GABAB receptor-mediated activation of astrocytes by gamma-hydroxybutyric acid

Timothy Gould, Lixin Chen, Zsuzsa Emri, Tiina Pirttimaki, Adam C. Errington, Vincenzo Crunelli, H. Rheinallt Parri

Research output: Contribution to journalArticle

Abstract

The gamma-aminobutyric acid (GABA) metabolite gamma-hydroxybutyric acid (GHB) shows a variety of behavioural effects when administered to animals and humans, including reward/addiction properties and absence seizures. At the cellular level, these actions of GHB are mediated by activation of neuronal GABAB receptors (GABABRs) where it acts as a weak agonist. Because astrocytes respond to endogenous and exogenously applied GABA by activation of both GABAA and GABABRs, here we investigated the action of GHB on astrocytes on the ventral tegmental area (VTA) and the ventrobasal (VB) thalamic nucleus, two brain areas involved in the reward and proepileptic action of GHB, respectively, and compared it with that of the potent GABABR agonist baclofen. We found that GHB and baclofen elicited dose-dependent (ED50: 1.6 mM and 1.3 µM, respectively) transient increases in intracellular Ca2+ in VTA and VB astrocytes of young mice and rats, which were accounted for by activation of their GABABRs and mediated by Ca2+ release from intracellular store release. In contrast, prolonged GHB and baclofen exposure caused a reduction in spontaneous astrocyte activity and glutamate release from VTA astrocytes. These findings have key (patho)physiological implications for our understanding of the addictive and proepileptic actions of GHB.

LanguageEnglish
Article number20130607
Number of pages8
JournalPilosophical Transactions B
Volume369
Issue number1654
Early online date15 Sep 2014
DOIs
Publication statusPublished - 19 Oct 2014

Fingerprint

astrocytes
Astrocytes
Chemical activation
receptors
acids
Ventral Tegmental Area
Baclofen
gamma-aminobutyric acid
Reward
gamma-Aminobutyric Acid
agonists
GABA-B Receptors
calcium
Absence Epilepsy
Thalamic Nuclei
GABA-A Receptors
seizures
Metabolites
4-hydroxybutyric acid
glutamates

Bibliographical note

© 2014 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.

Funding: Wellcome Trust (091882), the MRC (G0900671) and the EU (FP7 HEALTH-F2-2007-202167).

Keywords

  • absence seizures
  • baclofen
  • reward
  • thalamus
  • ventral tegmental area

Cite this

Gould, T., Chen, L., Emri, Z., Pirttimaki, T., Errington, A. C., Crunelli, V., & Parri, H. R. (2014). GABAB receptor-mediated activation of astrocytes by gamma-hydroxybutyric acid. Pilosophical Transactions B, 369(1654), [20130607]. https://doi.org/10.1098/rstb.2013.0607
Gould, Timothy ; Chen, Lixin ; Emri, Zsuzsa ; Pirttimaki, Tiina ; Errington, Adam C. ; Crunelli, Vincenzo ; Parri, H. Rheinallt. / GABAB receptor-mediated activation of astrocytes by gamma-hydroxybutyric acid. In: Pilosophical Transactions B. 2014 ; Vol. 369, No. 1654.
@article{86e4c512c2e0493b9d6c2dbbd770fbb0,
title = "GABAB receptor-mediated activation of astrocytes by gamma-hydroxybutyric acid",
abstract = "The gamma-aminobutyric acid (GABA) metabolite gamma-hydroxybutyric acid (GHB) shows a variety of behavioural effects when administered to animals and humans, including reward/addiction properties and absence seizures. At the cellular level, these actions of GHB are mediated by activation of neuronal GABAB receptors (GABABRs) where it acts as a weak agonist. Because astrocytes respond to endogenous and exogenously applied GABA by activation of both GABAA and GABABRs, here we investigated the action of GHB on astrocytes on the ventral tegmental area (VTA) and the ventrobasal (VB) thalamic nucleus, two brain areas involved in the reward and proepileptic action of GHB, respectively, and compared it with that of the potent GABABR agonist baclofen. We found that GHB and baclofen elicited dose-dependent (ED50: 1.6 mM and 1.3 µM, respectively) transient increases in intracellular Ca2+ in VTA and VB astrocytes of young mice and rats, which were accounted for by activation of their GABABRs and mediated by Ca2+ release from intracellular store release. In contrast, prolonged GHB and baclofen exposure caused a reduction in spontaneous astrocyte activity and glutamate release from VTA astrocytes. These findings have key (patho)physiological implications for our understanding of the addictive and proepileptic actions of GHB.",
keywords = "absence seizures, baclofen, reward, thalamus, ventral tegmental area",
author = "Timothy Gould and Lixin Chen and Zsuzsa Emri and Tiina Pirttimaki and Errington, {Adam C.} and Vincenzo Crunelli and Parri, {H. Rheinallt}",
note = "{\circledC} 2014 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited. Funding: Wellcome Trust (091882), the MRC (G0900671) and the EU (FP7 HEALTH-F2-2007-202167).",
year = "2014",
month = "10",
day = "19",
doi = "10.1098/rstb.2013.0607",
language = "English",
volume = "369",
journal = "Pilosophical Transactions B",
issn = "0962-8436",
publisher = "Royal Society of London",
number = "1654",

