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.
Highlights
Gamma-hydroxybutyric acid (GHB) is an endogenous central nervous system (CNS) substance that results from the metabolism of the neurotransmitter gamma-aminobutyric acid (GABA) [1,2,3], but can act as a source of neuronal GABA [4]
The main findings of this study are that GHB consistently elicits robust [Ca2þ]i transients in astrocytes of both the ventral tegmental area (VTA) and the VB thalamus of young rodents, two brain areas that are involved in the reward properties and the proabsence effect of this drug, respectively
This astrocytic GHB action is mediated by GABAB receptors (GABABRs) and is comparable to that evoked in astrocytes of the same regions by the selective GABABR agonist baclofen
Summary
Gamma-hydroxybutyric acid (GHB) is an endogenous central nervous system (CNS) substance that results from the metabolism of the neurotransmitter gamma-aminobutyric acid (GABA) [1,2,3], but can act as a source of neuronal GABA [4]. Systemic administration but importantly it occurs when it is injected directly into the ventrobasal (VB) nucleus of the thalamus [29], one of the key areas for the generation of these non-convulsive seizures [30] In both mice and rats, all behavioural and cellular actions of GHB, including its reward- and seizure-eliciting properties, can be explained by it acting as a weak agonist at GABAB receptors (GABABRs) [31,32], though the existence of a putative GHB receptor site has been suggested [33] (but see [3]). In contrast to many other studies which found that transient as well as sustained agonist-induced astrocytic [Ca2þ]i elevations result in increased gliotransmitter release, prolonged GHB and baclofen exposure causes a reduction in spontaneous glutamate release from VTA astrocytes
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