The Extraneural Distribution of γ‐Hydroxybutyrate

Nelson, Thomas; Kaufman, Elaine E.; Kline, J E; Sokoloff, Louis

doi:10.1111/j.1471-4159.1981.tb04689.x

Cited by 140 publications

(80 citation statements)

References 10 publications

(10 reference statements)

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“…However, findings that GHB appears to normalize sleep patterns in narcoleptic patients (Nishino and Mignot, 1997) and its increasing popularity as a recreational drug (Bernasconi et al, 1999) have led to a recent growth of interest in GHB (Nicholson and Balster, 2001). GHB is concentrated in specific regions of the mammalian brain where specific binding sites or receptors are located and, to a lesser extent, in some peripheral tissues (Nelson et al, 1981;Vayer and Maitre, 1988;Snead, 1996). GHB rapidly crosses into the central nervous system and is also rapidly metabolized (Bernasconi et al, 1999), the latter being a major factor contributing to its very short duration of action.…”

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confidence: 99%

A Tertiary Alcohol Analog of γ-Hydroxybutyric Acid as a Specific γ-Hydroxybutyric Acid Receptor Ligand

Zink

Carter

et al. 2003

J Pharmacol Exp Ther

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␥-Hydroxybutyric acid (GHB) shows great promise as a treatment for sleeping disorders but is also increasingly abused. The exact mechanism of action of GHB is yet to be delineated, but it is known to interact with specific GHB binding sites or receptors, to act as a weak agonist at GABA B receptors, and that GHB undergoes metabolism to GABA. In drug discrimination studies, GABA B agonists, and to a lesser extent GABA A -positive modulators, substitute for GHB. To delineate the relative contributions of each receptor system to the profile of GHB, tertiary alcohol analogs of GHB and its homolog, 5-hydroxypentanoic acid (UMB58), were prepared (UMB68 and UMB75, respectively), which cannot be metabolized to GABA-active compounds. Binding studies against ethanoic acid] showed that the tertiary alcohol analog of GHB (UMB68) has similar affinity to GHB, with the longer chain analogs possessing lower affinity. Against [ 3 H]GABA, UMB68 showed no affinity (IC 50 Ͼ100 M) at GABA A or GABA B receptors. In vivo studies showed that, at behaviorally active doses, rats trained to discriminate GHB did not recognize the novel ligands as GHB. Thus, UMB68 is a selective GHB receptor ligand in binding assays, will not undergo metabolism to GABAactive compounds, and does not show the same effects as GHB in vivo. These data suggest that, although UMB68 binds to the GHB receptor, it does not have the observed GABA receptor-mediated effects of GHB in vivo and could provide a novel tool for studying the pharmacology of the GHB receptor in the absence of complicating GABAergic effects.␥-Hydroxybutyric acid (GHB) (Fig. 1) is an endogenous compound that was initially thought to simply be an inactive metabolite of GABA. However, findings that GHB appears to normalize sleep patterns in narcoleptic patients (Nishino and Mignot, 1997) and its increasing popularity as a recreational drug (Bernasconi et al., 1999) have led to a recent growth of interest in GHB (Nicholson and Balster, 2001). GHB is concentrated in specific regions of the mammalian brain where specific binding sites or receptors are located and, to a lesser extent, in some peripheral tissues (Nelson et al., 1981;Vayer and Maitre, 1988;Snead, 1996). GHB rapidly crosses into the central nervous system and is also rapidly metabolized (Bernasconi et al., 1999), the latter being a major factor contributing to its very short duration of action. GHB has also been proposed to be an effective treatment for alcohol (Addolorato et al., 2000;Gessa et al., 2000) and opioid dependence (Gallimberti et al., 1994).Although GHB binding sites have been described (Benavides et al., 1982;Snead and Liu, 1984;Hechler et al., 1987;Snead and Nichols, 1987;Castelli et al., 2000, the exact mechanism of action of GHB remains elusive due, in part, to apparent GABA-mediated effects (Carai et al., 2001(Carai et al., , 2002. GHB is known to interact with GABA B receptors with low affinity (Bernasconi et al., 1992;Xie and Smart, 1992;Mathivet et al., 1997;Lingenhoehl et al., 1999), and it has been demonst...

