Binding characteristics of γ-hydroxybutyric acid as a weak but selective GABAB receptor agonist

Mathivet, Pascal; Bernasconi, R.; Barry, Jean de; Marescaux, Christian; Bittiger, H.

doi:10.1016/s0014-2999(96)00916-8

Cited by 125 publications

(97 citation statements)

References 32 publications

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“…This finding is consistent with GHB occasioning little or no drug-appropriate responding in rhesus monkeys trained to discriminate triazolam or pentobarbital (Woolverton et al, 1999), and with triazolam and pentobarbital (positive GABA A receptor modulators) having different pharmacological mechanisms of action than GHB, which is a GABA B receptor agonist (Mathivet et al, 1997) and specific GHB receptor ligand (Benavides et al, 1982). Given that the prototypical GABA B receptor agonist baclofen (Lioresal) is used therapeutically as a muscle relaxant, it is somewhat surprising that GHB was not identified as a muscle relaxant more often (two participants identified a dose of GHB as a muscle relaxant; one after 2 g/ 70 kg and one after 4 g/70 kg GHB), although this result might be due to participants' lack of experience with this class of compounds (muscle relaxants).…”

Section: Discussionsupporting

confidence: 78%

Relative Abuse Liability of GHB in Humans: A Comparison of Psychomotor, Subjective, and Cognitive Effects of Supratherapeutic Doses of Triazolam, Pentobarbital, and GHB

Carter

Richards

Mintzer

et al. 2006

Neuropsychopharmacol

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Although preclinical studies suggest that GHB has low likelihood for abuse, case reports indicate that GHB is abused. This study evaluated the relative abuse liability of GHB in 14 volunteers with histories of drug abuse. Psychomotor, subjective, and cognitive effects of a broad range of GHB doses (2-18 g/70 kg), up to a dose that produced severe behavioral impairment in each participant, were compared to placebo and two abused sedative/hypnotic drugs, triazolam (0.5 and 1 mg/70 kg) and pentobarbital (200 and 400 mg/70 kg), under double-blind, double-dummy conditions at a residential research facility. In general, GHB produced effects similar to triazolam and pentobarbital, although GHB was not identified as a benzodiazepine or barbiturate by participants that correctly identified triazolam and pentobarbital as such. On most measures of likelihood of abuse (eg ratings of liking, reinforcing effects), effects of pentobarbital were significantly greater than those of triazolam, with GHB being intermediate. GHB produced significantly greater negative subjective effects, including nausea, than the other drugs. Memory impairment after GHB was less than that after triazolam and pentobarbital. Within participants, the dose-effect function for sedation was steeper for GHB than for triazolam and pentobarbital. Also, at higher doses, GHB was associated with greater sedation and more variability across participants in sedation. Taken together, these data suggest that the profile of effects of GHB only partially overlaps with that of triazolam and pentobarbital. Although the likelihood for GHB to be abused is intermediate to triazolam and pentobarbital, the possibility of accidental overdose (ie greater sedation than intended) with GHB appears to be greater.

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Section: Discussionsupporting

confidence: 78%

Relative Abuse Liability of GHB in Humans: A Comparison of Psychomotor, Subjective, and Cognitive Effects of Supratherapeutic Doses of Triazolam, Pentobarbital, and GHB

Carter

Richards

Mintzer

et al. 2006

Neuropsychopharmacol

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“…Some behavioral effects of GHB have been attributed to its interaction with the GABAergic system [10,15,21]. GHB has weak affinity for the GABA B receptor [34]. Recently, it has been shown to bind with high affinity to the α4-containing GABA A receptor [1].…”

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 binds to GABA B receptors (Mathivet et al 1997;Lingenhoehl et al 1999) and specific GHB receptors (Benavides et al 1982;Snead and Liu 1984) in brain that are thought to be involved in the behavioral effects of GHB. At present, there appears to be little evidence for a role for GHB receptors in the in vivo effects of GHB (Wong et al 2004).…”

Section: Introductionmentioning

confidence: 99%

Cataleptic effects of γ-hydroxybutyrate (GHB) and baclofen in mice: mediation by GABAB receptors, but differential enhancement by N-methyl-d-aspartate (NMDA) receptor antagonists

Koek

2008

Psychopharmacology

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Rationale-Gamma-hydroxybutyrate (GHB) is a gamma-aminobutyric acid (GABA) analog that is used to treat narcolepsy but that is also abused. GHB has many actions in common with the GABA B receptor agonist baclofen, but their underlying GABA B receptor mechanisms may be different.Objective-The aim of this study is to further investigate a possible differential role of glutamate in GABA B receptor-mediated effects of GHB and baclofen. Materials and methods-The experiments examined the effects of non-competitive antagonists at the N-methyl-d-asparate (NMDA) subtype of glutamate receptors on GHB-induced catalepsy and compared these effects with those on baclofen-induced catalepsy.Results-In C57BL/6J mice, ketamine, phencyclidine (PCP), and dizocilpine (MK-801) all enhanced GHB-induced catalepsy. They did so with a potency order (i.e., MK-801 > PCP > ketamine) consistent with their relative potencies as NMDA antagonists but not as inhibitors of dopamine or organic cation transporters. Ketamine, PCP, and MK-801 enhanced catalepsy along inverted U-shaped dose-response curves likely because higher doses affected motor coordination, which limited their catalepsy-enhancing effects. Doses that were maximally effective to enhance GHB-induced catalepsy did not affect the cataleptic effects of baclofen.Conclusions-The finding that NMDA receptor antagonists enhance the cataleptic effects of GHB but not those of baclofen is further evidence that the GABA B receptor mechanisms mediating the effects of GHB and GABA B agonists are not identical. Differential interactions of glutamate with the GABA B receptor mechanisms mediating the effects of GHB and baclofen may explain why GHB is effective for treating narcolepsy and is abused, whereas baclofen is not.

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Binding characteristics of γ-hydroxybutyric acid as a weak but selective GABAB receptor agonist

Cited by 125 publications

References 32 publications

Relative Abuse Liability of GHB in Humans: A Comparison of Psychomotor, Subjective, and Cognitive Effects of Supratherapeutic Doses of Triazolam, Pentobarbital, and GHB

Relative Abuse Liability of GHB in Humans: A Comparison of Psychomotor, Subjective, and Cognitive Effects of Supratherapeutic Doses of Triazolam, Pentobarbital, and GHB

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

Cataleptic effects of γ-hydroxybutyrate (GHB) and baclofen in mice: mediation by GABAB receptors, but differential enhancement by N-methyl-d-aspartate (NMDA) receptor antagonists

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