γ-Hydroxybutyrate is a weak agonist at recombinant GABAB receptors

Lingenhoehl, Kurt; Brom, R. H.G. van den; Heid, Jakob; Beck, Pascal; Froestl, Wolfgang; Kaupmann, Klemens; Bettler, Bernhard; Mosbacher, Johannes

doi:10.1016/s0028-3908(99)00131-8

Cited by 177 publications

(112 citation statements)

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“…The lowest dose of GHB and baclofen that produced near-maximal catalepsy in the cumulative dosing procedure used here (i.e., 320 and 10 mg/kg i.p., respectively) was the same as in the single dosing procedure used previously (Carter et al 2005;Koek et al 2007b), suggesting that, under the conditions of these experiments, the potency of GHB and baclofen to produce catalepsy in C57BL/6J mice is not markedly affected by the use of single or cumulative dosing. The observation that GHB, which has agonist activity at GABA B receptors (Lingenhoehl et al 1999), has cataleptic effects in common with a wellcharacterized GABA B receptor agonist and the finding that these effects can be blocked by the GABA B receptor antagonist CGP35348 (e.g., Koek et al 2007b) are further evidence that GABA B receptors are involved in GHB-induced catalepsy.…”

Section: Discussionmentioning

confidence: 95%

“…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%

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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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Section: Discussionmentioning

confidence: 95%

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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“…In mammalian brain GHB levels approximate 1-4 µM (Doherty et al, 1978;Snead, 1991), while in Aldh5a1 −/− mice this level rises to ~250 µM (Hogema et al, 2001). This concentration of GHB is still well below that which is believed to activate GABA B receptors (~5 mM; Lingenhoehl et al, 1999;Wu et al, 2004). On the other hand, some of this GHB may interconvert to GABA, as the enzymes responsible for this are still operative (Rumigny et al, 1981), hence elevating the excess GABA due to the block in Aldh5a1 even more (Snead & Gibson, 2005).…”

Section: Role Of Gaba and Ghb In Kd's Mechanismmentioning

confidence: 99%

A ketogenic diet rescues the murine succinic semialdehyde dehydrogenase deficient phenotype

Nylen

Velázquez

Likhodii

et al. 2008

Experimental Neurology

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Succinic semialdehyde dehydrogenase (SSADH) deficiency is an heritable disorder of GABA degradation characterized by ataxia, psychomotor retardation and seizures. To date, there is no effective treatment for SSADH deficiency. We tested the hypothesis that a ketogenic diet (KD) would improve outcome in an animal model of SSADH deficiency, the SSADH knockout mouse (Aldh5a1 −/− ). Using a 4:1 ratio of fat to combined carbohydrate and protein KD we set out to compare the general phenotype, in vivo and in vitro electrophysiology and [ 35 S]TBPS binding in both Aldh5a1 −/− mice and control (Aldh5a1 +/+ ) mice. We found that the KD prolonged the lifespan of mutant mice by >300% with normalization of ataxia, weight gain and EEG compared to mutants fed a control diet. Aldh5a1 −/− mice showed significantly reduced mIPSC frequency in CA1 hippocampal neurons as well as significantly decreased [ 35 S]TBPS binding in all brain areas examined. In KD fed mutants, mIPSC activity normalized and [ 35 S]TBPS binding was restored in the cortex and hippocampus. The KD appears to reverse toward normal the perturbations seen in Aldh5a1 −/− mice. Our data suggest that the KD may work in this model by restoring GABAergic inhibition. These data demonstrate a successful experimental treatment for murine SSADH deficiency using a KD, giving promise to the idea that the KD may be successful in the clinical treatment of SSADH deficiency.

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“…Studies with recombinant GABA B receptors indicate that GHB is a weak, isosteric GABA B receptor agonist (8), as does the discovery that the hypolocomotion and hypothermia caused by GHB are absent in GABA B receptor-deficient mice (9) At least some of the pharmacological effects of GHB are due to its activation of extrasynaptic GABA A receptors.…”

mentioning

confidence: 99%

Extrasynaptic site of action for γ-hydroxybutyrate

Enna

2012

Proc. Natl. Acad. Sci. U.S.A.

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γ-Hydroxybutyrate is a weak agonist at recombinant GABAB receptors

Cited by 177 publications

References 29 publications

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

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

A ketogenic diet rescues the murine succinic semialdehyde dehydrogenase deficient phenotype

Extrasynaptic site of action for γ-hydroxybutyrate

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