Quantitative autoradiographic distribution of γ-hydroxybutyric acid binding sites in human and monkey brain

Castelli, Paola; Mocci, Ignazia; Langlois, Xavier; Gommeren, W.; Luyten, Walter; Leysen, Josée E.; Gessa, Gian Luigi

doi:10.1016/s0169-328x(00)00078-4

Cited by 59 publications

(57 citation statements)

References 49 publications

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“…The wide range of behavioral effects that can be observed following administration of GHB is likely due to its multiple mechanisms of action. Specific GHB receptors have been hypothesized (Benavides et al, 1982;Snead and Liu, 1984;Hechler et al, 1987;Castelli et al, 2000;Mehta et al, 2001) and recently cloned (Andriamampandry et al, 2003). However, behavioral studies suggest an important role for GABA B receptors (Colombo et al, 1998;Lobina et al, 1999;Carai et al, 2001Carai et al, , 2002aCarter et al, 2003Carter et al, , 2004aRen and Mody, 2003), consistent with the finding that GHB binds to these receptors (Bernasconi et al, 1992;Xie and Smart, 1992;Mathivet et al, 1997;Lingenhoehl et al, 1999).…”

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confidence: 72%

Novel γ-Hydroxybutyric Acid (GHB) Analogs Share Some, but Not All, of the Behavioral Effects of GHB and GABA_BReceptor Agonists

Carter

Chen

et al. 2005

J Pharmacol Exp Ther

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␥-Hydroxybutyrate (GHB), a therapeutic for narcolepsy and a drug of abuse, has several mechanisms of action that involve GHB and GABA B receptors, metabolism to GABA, and modulation of dopaminergic signaling. The aim of these studies was to examine the role of GHB and GABA B receptors in the behavioral effects of GHB. Three approaches were used to synthesize GHB analogs that bind selectively to GHB receptors and are not metabolized to GABA-active compounds. Radioligand binding assays identified UMB86 (4-hydroxy-4-napthylbutanoic acid, sodium salt), UMB72 [4-(3-phenylpropyloxy)butyric acid, sodium salt], UMB73 (4-benzyloxybutyric acid, sodium salt), 2-hydroxyphenylacetic acid, 3-hydroxyphenylacetic acid (3-HPA), and 4-hydroxy-4-phenylbutyric acid as compounds that displace In rats and pigeons, GHB discriminative stimulus effects were not mimicked or attenuated by UMB86, UMB72, or 3-HPA up to doses that decreased responding. In mice, GHB, GHB precursors (␥-butyrolactone and 1,4-butanediol) and GABA B receptor agonists [SKF97541 [3-aminopropyl(methyl)phosphinic acid hydrochloride] and baclofen] dose-dependently produced hypolocomotion, catalepsy, ataxia, and loss of righting. The GABA B receptor antagonist CGP35348 (3-aminopropyl(diethoxymethyl)phosphinic acid) attenuated catalepsy and ataxia that was observed after GHB and GABA B receptor agonists SKF97541 and baclofen. UMB86, UMB72, UMB73, and 3-HPA, like GHB, produced hypolocomotion, ataxia, and loss of righting; however, catalepsy was never observed with these compounds, which is consistent with the cataleptic effects of GHB being

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confidence: 72%

Novel γ-Hydroxybutyric Acid (GHB) Analogs Share Some, but Not All, of the Behavioral Effects of GHB and GABA_BReceptor Agonists

Carter

Chen

et al. 2005

J Pharmacol Exp Ther

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“…In the mammalian central nervous system, systemically administered GHB has been shown to have affinity for specific GHB binding sites, referred to as the GHB receptor [3,12,14,25,36,54,65]. High affinity GHB binding sites are thought to contribute to the biological effects of GHB [65].…”

Section: Introductionmentioning

confidence: 99%

Systemic Administration of γ-Hydroxybutyric Acid in Adolescent Rat Impairs Contextual Fear Conditioning, But Not Cued Conditioning

Sircar

Ishiwari²

2014

Journal of Drug and Alcohol Research

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γ-hydroxybutyric acid (GHB) causes retrograde amnesia in juveniles and young adults. Earlier, we have reported that in adolescent rat, GHB impairs the hidden platform task performance in the Morris water maze. In the present study, a classical fear conditioning paradigm was used to examine the effects of GHB on the acquisition of contextual conditioning, a hippocampus-dependent associative task, and cued tone conditioning, a hippocampus-independent task, in adolescent rats. Administration of GHB before the presentation of tone-shock pairings dose-dependently disrupted the acquisition of contextual conditioning with no effect on tone conditioning, when conditioned fear was measured 24 h later. Administering GHB prior to testing did not disrupt either contextual or tone conditioning. These results demonstrate that in the adolescent rat exposure to GHB preferentially disrupt hippocampal-dependent learning.

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“…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 demonstrated that GHB is metabolized to GABA (Hechler at al., 1997;Bernasconi et al, 1999).…”

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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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Quantitative autoradiographic distribution of γ-hydroxybutyric acid binding sites in human and monkey brain

Cited by 59 publications

References 49 publications

Novel γ-Hydroxybutyric Acid (GHB) Analogs Share Some, but Not All, of the Behavioral Effects of GHB and GABA_BReceptor Agonists

Novel γ-Hydroxybutyric Acid (GHB) Analogs Share Some, but Not All, of the Behavioral Effects of GHB and GABA_BReceptor Agonists

Systemic Administration of γ-Hydroxybutyric Acid in Adolescent Rat Impairs Contextual Fear Conditioning, But Not Cued Conditioning

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

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Quantitative autoradiographic distribution of γ-hydroxybutyric acid binding sites in human and monkey brain

Cited by 59 publications

References 49 publications

Novel γ-Hydroxybutyric Acid (GHB) Analogs Share Some, but Not All, of the Behavioral Effects of GHB and GABABReceptor Agonists

Novel γ-Hydroxybutyric Acid (GHB) Analogs Share Some, but Not All, of the Behavioral Effects of GHB and GABABReceptor Agonists

Systemic Administration of γ-Hydroxybutyric Acid in Adolescent Rat Impairs Contextual Fear Conditioning, But Not Cued Conditioning

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

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Novel γ-Hydroxybutyric Acid (GHB) Analogs Share Some, but Not All, of the Behavioral Effects of GHB and GABA_BReceptor Agonists

Novel γ-Hydroxybutyric Acid (GHB) Analogs Share Some, but Not All, of the Behavioral Effects of GHB and GABA_BReceptor Agonists