Ethanol inhibits clearance of brain serotonin by a serotonin transporter-independent mechanism

Lynette C Daws, Sylvia Montañez, Jaclyn L. Munn, W. Anthony Owens, Nicole L. Baganz, Janel M. Boyce-Rustay, Rachel A. Millstein, Lisa M. Wiedholz, Dennis L. Murphy, Andrew Holmes

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

Brain serotonin (5-HT) modulates the neural and behavioral effects of ethanol in a manner that remains poorly understood. Here we show that treatment with physiologically relevant (i.e., moderately intoxicating) doses of ethanol inhibits clearance of 5-HT from extracellular fluid in the mouse hippocampus. This finding demonstrates, in vivo, a key molecular mechanism by which ethanol modulates serotonergic neurotransmission. The 5-HT transporter (5-HTT) is the principle means of 5-HT reuptake in the brain and an obvious candidate mechanism for the effect of ethanol to inhibit 5-HT clearance. However, our second major finding was that genetic inactivation of the 5-HTT in a knock-out mouse not only failed to prevent ethanol-induced inhibition of 5-HT clearance, but actually potentiated this effect. Ethanol-induced inhibition of 5-HT clearance was also potentiated in nonmutant mice by cotreatment with a 5-HTT antagonist. Providing a link with potential behavioral manifestations of this neural phenotype, 5-HTT knock-out mice also exhibited exaggerated sensitivity to behavioral intoxication, as assayed by the sedative/hypnotic effects of ethanol. This clearly demonstrates that the 5-HTT is not necessary for the neural and behavioral effects of ethanol observed herein and that genetic or pharmacological inactivation of the 5-HTT unmasks involvement of other principle mechanisms. These data are intriguing given growing evidence implicating the 5-HTT in the pathophysiology and treatment of alcoholism and neuropsychiatric conditions frequently comorbid with alcoholism, such as depression. The present findings provide new insights into the actions of ethanol on brain function and behavior.

Original languageEnglish (US)
Pages (from-to)6431-6438
Number of pages8
JournalJournal of Neuroscience
Volume26
Issue number24
DOIs
StatePublished - 2006

Fingerprint

Serotonin Plasma Membrane Transport Proteins
Serotonin
Ethanol
Brain
Hypnotics and Sedatives
Knockout Mice
Alcoholism
Serotonin Antagonists
Extracellular Fluid
Synaptic Transmission
Hippocampus

Keywords

  • 5-HT
  • Alcohol
  • Clearance
  • Gene
  • Mouse
  • Serotonin transporter

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Daws, L. C., Montañez, S., Munn, J. L., Owens, W. A., Baganz, N. L., Boyce-Rustay, J. M., ... Holmes, A. (2006). Ethanol inhibits clearance of brain serotonin by a serotonin transporter-independent mechanism. Journal of Neuroscience, 26(24), 6431-6438. https://doi.org/10.1523/JNEUROSCI.4050-05.2006

Ethanol inhibits clearance of brain serotonin by a serotonin transporter-independent mechanism. / Daws, Lynette C; Montañez, Sylvia; Munn, Jaclyn L.; Owens, W. Anthony; Baganz, Nicole L.; Boyce-Rustay, Janel M.; Millstein, Rachel A.; Wiedholz, Lisa M.; Murphy, Dennis L.; Holmes, Andrew.

In: Journal of Neuroscience, Vol. 26, No. 24, 2006, p. 6431-6438.

Research output: Contribution to journalArticle

Daws, LC, Montañez, S, Munn, JL, Owens, WA, Baganz, NL, Boyce-Rustay, JM, Millstein, RA, Wiedholz, LM, Murphy, DL & Holmes, A 2006, 'Ethanol inhibits clearance of brain serotonin by a serotonin transporter-independent mechanism', Journal of Neuroscience, vol. 26, no. 24, pp. 6431-6438. https://doi.org/10.1523/JNEUROSCI.4050-05.2006
Daws, Lynette C ; Montañez, Sylvia ; Munn, Jaclyn L. ; Owens, W. Anthony ; Baganz, Nicole L. ; Boyce-Rustay, Janel M. ; Millstein, Rachel A. ; Wiedholz, Lisa M. ; Murphy, Dennis L. ; Holmes, Andrew. / Ethanol inhibits clearance of brain serotonin by a serotonin transporter-independent mechanism. In: Journal of Neuroscience. 2006 ; Vol. 26, No. 24. pp. 6431-6438.
@article{e9f96273aed0415b899f5958c9d6d731,
title = "Ethanol inhibits clearance of brain serotonin by a serotonin transporter-independent mechanism",
abstract = "Brain serotonin (5-HT) modulates the neural and behavioral effects of ethanol in a manner that remains poorly understood. Here we show that treatment with physiologically relevant (i.e., moderately intoxicating) doses of ethanol inhibits clearance of 5-HT from extracellular fluid in the mouse hippocampus. This finding demonstrates, in vivo, a key molecular mechanism by which ethanol modulates serotonergic neurotransmission. The 5-HT transporter (5-HTT) is the principle means of 5-HT reuptake in the brain and an obvious candidate mechanism for the effect of ethanol to inhibit 5-HT clearance. However, our second major finding was that genetic inactivation of the 5-HTT in a knock-out mouse not only failed to prevent ethanol-induced inhibition of 5-HT clearance, but actually potentiated this effect. Ethanol-induced inhibition of 5-HT clearance was also potentiated in nonmutant mice by cotreatment with a 5-HTT antagonist. Providing a link with potential behavioral manifestations of this neural phenotype, 5-HTT knock-out mice also exhibited exaggerated sensitivity to behavioral intoxication, as assayed by the sedative/hypnotic effects of ethanol. This clearly demonstrates that the 5-HTT is not necessary for the neural and behavioral effects of ethanol observed herein and that genetic or pharmacological inactivation of the 5-HTT unmasks involvement of other principle mechanisms. These data are intriguing given growing evidence implicating the 5-HTT in the pathophysiology and treatment of alcoholism and neuropsychiatric conditions frequently comorbid with alcoholism, such as depression. The present findings provide new insights into the actions of ethanol on brain function and behavior.",
keywords = "5-HT, Alcohol, Clearance, Gene, Mouse, Serotonin transporter",
author = "Daws, {Lynette C} and Sylvia Monta{\~n}ez and Munn, {Jaclyn L.} and Owens, {W. Anthony} and Baganz, {Nicole L.} and Boyce-Rustay, {Janel M.} and Millstein, {Rachel A.} and Wiedholz, {Lisa M.} and Murphy, {Dennis L.} and Andrew Holmes",
year = "2006",
doi = "10.1523/JNEUROSCI.4050-05.2006",
language = "English (US)",
volume = "26",
pages = "6431--6438",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "24",

