Gamma-butyrolactone Research Articles

Medical and legal confusion surrounding gamma-hydroxybutyrate (GHB) and its precursors gamma-butyrolactone (GBL) and 1,4-butanediol (1,4BD)

Gamma-hydroxybutyrate (GHB) is used as a recreational drug, with significant associated morbidity and mortality; it is therefore a class C drug under the Misuse of Drugs Act (1971). However, its precursors gamma-butyrolactone (GBL) and 1,4-butanediol (1,4BD) remain legally available despite having similar clinical effects. The aim of this study was to determine whether the relative proportions of self-reported ingestions of GHB or its precursors GBL and 1,4BD were similar to those seen in analysis of seized drugs. Retrospective review of our clinical toxicology database to identify all cases of self-reported recreational GHB, GBL and 1,4BD use associated with ED presentation in 2006. Additionally all seized substances on people attending local club venues were analysed by a Home Office approved laboratory to identify any illicit substances present. In 2006, there were a total of 158 ED presentations, of which 150 (94.9%) and 8 (5.1%) were GHB and GBL self-reported ingestions respectively; 96.8% (153) were recreational use. Of the 418 samples seized, 225 (53.8%) were in liquid form; 85 (37.8%) contained GHB and 140 (62.2%) contained GBL. None of the seized samples contained 1,4BD and there were no self-reported 1,4BD ingestions. Self-reported GHB ingestion was much more common than GBL ingestion, whereas GBL was more commonly found in the seized samples. These differences suggest that GBL use may be more common than previously thought and we suggest that there should be further debate about the legal status of the precursors of GHB.

UFT and its metabolite γ-butyrolactone (GBL) inhibit angiogenesis induced by vascular endothelial growth factor in advanced cervical carcinoma

The aim of this study was to evaluate the potential role of UFT and its metabolite gamma-butyrolactone (GBL) for inhibition of angiogenesis induced by vascular endothelial growth factor (VEGF) in advanced cervical carcinoma by the determination of serum GBL and VEGF, and by immunohistochemical staining to assess VEGF protein expression, before and after UFT therapy. The subjects were 35 patients with an advanced cervical carcinoma and five healthy volunteers between 2002 and 2003 at Hiroshima University Hospital, under informed consent. The patients received two courses of oral fluoropyrimidine (UFT) therapy at a dose of 600 mg/day for 5 and 2 days off treatment. Serum GBL and VEGF was measured before and after UFT therapy by the gas chromatography mass spectrometry and ELISA-kit in 22 patients and five healthy volunteers, respectively. Immunohistochemical detection of VEGF protein was done in 35 cervical cancers. Results The mean serum GBL level before and after UFT therapy was 21.9 +/- 2.3 and 79.3 +/- 6.2 ng/ml, respectively, and it was significantly increased after UFT administration (P < 0.0001). The mean serum VEGF level before and after UFT therapy was 95.3 +/- 28.1 and 67.5 +/- 11.2 pg/ml, respectively, and it was decreased by UFT administration. In 20 out of 33 (66.6%) patients who were detected with VEGF protein, VEGF protein expression was decreased by UFT therapy. The Delta GBL value (GBL after UFT--GBL before UFT therapy) showed a significant inverse correlation with Delta VEGF value (VEGF after therapy--VEGF before therapy) (r2 = 0.940). Our findings suggest that UFT and its metabolite GBL inhibit angiogenesis induced by VEGF to have an antitumor effect on cervical cancer.