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confidence: 99%

A Tertiary Alcohol Analog of γ-Hydroxybutyric Acid as a Specific γ-Hydroxybutyric Acid Receptor Ligand

Zink

Carter

et al. 2003

J Pharmacol Exp Ther

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“…GHB has been found in several extraneuronal tissues, including gastrointestinal tract, kidney, muscle, heart, liver, lung, brain fat, and blood (Nelson et al, 1981;Tedeschi et al, 2003). The endogenous concentrations of GHB in the kidney, gastrointestinal tract, heart, and muscle are much higher than those in brain and blood; however, the origin and function of GHB in extraneuronal tissues are not known.…”

Section: Discussionmentioning

confidence: 97%

“…GHB has been detected in various tissues other than brain, including heart, kidney, liver, lung, muscle, and gastrointestinal tract (Nelson et al, 1981;Tedeschi et al, 2003). GHB is approved in the United States for treatment of the sleep disorder narcolepsy (Mamelak et al, 1986) and is used in the treatment of alcohol dependence in Europe (Gallimberti et al, 2000).…”

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The Role of Monocarboxylate Transporter 2 and 4 in the Transport of γ-Hydroxybutyric Acid in Mammalian Cells

Wang

Morris

2007

Drug Metab Dispos

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“…However, the highest concentrations can be found in peripheral body tissues such as the kidneys and brown fat (Nelson et al, 1981). The cerebral concentrations of GHB are approximately 0.1% of the concentrations of GABA (Maitre, 1997).…”

Section: Neuropharmacology Of Ghbmentioning

confidence: 99%

Reconsidering GHB: orphan drug or new model antidepressant?

et al. 2011

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For six decades, the principal mode of action of antidepressant drugs is the inhibition of monoamine re-uptake from the synaptic cleft. Tricyclic antidepressants, selective serotonin re-uptake inhibitors (SSRIs) and the new generation of dual antidepressants all exert their antidepressant effects by this mechanism. In the early days of the monoaminergic era, other efforts have been made to ameliorate the symptoms of depression by pharmacological means. The gamma-aminobutyric acid (GABA) system was and possibly still is one of the main alternative drug targets. Gammahydroxybutyrate (GHB) was developed as an orally active GABA analogue. It was tested in animal models of depression and human studies. The effects on sleep, agitation, anhedonia and depression were promising. However, the rise of benzodiazepines and tricyclic antidepressants brought GHB out of the scope of possible treatment alternatives. GHB is a GABA(B) and GHB receptor agonist with a unique spectrum of behavioural, neuroendocrine and sleep effects, and improves daytime sleepiness in various disorders such as narcolepsy, Parkinson's disease and fibromyalgia. Although it was banned from the US market at the end of the 1990s because of its abuse and overdose potential, it later was approved for the treatment of narcolepsy. New research methods and an extended view on other neurotransmitter systems as possible treatment targets of antidepressant treatment brought GHB back to the scene. This article discusses the unique neurobiological effects of GHB, its misuse potential and possible role as a model substance for the development of novel pharmacological treatment strategies in depressive disorders. AbstractFor six decades, the principal mode of action of antidepressant drugs is the inhibition of monoamine re-uptake from the synaptic cleft. Tricyclic antidepressants, selective serotonin re-uptake inhibitors (SSRIs) and the new generation of dual antidepressants all exert their antidepressant effects by this mechanism. In the early days of the monoaminergic era, other intents have been made to ameliorate symptoms of depression by pharmacological means.The gamma-aminobutyric acid (GABA) system was and possibly still is one of the main alternative drug targets. Gammahydroxybutyrate (GHB) was developed as an orally activeGABA analogue. It was tested in animal models of depression and human studies. The effects on sleep, agitation, anhedonia and depression were promising. But the rise of benzodiazepines and tricyclic antidepressants brought GHB out of scope of possible treatment alternatives. GHB is a GABA B and GHB receptor agonist with a unique spectrum of behavioral, neuroendocrine and sleep effects, and improves daytime sleepiness in various disorders such as narcolepsy, Parkinson's disease and fibromyalgia. Although it was banned from the US-market end of the 1990-ies because of its abuse and overdose potential, it later was approved for the treatment of narcolepsy. New research methods and an extended view on other neurotransmitter systems a...

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The Extraneural Distribution of γ‐Hydroxybutyrate

Cited by 140 publications

References 10 publications

A Tertiary Alcohol Analog of γ-Hydroxybutyric Acid as a Specific γ-Hydroxybutyric Acid Receptor Ligand

A Tertiary Alcohol Analog of γ-Hydroxybutyric Acid as a Specific γ-Hydroxybutyric Acid Receptor Ligand

The Role of Monocarboxylate Transporter 2 and 4 in the Transport of γ-Hydroxybutyric Acid in Mammalian Cells

Reconsidering GHB: orphan drug or new model antidepressant?

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