title: GABA(B) 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 GABA(B) receptors (GABA(B)Rs) where it acts as a weak agonist. Because astrocytes respond to endogenous and exogenously applied GABA by activation of both GABA(A) and GABA(B)Rs, 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 GABA(B)R agonist baclofen. We found that GHB and baclofen elicited dose-dependent (ED50: 1.6 mM and 1.3 µM, respectively) transient increases in intracellular Ca(2+) in VTA and VB astrocytes of young mice and rats, which were accounted for by activation of their GABA(B)Rs and mediated by Ca(2+) 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.
authors.affiliation: Neuroscience Division, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Gould
authors.affiliation: Neuroscience Division, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK.
authors.forename: Lixin
authors.initials: L
authors.lastname: Chen
authors.affiliation: Neuroscience Division, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK.
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Emri
authors.affiliation: School of Life and Health Sciences, Aston University, Birmingham B4 7ET, UK.
authors.forename: Tiina
authors.initials: T
authors.lastname: Pirttimaki
authors.affiliation: Neuroscience Division, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Errington
authors.affiliation: Neuroscience Division, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK crunelli@cardiff.ac.uk.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Crunelli
authors.affiliation: School of Life and Health Sciences, Aston University, Birmingham B4 7ET, UK parrihr@aston.ac.uk.
authors.forename: H Rheinallt
authors.initials: HR
authors.lastname: Parri
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001418:Baclofen / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006885:Hydroxybutyrates / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D051381:Rats; D017208:Rats, Wistar; D018080:Receptors, GABA-B / Q000378:metabolism*; D012201:Reward; D017557:Ventral Tegmental Area / Q000166:cytology / Q000378:metabolism*; D020651:Ventral Thalamic Nuclei / Q000166:cytology / Q000378:metabolism*
chemical_list: D006885:Hydroxybutyrates; D018080:Receptors, GABA-B; C111420:4-hydroxybutyric acid; D001418:Baclofen
keywords: absence seizures; baclofen; reward; thalamus; ventral tegmental area