A comparison of the acute behavioral effects of gamma‐butyrolactone (GBL), and 1,4‐butanediol (1,4‐BD) to those of gamma‐hydroxybutyrate (GHB) in baboons

A comparison of the acute behavioral effects of gamma‐butyrolactone (GBL), and 1,4‐butanediol (1,4‐BD) to those of gamma‐hydroxybutyrate (GHB) in baboons

Proteomic analysis of γ‐butyrolactone‐treated mouse thalamus reveals dysregulated proteins upon absence seizure

Absence seizure has been of interest because the symptom is related to sensory processing. However, the mechanism that causes the disease is not understood yet. To better understand the molecular mechanism related to the disease progress at protein level, we performed proteomic studies using the thalamus of mice for which absence seizure was induced by gamma-butyrolactone (GBL). Differential proteome expression between GBL-treated mice and control mice was examined by fluorescence 2D difference gel electrophoresis (DIGE) at three different time points (5, 10, and 30 min) after GBL-administration. We identified 16 proteins differentially expressed by >1.4-fold at any of the three time points. All proteins besides the serine protease inhibitor EIA were down-regulated in absence seizure-induced mice. The down-regulated proteins can be classified into five groups by their biological functions: cytoskeleton rearrangement, neuroprotection, neurotransmitter secretion, calcium binding, and metabolism. The maximum level of change was reached by 10 min after GBL-treatment, with the expression level returning back to the original at 30 min when mice were awakened from absence seizure thereby demonstrating the proteomic response is reversible. Our results suggest that absence seizures are associated with restricted functional sets of proteins, whose down-regulation may interfere with general function of neuronal cells.

Cataleptic effects of γ-hydroxybutyrate (GHB), its precursor γ-butyrolactone (GBL), and GABAB receptor agonists in mice: differential antagonism by the GABAB receptor antagonist CGP35348

Gamma-hydroxybutyrate (GHB) is used to treat narcolepsy but is also abused. GHB has many actions in common with the GABA(B) receptor agonist baclofen. To further study the role of GABA(B) receptors in the effects of GHB. The experiments examined the ability of the GABA(B) receptor antagonist CGP35348 to attenuate GHB-induced catalepsy in comparison with its ability to attenuate the cataleptic effects of GABA(B) receptor agonists. In C57BL/6J mice, GHB, the GHB precursor gamma-butyrolactone (GBL), and the GABA(B) receptor agonists baclofen and SKF97541 all produced catalepsy but differed in potency (i.e., SKF97541>baclofen>GBL>GHB) and in onset of action. The cataleptic effects of drug combinations were assessed at the time of peak effect of each compound, i.e., 60 min after CGP35348 and 60, 30, 30, and 15 min after baclofen, SKF97541, GHB, and GBL, respectively. At 100 mg/kg, CGP35348 shifted the dose-response curves of baclofen and SKF97541 to the right but not those of GHB and GBL; at 320 mg/kg, CGP35348 shifted the curves of all four compounds to the right. The finding that CGP35348 was about threefold less potent to antagonize GHB and GBL than baclofen and SKF97541 is further evidence that the mechanisms mediating the effects of GHB and GABA(B) agonists are not identical. Differential involvement of GABA(B) receptor subtypes, or differential interactions with GABA(B) receptors, may possibly explain why GHB is effective for treating narcolepsy and is abused whereas baclofen is not.

Neuropharmacological profile of tetrahydrofuran in mice

Since the regulation of illicit gamma-hydroxybutyric acid (GHB) as a Federal Schedule I drug, the use of substitute chemical precursors such as gamma-butyrolactone (GBL) and 1,4-butanediol have emerged. Most recently there have been concerns about another potential analog of GHB, namely tetrahydrofuran (THF). While there is some suggestion that THF can be converted to GHB or GBL, little is known about the pharmacology of THF. Various doses of THF and GBL were studied in neurobehavioral tests to better characterize the pharmacology of THF. The TD 50's (with 95% confidence intervals) of THF for loss of the righting reflex and failure of performance on the rotarod test were 15.18 (11.88–19.39) and 7.00 (5.22–9.40) mmol/kg, respectively. These values were significantly greater ( p < 0.05) than those determined for GBL: 4.60 (3.25–6.51), and 0.85 (0.52–1.38) mmol/kg, respectively. The effects of THF on the impairment of motor function in the rotarod test were antagonized by pretreatment with the GABA B receptor antagonist CGP-35348 (200 mg/kg, i.p.).While both THF and GBL had depressant effects on open-field locomotor activity, the pattern of activity at the lower doses of THF and GBL were dissimilar. Chronic treatment with low dose THF (5 or 10 mmol/kg, i.p.) followed by acute challenge with THF (15 mmol/kg, i.p.) demonstrated tolerance to the observed sedative effects. While some of the mechanisms of the THF actions on the central nervous system appear likely to involve direct or indirect interactions with the GABA B receptor, some differences in its qualitative and quantitative pharmacology suggests other mechanisms are also likely involved in the observed neurobehavioral effects of these selected doses of THF in mice.

