GHB receptor targets in the CNS: Focus on high-affinity binding sites

Bay, Tina; Eghorn, Laura F.; Klein, Anders Bue; Wellendorph, Petrine

doi:10.1016/j.bcp.2013.10.028

Cited by 101 publications

(118 citation statements)

References 72 publications

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“…This makes it difficult to exclude involvement of these receptors even at low doses of GHB (Bay et al, 2014). Others have used the compound NCS-382 as a specific antagonist (Maitre et al, 1990), although its intrinsic activity has been questioned (Castelli et al, 2004;Crunelli et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…As a drug of abuse, GHB was recently ranked ninth on a list of drugs that correlate with significant societal costs (Nutt et al, 2010). Although much work has been carried out to describe the pharmacologic actions of GHB, using both molecular and behavioral studies, little is known about the physiologic role of the compound (Bay et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…The most well described and prominent target is the GABA B receptor, which produces many of the known pharmacologic effects of GHB (Kaupmann et al, 2003;Carter et al, 2009;Vienne et al, 2010;Black et al, 2014); however, since GHB is only a low-affinity, weak partial agonist at this target (Mathivet et al, 1997;Lingenhoehl et al, 1999), millimolar concentrations of compound are required to elicit these effects; therefore, effects of lower GHB concentrations mediated by other more sensitive targets cannot be ruled out. These can be known or unknown targets that bind GHB with much higher affinity (Bay et al, 2014), such as certain subtypes of ionotropic GABA A receptors (Absalom et al, 2012), although their physiologic importance in relation to GHB effects have been debated (Connelly et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…To study the role of the high-affinity GHB sites in further detail, compounds have been developed that are devoid of affinity for GABA B receptors (Wellendorph et al, 2005;Høg et al, 2008;Bay et al, 2014). One of these compounds is the conformationally restricted GHB analog, HOCPCA (3-hydroxycyclopent-1-enecarboxylic acid) (Wellendorph et al, 2005) (Fig.…”

Section: Introductionmentioning

confidence: 99%

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In Vitro and In Vivo Evidence for Active Brain Uptake of the GHB Analog HOCPCA by the Monocarboxylate Transporter Subtype 1

Thiesen

Kehler

Clausen

et al. 2015

J Pharmacol Exp Ther

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g-Hydroxybutyric acid (GHB) is a recreational drug, a clinically prescribed drug in narcolepsy and alcohol dependence, and an endogenous substance that binds to both high-and lowaffinity sites in the brain. For studying the molecular mechanisms and the biologic role of the GHB high-affinity binding sites, ligands with high and specific affinity are essential. The conformationally restricted GHB analog HOCPCA (3-hydroxycyclopent-1-enecarboxylic acid) is one such compound. The objective of this study was to investigate the transport of HOCPCA across the blood-brain barrier in vitro and in vivo and to investigate the hypothesis that HOCPCA, like GHB, is a substrate for the monocarboxylate transporters (MCTs). For in vitro uptake studies, MCT1, -2, and -4 were recombinantly expressed in Xenopus laevis oocytes, and the previously reported radioligand

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

In Vitro and In Vivo Evidence for Active Brain Uptake of the GHB Analog HOCPCA by the Monocarboxylate Transporter Subtype 1

Thiesen

Kehler

Clausen

et al. 2015

J Pharmacol Exp Ther

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“…Following oral ingestion this crosses the blood brain barrier and is converted into gamma-aminobutyric acid (GABA). (17) As an ethanol analogue it has been successfully trialed in a single blinded setting in other alcohol responsive movement disorders. (18)(19)(20) Furthermore the use of this medication has also been extended to SD with the trial of Xyrem® in a single SD patient.…”

Section: Chapter 3 -The Use Of the Novel Therapeutic Agent Xyrem® On mentioning

confidence: 99%

Spasmodic dysphonia and voice tremor: an analysis of the neuropathophysiology, clinical features and treatment options

