Abstract
gamma-Hydroxybutyrate (GHB), a metabolite of gamma-aminobutyric acid (GABA), is proposed to function as a neurotransmitter or neuromodulator. gamma-Hydroxybutyrate and its prodrug, gamma-butyrolactone (GBL), recently received increased public attention as they emerged as popular drugs of abuse. The actions of GHB/GBL are believed to be mediated by GABAB and/or specific GHB receptors, the latter corresponding to high-affinity [3H]GHB-binding sites coupled to G-proteins. To investigate the contribution of GABAB receptors to GHB actions we studied the effects of GHB in GABAB(1)-/- mice, which lack functional GABAB receptors. Autoradiography reveals a similar spatial distribution of [3H]GHB-binding sites in brains of GABAB(1)-/- and wild-type mice. The maximal number of binding sites and the KD values for the putative GHB antagonist [3H]6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylidene acetic acid (NCS-382) appear unchanged in GABAB(1)-/- compared with wild-type mice, demonstrating that GHB- are distinct from GABAB-binding sites. In the presence of the GABAB receptor positive modulator 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol GHB induced functional GTPgamma[35S] responses in brain membrane preparations from wild-type but not GABAB(1)-/- mice. The GTPgamma[35S] responses in wild-type mice were blocked by the GABAB antagonist [3-[[1-(S)-(3,4dichlorophenyl)ethyl]amino]-2-(S)-hydroxy-propyl]-cyclohexylmethyl phosphinic acid hydrochloride (CGP54626) but not by NCS-382. Altogether, these findings suggest that the GHB-induced GTPgamma[35S] responses are mediated by GABAB receptors. Following GHB or GBL application, GABAB(1)-/- mice showed neither the hypolocomotion, hypothermia, increase in striatal dopamine synthesis nor electroencephalogram delta-wave induction seen in wild-type mice. It, therefore, appears that all studied GHB effects are GABAB receptor dependent. The molecular nature and the signalling properties of the specific [3H]GHB-binding sites remain elusive.
Original language | English |
---|---|
Journal | European Journal of Neuroscience |
Volume | 18 |
Issue number | 10 |
Pages (from-to) | 2722-30 |
ISSN | 0953-816X |
Publication status | Published - Nov 2003 |
Keywords
- 4-Butyrolactone
- Adjuvants, Anesthesia
- Animals
- Anticonvulsants
- Autoradiography
- Baclofen
- Behavior, Animal
- Benzocycloheptenes
- Binding, Competitive
- Body Weight
- Brain
- Cell Membrane
- Chromatography, High Pressure Liquid
- Dihydroxyphenylalanine
- Dose-Response Relationship, Drug
- Drug Interactions
- Electrochemistry
- Electroencephalography
- GABA-B Receptor Agonists
- Guanosine 5'-O-(3-Thiotriphosphate)
- Mice
- Mice, Inbred BALB C
- Mice, Knockout
- Motor Activity
- Organophosphorus Compounds
- Phenols
- Radioligand Assay
- Receptors, GABA-B
- Sodium Oxybate
- Time Factors
- gamma-Aminobutyric Acid