Ionic liquid-based electrolytes for capacitor applications

Abstract In this work we have synthesized several novel ionic liquids (ILs) based on imidazolium/pyrrolidinium cations and maleate/phthalate anions. The 1.5 mol/L solutions of the ILs in gamma-butyrolactone (GBL) solvent were prepared as the electrolytes of electrochemical energy storage devices such as electrochemical capacitors and electrolytic capacitors. The conductivity, electrochemical stability, sparking voltage and thermal stability of these electrolytes have been investigated systematically in this work. The relatively high room temperature conductivity (up to 18.22 mS cm −1 ), wide electrochemical window (up to 3.6 V) and good high-temperature durability of the 1-ethyl-3-methylimidazolium and N , N ′-dimethylpyrrolidinium cation-based electrolytes make them attractive for capacitor applications. In addition, these types of electrolytes could only be utilized in low-voltage type electrolytic capacitors due to their comparatively low sparking voltage (∼100 V). The temperature dependence of conductivity was also discussed in this study. The Vogel–Tammann–Fulcher (VTF) equation accurately describes the dependence of conductivity on temperature.

Lack of effects of GHB precursors GBL and 1,4‐BD following i.c.v. administration in rats

Gamma-hydroxybutyrate (GHB) is used therapeutically and recreationally worldwide. Since the scheduling of GHB by the USA and the United Nations in 2000-2001, the recreational use of GHB precursors has reportedly increased. The aim of this study was to examine if potency differences of GHB and GHB-like compounds are due to their blood-brain barrier permeability. The effects of peripheral and central administration of GHB, GHB precursors gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD), and the gamma-aminobutyric acid (GABA)(B) receptor agonist baclofen on schedule-controlled responding were examined in rats. GHB and baclofen were 276- and 253-fold more potent, respectively, after intracerebroventricular (i.c.v.) administration than after intraperitoneal (i.p.) administration, whereas GBL and 1,4-BD, up to a dose of 1780 microg were without effect after i.c.v. administration. These data suggest that GBL and 1,4-BD are not metabolically converted to GHB in the brain, that enhanced brain penetration cannot account for potency differences between compounds, and that baclofen, like GHB, can readily cross the blood-brain barrier.

A new UV lithography photoresist based on composite of EPON resins 165 and 154 for fabrication of high-aspect-ratio microstructures

We report a new type of negative-tone photoresist in this paper. The resist is based on a composite of EPON resins 154 and 165 (both from Hexion Specialty Chemicals, Inc., Columbus, OH 43215). These two epoxy-based resins were mixed in an optimal ratio and dissolved in gamma-butyrolactone (GBL) solvent. The mixture was then photosensitized by adding a given amount of triaryl sulfonium salt to obtain a new negative-tone photoresist that can be used in for ultra-high-aspect-ratio microstructure fabrication with UV lithography. Preliminary studies have found that microstructures with heights of more than 1000μm and feature sizes down to 10μm (aspect-ratios of more than 100) can be obtained using the new resist film with ultraviolet lithography. The microstructures have excellent sidewall quality. In this paper, both the material properties and lithography properties of this new type of UV resist will be presented. The potential applications of the new resist in microfabrication and MEMS systems are also discussed.