}

TY - JOUR

T1 - Ethanol inhibits clearance of brain serotonin by a serotonin transporter-independent mechanism

AU - Daws, Lynette C

AU - Montañez, Sylvia

AU - Munn, Jaclyn L.

AU - Owens, W. Anthony

AU - Baganz, Nicole L.

AU - Boyce-Rustay, Janel M.

AU - Millstein, Rachel A.

AU - Wiedholz, Lisa M.

AU - Murphy, Dennis L.

AU - Holmes, Andrew

PY - 2006

Y1 - 2006

N2 - Brain serotonin (5-HT) modulates the neural and behavioral effects of ethanol in a manner that remains poorly understood. Here we show that treatment with physiologically relevant (i.e., moderately intoxicating) doses of ethanol inhibits clearance of 5-HT from extracellular fluid in the mouse hippocampus. This finding demonstrates, in vivo, a key molecular mechanism by which ethanol modulates serotonergic neurotransmission. The 5-HT transporter (5-HTT) is the principle means of 5-HT reuptake in the brain and an obvious candidate mechanism for the effect of ethanol to inhibit 5-HT clearance. However, our second major finding was that genetic inactivation of the 5-HTT in a knock-out mouse not only failed to prevent ethanol-induced inhibition of 5-HT clearance, but actually potentiated this effect. Ethanol-induced inhibition of 5-HT clearance was also potentiated in nonmutant mice by cotreatment with a 5-HTT antagonist. Providing a link with potential behavioral manifestations of this neural phenotype, 5-HTT knock-out mice also exhibited exaggerated sensitivity to behavioral intoxication, as assayed by the sedative/hypnotic effects of ethanol. This clearly demonstrates that the 5-HTT is not necessary for the neural and behavioral effects of ethanol observed herein and that genetic or pharmacological inactivation of the 5-HTT unmasks involvement of other principle mechanisms. These data are intriguing given growing evidence implicating the 5-HTT in the pathophysiology and treatment of alcoholism and neuropsychiatric conditions frequently comorbid with alcoholism, such as depression. The present findings provide new insights into the actions of ethanol on brain function and behavior.

AB - Brain serotonin (5-HT) modulates the neural and behavioral effects of ethanol in a manner that remains poorly understood. Here we show that treatment with physiologically relevant (i.e., moderately intoxicating) doses of ethanol inhibits clearance of 5-HT from extracellular fluid in the mouse hippocampus. This finding demonstrates, in vivo, a key molecular mechanism by which ethanol modulates serotonergic neurotransmission. The 5-HT transporter (5-HTT) is the principle means of 5-HT reuptake in the brain and an obvious candidate mechanism for the effect of ethanol to inhibit 5-HT clearance. However, our second major finding was that genetic inactivation of the 5-HTT in a knock-out mouse not only failed to prevent ethanol-induced inhibition of 5-HT clearance, but actually potentiated this effect. Ethanol-induced inhibition of 5-HT clearance was also potentiated in nonmutant mice by cotreatment with a 5-HTT antagonist. Providing a link with potential behavioral manifestations of this neural phenotype, 5-HTT knock-out mice also exhibited exaggerated sensitivity to behavioral intoxication, as assayed by the sedative/hypnotic effects of ethanol. This clearly demonstrates that the 5-HTT is not necessary for the neural and behavioral effects of ethanol observed herein and that genetic or pharmacological inactivation of the 5-HTT unmasks involvement of other principle mechanisms. These data are intriguing given growing evidence implicating the 5-HTT in the pathophysiology and treatment of alcoholism and neuropsychiatric conditions frequently comorbid with alcoholism, such as depression. The present findings provide new insights into the actions of ethanol on brain function and behavior.

KW - 5-HT

KW - Alcohol

KW - Clearance

KW - Gene

KW - Mouse

KW - Serotonin transporter

UR - http://www.scopus.com/inward/record.url?scp=33745773333&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33745773333&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.4050-05.2006

DO - 10.1523/JNEUROSCI.4050-05.2006

M3 - Article

C2 - 16775130

AN - SCOPUS:33745773333

VL - 26

SP - 6431

EP - 6438

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 24

ER -