Kirke¹

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Spasmodic dysphonia (SD) is a focal laryngeal dystonia that affects speech production. It is a rare disease that can remain undiagnosed and untreated in many. It usually develops in midlife and is socially and occupationally disabling. It can be sub-classified into adductor SD (ADSD), abductor SD (ABSD) and mixed SD. In one -third of patients, SD is also associated with vocal tremor (SD/VT). This further complicates the diagnosis, as this element of the disease has a more variable response to the gold standard of management Botulinum toxin (BoNT) than SD alone. The reasons for this are unclear, but a lack of the full understanding of the aetiology, pathophysiology and clinical features of SD with or without VT (SD+/-VT) certainly contribute.Whilst there has been some recent progress made in understanding the brain functional and structural alterations of SD, there has been no commensurate progress in understanding the VT component of SD/VT. As such this prevents the true understanding of the nature of SD+/-VT, and thus improved management of the disorder. Therefore the first aim of this work was to determine specific brain abnormalities contributing to both SD and SD/VT, via examining functional and structural brain abnormalities in 20 SD vs. 20 SD/VT vs. healthy controls (HV), using functional MRI (fMRI) during symptomatic speech production, voxel based morphometry (VBM) and diffusion weighted imaging (DWI). This revealed that both SD and SD/VT groups showed increased activation in the sensorimotor cortex, inferior frontal (IFG) and superior temporal gyri (STG), putamen and ventral thalamus, as well as deficient activation in the inferior parietal cortex and middle frontal gyrus (MFG). Common structural alterations were observed in the IFG and putamen, which were further coupled with functional abnormalities in both patient groups (Coordinates at the peak of significant clusters are given in the AFNI standard Talairach-Tournoux space at an FWE-corrected p ≤ 0.05). Abnormal activation in the left putamen was correlated with SD onset (r = 0.61, p = 0.004), whereas SD/VT onset was associated with right putaminal volumetric changes (r = -0.48, p = 0.032). These and further findings explored in the thesis demonstrate that SD and SD/VT, are heterogeneous disorders at different ends of the same clinical spectrum, with each disorder carrying a characteristic neural signature, which may potentially help the development of differential markers for these two conditions.The secondary aim of this Masters, was to explore some of the clinical characteristics of SD+/-VT. It has been acknowledged anecdotally that the symptoms of both SD and SD/VT respond positively to the consumption of alcohol. This has been published in the setting of VT alone, however it has never been formally explored in the setting of SD. Therefore the secondary aim of this work was to conduct a cross sectional online survey of patients with SD and SD/VT in order to 3 ascertain their degree of alcohol consumption and the effect it has on their sym...

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Torin 1 partially corrects vigabatrin‐induced mitochondrial increase in mouse

Vogel

et al. 2015

Ann Clin Transl Neurol

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Recent findings in mice with targeted deletion of the GABA-metabolic enzyme succinic semialdehyde dehydrogenase revealed a new role for supraphysiological GABA (4-aminobutyric acid) in the activation of the mechanistic target of rapamycin (mTOR) that results in disruption of endogenous mitophagy. Employing biochemical and electron microscopic methodology, we examined the hypothesis that similar outcomes would be observed during intervention with vigabatrin, whose antiepileptic capacity hinges on central nervous system GABA elevation. Vigabatrin intervention was associated with significantly enhanced mitochondrial numbers and areas in normal mice that could be selectively normalized with the rapalog and mechanistic target of rapamycin inhibitor, Torin 1. Moreover, short-term administration of vigabatrin induced apoptosis and enhanced phosphorylation of mechanistic target of rapamycin Ser 2448 in liver. Our results provide new insight into adverse outcomes associated with vigabatrin intervention, and the first evidence that its administration is associated with increased mitochondrial number in central and peripheral tissues that may associate with mechanistic target of rapamycin function and enhanced cell death.

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GHB receptor targets in the CNS: Focus on high-affinity binding sites

Cited by 101 publications

References 72 publications

In Vitro and In Vivo Evidence for Active Brain Uptake of the GHB Analog HOCPCA by the Monocarboxylate Transporter Subtype 1

In Vitro and In Vivo Evidence for Active Brain Uptake of the GHB Analog HOCPCA by the Monocarboxylate Transporter Subtype 1

Spasmodic dysphonia and voice tremor: an analysis of the neuropathophysiology, clinical features and treatment options

Torin 1 partially corrects vigabatrin‐induced mitochondrial increase in mouse

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