Applications of Ion Mobility Spectrometry (IMS) to the Analysis of gamma-Hydroxybutyrate and gamma-Hydroxyvalerate in Toxicological Matrices

The predator drug gamma-hydroxybutyrate (GHB) and its lactone form gamma-butyrolactone (GBL) continue to present significant analytical challenges to forensic toxicologists and chemists. The five-carbon analogue (gamma hydroxyvalerate GHV) and the corresponding lactone GVL) are emerging as substitutes for GHB, adding further complications. Ion mobility spectrometry (IMS) was investigated as a method of screening urine and breath for the presence of these drugs and their degradation products. Sample was introduced into the instrument via a programmable split/splitless injection port with thermal desorption. The injection method in effect replaces problematic solvent extraction methods with a physical extraction, an efficient method in the present case considering the hydrophilic nature of GHB. No chromatography was employed and results were obtained within a few seconds. The negative ion mode showed the greatest sensitivity with detection limits in the low parts-per-million range for GHB and GHV. Because GHB is often delivered in alcoholic beverages, ethanol and acetaldehyde, along with potential interfering compounds methanol, isopropanol, and acetone, were also analyzed. None were found to interfere. The thermally induced ring opening prevented differentiation of GHB and GBL using direct injection/thermal desorption protocol, but IMS does show promise as a rapid, simple, and affordable screening technique for GHB and related compounds.

Chronic intragastric administration of gamma-butyrolactone produces physical dependence in baboons

Abuse of gamma-hydroxybutyrate (GHB) and its precursors is a public health concern. Gamma-butyrolactone (GBL) is found in commercially available products and, when ingested, is metabolized to GHB. The goal was to evaluate the physical dependence potential and behavioral effects of GBL. Vehicle and then GBL were administered continuously (24 h per da y) in baboons (Papio anubis, n=5) via intragastric catheters. GBL dosing was initiated at 100 mg/kg/day and then progressively increased stepwise by increments of 100 mg/kg to a final dose of 600 mg/kg. The number of food pellets earned, fine-motor task performance, and observed behaviors were used as dependent measures. Precipitated withdrawal was evaluated after administration of GABA-B and benzodiazepine receptor antagonists during chronic GBL dosing (400-600 mg/kg). Spontaneous withdrawal was evaluated after discontinuation of chronic GBL 600 mg/kg. Blood GHB levels were determined during chronic dosing of each GBL dose by isotope dilution assay. Chronic GBL dose-dependently decreased food-maintained behavior, disrupted performance on the fine-motor task, and produced signs of sedation and muscle relaxation. The GABA-B antagonist SGS742 [56 mg/kg, intramuscular (IM)] precipitated a withdrawal syndrome, whereas the benzodiazepine antagonist flumazenil (5 mg/kg, IM) produced little or no effect. Signs of physical dependence were also demonstrated when chronic GBL dosing was discontinued. Analysis of plasma indicated GBL was metabolized to GHB; levels were 825 to 1,690 micromol l(-1) GHB and 2,430 to 3,785 micromol l(-1) GHB after week 1 of 400 and 600 mg/kg/day, respectively. These data indicate that, like GHB, chronic GBL dosing produced physical dependence that likely involved the GABA-B receptor.

GC-MS-MS Determination of Gamma-Hydroxybutyrate in Blood and Urine

A gas chromatographic-tandem mass spectrometric (GC-MS-MS) method for determining trace concentrations of gamma-hydroxybutyrate (GHB) in blood and urine has been developed. Multiple reaction monitoring was used to detect parent and daughter ions of GHB, 233 and 147, respectively, following liquid-liquid extraction with acetonitrile and derivatisation with N,O-bis[trimethylsilyl]trifluoroacetamide (BSTFA). Deuterated GHB was used as an internal standard. The assay produced excellent linearity and sensitivity without conversion to gamma butyrolactone. The lower limit of quantitation (LLOQ) in 50 microL of sample was 2.5 microg/mL. The expanded uncertainty values for intra- and interassay results were +/- 0.097 and +/- 0.123 ng/mL at a confidence level of 95% for blood and urine, respectively. Endogenous concentrations of GHB were found to be in the range of 0.3 to 6 microg/mL in urine and 0.5 to 2.3 microg/mL in blood, confirming previously suggested cut-off values for forensic analysis.

