vol. 163.
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abstract = "Anxiety disorders often co-occur with alcohol use disorders, but the mechanisms underlying this comorbidity remain elusive. Previously, we reported that rats withdrawn from chronic alcohol consumption (Post-EtOH rats) exhibited robust anxiety-like behaviors (AB), which were accompanied by neuronal hyperexcitability, and the downregulation of M-type potassium channels (M-channels) in the lateral habenula (LHb); and that serotonin (5-HT) stimulated LHb neurons via type 2C receptors (5-HT2CRs). Also, 5-HT2CR activation is known to inhibit M-current in mouse hypothalamic neurons. The present study investigated whether LHb 5-HT2CRs and M-channels contribute to AB in adult male Long-Evans rats. We used the intermittent-access to 20{\%} ethanol two-bottle free-choice drinking paradigm to induce dependence. We measured AB with the elevated plus-maze, open-field, and marble-burying tests at 24 h withdrawal. We found that intra-LHb infusion of SB242084, a selective 5-HT2CR antagonist alleviated AB and reduced the elevated c-Fos expression in the LHb of Post-EtOH rats. By contrast, intra-LHb infusion of the selective 5-HT2CR agonist WAY161503 induced AB and increased c-Fos expression in the LHb in alcohol-naive but not Post-EtOH rats. Also, intra-LHb SB242084 significantly reduced self-administration of alcohol intake in the operant chambers. Furthermore, both 5-HT2CR protein levels and 5-HIAA/5-HT ratio was increased in the LHb of Post-EtOH rats. Finally, intra-LHb SB242084 increased LHb KCNQ2/3 membrane protein expression in Post-EtOH rats. Collectively, these results suggest that enhanced LHb 5-HT2CR signaling that interacted with M-channels triggers AB in Post-EtOH rats and that 5-HT2CRs may be a promising target for treating comorbid anxiety disorders in alcoholics.",
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Anxiety during alcohol withdrawal involves 5-HT2C receptors and M-channels in the lateral habenula. / Fu, Rao; Mei, Qinghua; Shiwalkar, Nimisha; Zuo, Wanhong; Zhang, Haifeng; Gregor, Danielle; Patel, Shivani; Ye, Jiang Hong.

In: Neuropharmacology, Vol. 163, 107863, 02.2020.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Anxiety during alcohol withdrawal involves 5-HT2C receptors and M-channels in the lateral habenula

AU - Fu, Rao

AU - Mei, Qinghua

AU - Shiwalkar, Nimisha

AU - Zuo, Wanhong

AU - Zhang, Haifeng

AU - Gregor, Danielle

AU - Patel, Shivani

AU - Ye, Jiang Hong

PY - 2020/2

Y1 - 2020/2

N2 - Anxiety disorders often co-occur with alcohol use disorders, but the mechanisms underlying this comorbidity remain elusive. Previously, we reported that rats withdrawn from chronic alcohol consumption (Post-EtOH rats) exhibited robust anxiety-like behaviors (AB), which were accompanied by neuronal hyperexcitability, and the downregulation of M-type potassium channels (M-channels) in the lateral habenula (LHb); and that serotonin (5-HT) stimulated LHb neurons via type 2C receptors (5-HT2CRs). Also, 5-HT2CR activation is known to inhibit M-current in mouse hypothalamic neurons. The present study investigated whether LHb 5-HT2CRs and M-channels contribute to AB in adult male Long-Evans rats. We used the intermittent-access to 20% ethanol two-bottle free-choice drinking paradigm to induce dependence. We measured AB with the elevated plus-maze, open-field, and marble-burying tests at 24 h withdrawal. We found that intra-LHb infusion of SB242084, a selective 5-HT2CR antagonist alleviated AB and reduced the elevated c-Fos expression in the LHb of Post-EtOH rats. By contrast, intra-LHb infusion of the selective 5-HT2CR agonist WAY161503 induced AB and increased c-Fos expression in the LHb in alcohol-naive but not Post-EtOH rats. Also, intra-LHb SB242084 significantly reduced self-administration of alcohol intake in the operant chambers. Furthermore, both 5-HT2CR protein levels and 5-HIAA/5-HT ratio was increased in the LHb of Post-EtOH rats. Finally, intra-LHb SB242084 increased LHb KCNQ2/3 membrane protein expression in Post-EtOH rats. Collectively, these results suggest that enhanced LHb 5-HT2CR signaling that interacted with M-channels triggers AB in Post-EtOH rats and that 5-HT2CRs may be a promising target for treating comorbid anxiety disorders in alcoholics.

AB - Anxiety disorders often co-occur with alcohol use disorders, but the mechanisms underlying this comorbidity remain elusive. Previously, we reported that rats withdrawn from chronic alcohol consumption (Post-EtOH rats) exhibited robust anxiety-like behaviors (AB), which were accompanied by neuronal hyperexcitability, and the downregulation of M-type potassium channels (M-channels) in the lateral habenula (LHb); and that serotonin (5-HT) stimulated LHb neurons via type 2C receptors (5-HT2CRs). Also, 5-HT2CR activation is known to inhibit M-current in mouse hypothalamic neurons. The present study investigated whether LHb 5-HT2CRs and M-channels contribute to AB in adult male Long-Evans rats. We used the intermittent-access to 20% ethanol two-bottle free-choice drinking paradigm to induce dependence. We measured AB with the elevated plus-maze, open-field, and marble-burying tests at 24 h withdrawal. We found that intra-LHb infusion of SB242084, a selective 5-HT2CR antagonist alleviated AB and reduced the elevated c-Fos expression in the LHb of Post-EtOH rats. By contrast, intra-LHb infusion of the selective 5-HT2CR agonist WAY161503 induced AB and increased c-Fos expression in the LHb in alcohol-naive but not Post-EtOH rats. Also, intra-LHb SB242084 significantly reduced self-administration of alcohol intake in the operant chambers. Furthermore, both 5-HT2CR protein levels and 5-HIAA/5-HT ratio was increased in the LHb of Post-EtOH rats. Finally, intra-LHb SB242084 increased LHb KCNQ2/3 membrane protein expression in Post-EtOH rats. Collectively, these results suggest that enhanced LHb 5-HT2CR signaling that interacted with M-channels triggers AB in Post-EtOH rats and that 5-HT2CRs may be a promising target for treating comorbid anxiety disorders in alcoholics.

KW - Alcohol-self administration

KW - Elevated plus-maze

KW - Marble burying test

KW - Open filed test

KW - cFos

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