}

Gould, T, Chen, L, Emri, Z, Pirttimaki, T, Errington, AC, Crunelli, V & Parri, HR 2014, 'GABAB receptor-mediated activation of astrocytes by gamma-hydroxybutyric acid' Pilosophical Transactions B, vol. 369, no. 1654, 20130607. https://doi.org/10.1098/rstb.2013.0607

GABAB receptor-mediated activation of astrocytes by gamma-hydroxybutyric acid. / Gould, Timothy; Chen, Lixin; Emri, Zsuzsa; Pirttimaki, Tiina; Errington, Adam C.; Crunelli, Vincenzo; Parri, H. Rheinallt.

In: Pilosophical Transactions B, Vol. 369, No. 1654, 20130607, 19.10.2014.

Research output: Contribution to journalArticle

TY - JOUR

T1 - GABAB receptor-mediated activation of astrocytes by gamma-hydroxybutyric acid

AU - Gould, Timothy

AU - Chen, Lixin

AU - Emri, Zsuzsa

AU - Pirttimaki, Tiina

AU - Errington, Adam C.

AU - Crunelli, Vincenzo

AU - Parri, H. Rheinallt

N1 - © 2014 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited. Funding: Wellcome Trust (091882), the MRC (G0900671) and the EU (FP7 HEALTH-F2-2007-202167).

PY - 2014/10/19

Y1 - 2014/10/19

N2 - The gamma-aminobutyric acid (GABA) metabolite gamma-hydroxybutyric acid (GHB) shows a variety of behavioural effects when administered to animals and humans, including reward/addiction properties and absence seizures. At the cellular level, these actions of GHB are mediated by activation of neuronal GABAB receptors (GABABRs) where it acts as a weak agonist. Because astrocytes respond to endogenous and exogenously applied GABA by activation of both GABAA and GABABRs, here we investigated the action of GHB on astrocytes on the ventral tegmental area (VTA) and the ventrobasal (VB) thalamic nucleus, two brain areas involved in the reward and proepileptic action of GHB, respectively, and compared it with that of the potent GABABR agonist baclofen. We found that GHB and baclofen elicited dose-dependent (ED50: 1.6 mM and 1.3 µM, respectively) transient increases in intracellular Ca2+ in VTA and VB astrocytes of young mice and rats, which were accounted for by activation of their GABABRs and mediated by Ca2+ release from intracellular store release. In contrast, prolonged GHB and baclofen exposure caused a reduction in spontaneous astrocyte activity and glutamate release from VTA astrocytes. These findings have key (patho)physiological implications for our understanding of the addictive and proepileptic actions of GHB.

AB - The gamma-aminobutyric acid (GABA) metabolite gamma-hydroxybutyric acid (GHB) shows a variety of behavioural effects when administered to animals and humans, including reward/addiction properties and absence seizures. At the cellular level, these actions of GHB are mediated by activation of neuronal GABAB receptors (GABABRs) where it acts as a weak agonist. Because astrocytes respond to endogenous and exogenously applied GABA by activation of both GABAA and GABABRs, here we investigated the action of GHB on astrocytes on the ventral tegmental area (VTA) and the ventrobasal (VB) thalamic nucleus, two brain areas involved in the reward and proepileptic action of GHB, respectively, and compared it with that of the potent GABABR agonist baclofen. We found that GHB and baclofen elicited dose-dependent (ED50: 1.6 mM and 1.3 µM, respectively) transient increases in intracellular Ca2+ in VTA and VB astrocytes of young mice and rats, which were accounted for by activation of their GABABRs and mediated by Ca2+ release from intracellular store release. In contrast, prolonged GHB and baclofen exposure caused a reduction in spontaneous astrocyte activity and glutamate release from VTA astrocytes. These findings have key (patho)physiological implications for our understanding of the addictive and proepileptic actions of GHB.

KW - absence seizures

KW - baclofen

KW - reward

KW - thalamus

KW - ventral tegmental area

UR - http://www.scopus.com/inward/record.url?scp=84907211075&partnerID=8YFLogxK

U2 - 10.1098/rstb.2013.0607

DO - 10.1098/rstb.2013.0607

M3 - Article

VL - 369

JO - Pilosophical Transactions B

T2 - Pilosophical Transactions B

JF - Pilosophical Transactions B

SN - 0962-8436

IS - 1654

M1 - 20130607

ER -

Gould T, Chen L, Emri Z, Pirttimaki T, Errington AC, Crunelli V et al. GABAB receptor-mediated activation of astrocytes by gamma-hydroxybutyric acid. Pilosophical Transactions B. 2014 Oct 19;369(1654). 20130607. https://doi.org/10.1098/rstb.2013.0607