Discriminative stimulus effects of flumazenil: perceptual masking by baclofen, and lack of substitution with gamma-hydroxybutyrate and its precursors 1,4-butanediol and gamma-butyrolactone

Pigeons trained to discriminate 0.1 mg/kg flumazenil, proposed as an in-vivo model to study interactions with diazepam-insensitive gamma-aminobutyric acid (GABA)A receptors, were tested with various GABAergic and non-GABAergic compounds. As a result of its pharmacological selectivity, the model was suitable for further examining previously reported flumazenil-like effects of gamma-hydroxybutyrate (GHB). Flumazenil and the GABAA negative modulator Ro 15-4513 produced 82-100% flumazenil-appropriate responding. Diazepam and the direct-acting GABAA agonists muscimol and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol (THIP) produced 38-64% flumazenil-appropriate responding. GHB, its precursors 1,4-butanediol (1,4-BD) and gamma-butyrolactone (GBL), and the GABAB agonists baclofen and SKF97541 produced 0-24% flumazenil-appropriate responding. Baclofen shifted the flumazenil dose-response curve to the right and down, possibly involving perceptual masking of the discriminative stimulus effects of flumazenil by agonist activity at GABAB receptors. These masking effects of baclofen were blocked by the GABAB antagonist CGP35348. When CGP35348 was given together with GHB to block its GABAB agonist effects, GHB did not produce flumazenil-appropriate responding. Conceivably, effects of GHB at non-GABAB receptors (e.g. diazepam-sensitive GABAA receptors and GHB receptors) may interfere with the expression of its flumazenil-like discriminative stimulus effects. The asymmetric substitution between GHB and flumazenil is consistent with the hypothesis that the discriminative stimulus effects of GHB consist of several components, not all of which are mimicked by flumazenil.

GHB Free Acid: I. Solution Formation Studies and Spectroscopic Characterization by 1HNMR and FT‐IR

In forensic evidence, gamma-hydroxybutyric acid (GHB) has frequently been encountered in one of its salt forms (gamma-hydroxybutyrate), but has also been encountered in its free acid form (GHB). Owing to the physical properties, encounters of the free acid have been largely restricted to forensic exhibits comprising aqueous solutions, such as acidic beverages that have been "spiked" or formulated with GHB salts or gamma-butyrolactone (GBL). The analysis of GHB free acid presents particular difficulties including the potential for altering the original proportions of GHB free acid, GHB carboxylate, and GBL in the course of analysis, and discrimination between GHB free acid and carboxylate forms. In this work, the formation of GHB free acid in aqueous solutions (water and/or D2O) was studied as a function of solution pH. Proton nuclear magnetic resonance (1HNMR) and Fourier-transform infrared spectrometry (FT-IR) measurements were obtained on freshly prepared mixtures of NaGHB and HCl stock solutions representing a series of points along the GHB titration curve. Both 1HNMR and FT-IR were shown to track the changing proportions of GHB free acid and carboxylate forms as a function of pH, while simultaneously monitoring for the formation of the lactone (GBL). The results were consistent with acid-base conversion behavior for a carboxylic acid. 1HNMR was shown to provide an ideal means for analysis of aqueous-based GHB/GBL forensic exhibits based on simple dilution of the neat liquid exhibit, without altering the original proportions of GHB free acid, carboxylate, and GBL in the samples.

