Abstract
γ-Hydroxybutyric acid (GHB) is an endogenous neurotransmitter that is abused because of its sedative/hypnotic and euphoric effects. The objectives of this study were to evaluate the concentration-effect relationships of GHB in plasma, cerebrospinal fluid (CSF), brain (whole and discrete brain regions), and brain frontal cortex extracellular fluid. This information is crucial for future studies to evaluate effects of therapeutic interventions on the toxicodynamics of GHB. GHB (200–1000 mg/kg) was administered intravenously to rats, and plasma and frontal cortex microdialysate samples were collected for up to 6 h after the dose, or plasma, CSF, and brain (whole, frontal cortex, striatum, and hippocampus) concentrations were determined at the offset of its sedative/hypnotic effect [return to righting reflex (RRR)]. GHB-induced changes in the brain neurotransmitters γ-aminobutyric acid (GABA) and glutamate were also determined. GHB, GABA, and glutamate concentrations were measured by liquid chromatography/tandem mass spectrometry. GHB-induced sleep time significantly increased in a dose-dependent manner (20-fold increase from 200 to 1000 mg/kg). GHB concentrations in plasma (300–400 μg/ml), whole brain (70 μg/g), discrete brain regions (80–100 μg/g), and brain microdialysate (29–39 μg/ml) correlated with RRR. In contrast, CSF GHB and GABA and glutamate concentrations in discrete brain regions exhibited no relationship with RRR. Our results suggest that GHB-induced sedative/hypnotic effects are mediated directly by GHB and that at high GHB doses, GABA formation from GHB may not contribute to the observed sedative/hypnotic effect. These results support the use of a clinical GHB detoxification strategy aimed at decreasing plasma and brain GHB concentrations after GHB overdoses.
Footnotes
This work was supported in part by the National Institutes of Health National Institute of Drug Abuse [Grant DA023223]; and a fellowship from Pfizer Global Research and Development.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.165381.
-
ABBREVIATIONS:
- GHB
- γ-hydroxybutyric acid
- GABA
- γ-aminobutyric acid
- LRR
- loss of righting reflex
- RRR
- return to righting reflex
- MCT
- monocarboxylate transporter
- TK
- toxicokinetic(s)
- CSF
- cerebrospinal fluid
- TD
- toxicodynamic(s)
- GHB-d6
- deuterated GHB
- aCSF
- artificial cerebrospinal fluid
- HPLC
- high-performance liquid chromatography
- LC/MS/MS
- liquid chromatography/tandem mass spectrometry
- AUC
- area under the curve
- ECF
- extracellular fluid
- NCS-382
- 6,7,8,9-tetrahydro-5-(H)-benzocycloheptene-5-ol-4-ylideneacetic acid
- BCSFB
- blood-CSF barrier
- BBB
- blood-brain barrier
- CGP 46381
- 3-aminopropyl-cyclohexylmethylphosphinic acid
- SCH 50911
- (2S)(+)5,5-dimethyl-2-morpholineacetic acid.
- Received December 30, 2009.
- Accepted March 5, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|