Development of Many−Body Polarizable Force Fields for Li-Battery Applications: 2. LiTFSI-Doped Oligoether, Polyether, and Carbonate-Based Electrolytes

A quantum chemistry study of Li(+) interactions with ethers, carbonates, alkanes, and a trifluoromethanesulfonylimide anion (TFSI(-)) was performed at the MP2, B3LYP, and HF levels using the aug-cc-pvDz basis set for solvents and TFSI(-) anion, and [8s4p3d/5s3p2d]-type basis set for Li. A classical many-polarizable force field was developed for the LiTFSI salt interacting with ethylene carbonate (EC), gamma-butyrolactone (GBL), dimethyl carbonate (DMC), acetone, oligoethers, n-alkanes, and perfluoroalkanes. Molecular dynamics (MD) simulations were performed for EC/LiTFSI, PC/LiTFSI, GBL/LiTFSI, DMC/LiTFSI, 1,2-dimethoxyethane/LiTFSI, pentaglyme/LiTFSI, and poly(ethylene oxide) (MW = 2380)/LiTFSI electrolytes at temperatures from 298 to 423 K and salt concentrations from 0.3 to 5 M. The ion and solvent self-diffusion coefficients, electrolyte conductivity, electrolyte density, LiTFSI apparent molar volumes, and structure of the Li(+) cation environment predicted by MD simulations were found in good agreement with experimental data.

Trends in γ-Hydroxybutyrate (GHB) and Related Drug Intoxication: 1999 to 2003

To analyze changes in gamma-hydroxybutyrate (GHB) case reporting, we review GHB or congener drug cases reported to the California Poison Control System, comparing these to other data sets. We identified cases from the California Poison Control System computerized database using standardized codes and key terms for GHB and congener drugs ("gamma butyrolactone," "1,4-butanediol," "gamma valerolactone"). We noted California Poison Control System date, caller and exposure site, patient age and sex, reported coingestions, and outcomes. We compared California Poison Control System data to case incidence from American Association of Poison Control Centers and Drug Abuse Warning Network data and drug use prevalence from National Institute for Drug Abuse survey data. A total of 1,331 patients were included over the 5-year period (1999-2003). California Poison Control System-reported GHB exposures decreased by 76% from baseline (n=426) to the final study year (n=101). The absolute decrease was present across all case types, although there was a significant proportional decrease in routine drug abuse cases and an increase in malicious events, including GHB-facilitated sexual assault (P=.002). American Association of Poison Control Centers data showed a similar decrease from 2001 to 2003. Drug Abuse Warning Network incidence flattened from 2001 to 2002 and decreased sharply in 2003. National Institute for Drug Abuse survey time trends were inconsistent across age groups. Based on the precipitous decrease in California Poison Control System case incidence for GHB during 5 years, the parallel trend in American Association of Poison Control Centers data, and a more recent decrease in Drug Abuse Warning Network cases, a true decrease in case incidence is likely. This could be due to decreased abuse rates or because fewer abusers seek emergency medical care. Case reporting may account for part of the decrease in the incidence of poison center contacts involving GHB.

Ionic Limiting Molar Conductivity Calculation of Li-Ion Battery Electrolyte Based on Mode Coupling Theory

A method is proposed based on mode coupling theory in which the ion transference number is introduced into the theory. The ionic limiting molar conductivities of LiPF6, LiClO4, LiBF4, LiCF3SO3, Li(CF3SO3)2N, LiC4F9SO3, and LiAsF6 in PC(propylene carbonate), GBL(gamma-butyrolactone), PC(propylene carbonate)/EMC(ethylmethyl carbonate), and PC(propylene carbonate)/DME(dimethoxyethane) are calculated based on this method, which does not involve any adjustable parameter. The results fit well to the literature data which are calculated by an empirically adjusted formula. This presents a potential way to calculate the conductivities of Li-ion battery electrolytes.

Characteristics of ionic liquid-based electrolytes for chip type aluminum electrolytic capacitors

Since ionic liquids (ILs) possess several attractive properties, including chemical and thermal stability, nonflammability, high ionic conductivity, and negligible vapor pressure, a new electrolyte system based on ILs has been proposed for chip type aluminum electrolytic capacitors. Four ILs based on imidazolium/pyrrolidinium cations and maleate/phthalate anions have been synthesized and their thermal stabilities have been examined. The 25 wt.% solutions of the four ILs in gamma-butyrolactone (GBL) solvent were prepared as electrolytes of chip type aluminum electrolytic capacitors. The conductivity, sparking voltage and thermal stability of these electrolytes have been systematically investigated. The results revealed that the four IL-based electrolytes exhibited high conductivity. Furthermore, the conductivity of maleate anion-based electrolytes is higher than that of phthalate anion-based electrolytes, whereas the high-temperature durability of phthalate anion-based electrolytes in conductivity is superior to that of maleate anion-based electrolytes irrespective of pyrrolidinium or imidazolium cation. However, this type of electrolytes could only be utilized in low-voltage type capacitors due to their comparatively low sparking voltage. In addition, the capacitors utilizing the four IL-based electrolytes show excellent thermal stabilities during a reflow soldering process.

Clinical features of gamma-hydroxybutyrate and gamma-butyrolactone toxicity and concomitant drug and alcohol use

Objective To describe the clinical features of gamma-hydroxybutyrate (GHB) and gamma-butyrolactone (GBL) toxicity. Methods Retrospective case-study of 65 GHB and GBL intoxications seen in an urban emergency department. Results 63% of intoxications occurred in male patients. The median age was 24 years (range 16–41 years). 65% co-ingested alcohol or illicit drugs, mostly MDMA and cocaine. 83% presented with coma. The mean ± S.D. time to regain consciousness among comatose patients was 111 ± 61 min and was significantly longer in patients who co-abused illicit drugs such as cocaine or MDMA (155 ± 60 min). Bradycardia occurred in 38%, hypotension in 6% and hypothermia in 48%. Agitation was observed in 17% of all patients and was significantly more frequent in patients with alcohol co-use (29%). Vomiting occurred in 31% of all patients and tended to be more frequent in patients who co-used alcohol (39%). Management of GHB and GBL overdose was supportive. Four patients needed admission to an intensive care unit for mechanical ventilation (6%). Conclusions Overdosing of GHB and GBL frequently results in non-reactive coma reflecting the severity of poisoning. Multiple drug use is common and significantly influences the clinical presentation.

Discriminative stimulus effects of gamma-hydroxybutyrate (GHB) and its metabolic precursor, gamma-butyrolactone (GBL) in rats

Gamma-hydroxybutyrate (GHB) is becoming an increasingly popular drug of abuse. Metabolic precursors of GHB, gamma-butyrolactone (GBL) and 1,4-butanediol (BDL), are commercially available industrial solvents that may also present potential health risks. Relatively little is known about the neurobehavioral effects of GHB and its precursors. The aim of the present investigation was to characterize the discriminative stimulus effects of GHB and its precursor, GBL. Male Sprague-Dawley rats were trained to discriminate GHB [300 mg/kg, i.g.; n=16] or GBL (150 mg/kg, i.p.; n=8) from vehicle under a fixed ratio 20 (FR 20) schedule of food reinforcement. Stimulus generalization tests were then conducted with several compounds. GHB and GBL produced cross-generalization and BDL was fully substituted for both GHB and GBL. Two benzodiazepines, alprazolam and diazepam, and the 5-HT1A agonist, buspirone, did not substitute for either training drug nor did ethanol or the NMDA antagonists, PCP and ketamine. The GHB antagonist, NCS-382, and the GABA(B) antagonist, CGP-35348, blocked the discriminative stimulus effects of GHB but not those of GBL. These findings suggest that GHB and its metabolic precursors produce similar subjective effects that differ from those of other sedative-hypnotic drugs. Further investigations into the neurochemical actions underlying the subjective effects of these drugs are warranted.