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ABSTRACT: The abuse of anabolic androgenic steroids (AASs), such as nandrolone, is not only a problem in the world of sports but is associated with the polydrug use of non-athletes. Among other adverse effects, AAS abuse has been associated with long term or even persistent psychiatric problems. We have previously found that nandrolone decanoate treatment could produce prolonged changes in rats' brain reward circuits associated to drug dependence. The aim in this study was to evaluate whether AAS-induced neurochemical and behavioral changes are reversible. The increases in extracellular dopamine (DA) and serotonin (5-HT) concentration, as well as stereotyped behavior and locomotor activity (LMA) evoked by cocaine were attenuated by pretreatment with nandrolone. The recovery period, which was needed for the DA system to return back to the basic level, was fairly long compared to the dosing period of the steroid. In the 5-HT system, the time that system needed to return back to the basal level, was even longer than in the DA system. The attenuation was still seen though there were no detectable traces of nandrolone in the blood samples. Given that accumbal outflow of DA and 5-HT, as well as LMA and stereotyped behavior are all related to reward of stimulant drugs, this study suggests that nandrolone decanoate has significant, long-lasting but reversible effects on the rewarding properties of cocaine.
Steroids 07/2011; 76(12):1310-6. · 2.83 Impact Factor
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ABSTRACT: Previously we have reported that sub-chronic administration of nandrolone modifies reward-related neurochemical effects of psychomotor stimulant drugs of abuse. The aim of the present study was to evaluate whether the ability of nandrolone (19-nortestosterone) to attenuate the effects of amphetamine depends on activation of androgen (AR) or estrogen receptors (ER). We used an in vivo microdialysis technique in fully conscious rats to monitor whether administration of the AR-antagonist flutamide (7x50 mg/kg) or the ER-antagonist clomiphene (7x20 mg/kg), attenuates nandrolone-induced modulation of dopaminergic and serotonergic effects of acute injections of amphetamine (1 mg/kg). Dopamine (DA), 5-hydroxytryptamine (5-HT) and their metabolites were measured from the samples using high performance liquid chromatography (HPLC). Blocking the androgen receptors with flutamide abolished the attenuating effect of nandrolone pre-treatment on amphetamine-induced elevation of extracellular DA concentration. Blocking the estrogen receptors with clomiphene did the same but to a lesser extent. In conclusion, the results of this study show that the ability of nandrolone to attenuate the effects of amphetamine depends on activation of androgen receptors or to a lesser extent, on estrogen receptors.
Pharmacology Biochemistry and Behavior 03/2010; 95(4):422-7. · 2.53 Impact Factor
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ABSTRACT: The abuse of anabolic androgenic steroids (AASs) is not only a problem in the world of sports but is associated with the polydrug use of nonathletes. Investigations of the neurochemical effects of AAS have focused in part on the monoaminergic systems, involving, among other things, the development of dependence. We have previously shown that pretreatment with nandrolone decanoate attenuates dose-dependently the increase in extracellular dopamine (DA) concentration evoked by amphetamine and 3,4-methylenedioyxymethamphetamine in the nucleus accumbens (NAc).
The aim of this study was to investigate whether the nandrolone pre-exposure modulates the acute neurochemical and behavioral effects of cocaine in rats and whether the effects are long lasting.
DA, 5-hydroxytryptamine (5-HT), and their metabolites were measured from samples collected from the NAc by microdialysis. The behavior of the animals was recorded.
The present study demonstrates that five injections of nandrolone (5 and 20 mg/kg) inhibited cocaine-evoked DA and 5-HT outflow in the NAc, locomotor activity (LMA), and stereotyped behavior in experimental animals, and that these effects are seen even after elimination of nandrolone from bloodstream.
Given that accumbal outflow of DA and 5-HT, as well as LMA and stereotyped behavior, is related to gratification of stimulant drugs, this study suggests that nandrolone, at the doses tested, has a significant effect on the pleasurable properties of cocaine. Furthermore, because neurochemical and behavioral responses were still attenuated after a fairly long recovery period, it seems that nandrolone may induce long-lasting changes in the brains of rat.
Psychopharmacologia 02/2010; 209(3):271-81. · 4.08 Impact Factor
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ABSTRACT: Misuse of anabolic-androgenic steroids (AASs) is increasing, and appears to have much in common with the use of substances known to induce drug dependence. Moreover, persons who abuse AASs also tend to abuse other psychotropic drugs such as amphetamine or 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"). The aim of this study was to investigate whether nandrolone (5 x 5 or 5 x 20 mg/kg) pre-exposure modulates the acute neurochemical and behavioral effects of amphetamine (1mg/kg) and MDMA (5 mg/kg) in rats. Dopamine (DA), 5-hydroxytryptamine (5-HT) and their metabolites were measured from samples collected from the nucleus accumbens (NAc) by in vivo microdialysis. The behavior of the animals was recorded on videotapes, from which it was later rated. Our results demonstrate that sub-chronic treatments with supraphysiological doses of nandrolone attenuate dose-dependently the increase in extracellular DA concentration evoked by amphetamine or MDMA. The lower dose of nandrolone attenuated MDMA-induced increase in 5-HT-levels, while the higher dose potentiated it. Analysis of the behavioral data suggests that effects of the amphetamine and MDMA are dose-dependently attenuated by AAS-treatment, paralleling DA results. In conclusion, the results of this study show that AAS-pre-treatment is able to modulate the reward-related neurochemical and behavioral effects of amphetamine and MDMA.
Behavioural Brain Research 06/2008; 189(1):191-201. · 3.42 Impact Factor
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ABSTRACT: Gamma-hydroxybutyrate (GHB) is an increasingly popular drug of abuse that causes stimulation, euphoria, anxiolysis or hypnosis, depending on the dose used. Low doses of the drug are used recreationally, and also implicated in drug-facilitated sexual assaults. Because of the unusually steep dose-response curves, accidental GHB overdosing, leading to coma, seizures or death can occur. Being a controlled substance, GHB is often substituted with its non-scheduled precursors gamma-butyrolactone (GBL) and 1,4-butanediol (BD), which are rapidly metabolized into GHB in the body. Here we describe an assay for GHB, GBL and BD in blood and/or urine samples. GHB and BD were extracted from diluted 200 microL aliquots of samples with t-butylmethylether (plus internal standard benzyl alcohol) in test tubes preloaded with NaCl. After acidification and centrifugation the solvent phase was transferred to a test tube preloaded with Na(2)SO(4), incubated for 30 min, centrifuged again, and evaporated in vacuum. The residue was mixed with N-methyl-N-trimethylsilyl-trifluoroacetamide (MSTFA) in acetonitrile, and injected into a GC-MS. When analyzing GBL, the salting-out step was omitted, and analysis was performed with a GC-FID apparatus. As revealed by the validation data this procedure is suitable for quantitative determination of GHB and its precursors in blood and/or urine samples.
Forensic science international 09/2007; 170(2-3):133-8. · 2.10 Impact Factor
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ABSTRACT: 1-Benzylpiperazine (also known as 'Legal X', 'Legal E', or 'A2') is a psychoactive compound increasingly encountered on the clandestine market. Previous experimental data suggest that the compound possesses addictive properties. In the present study, we used the conditioned place preference method in the rat to test whether 1-benzylpiperazine possesses rewarding properties. Furthermore, the mechanisms of the 1-benzylpiperazine reward were investigated using selected dopamine and serotonin receptor antagonists. 1-Benzylpiperazine (1.25, 5, and 20 mg/kg) induced dose-dependently place preference. This place preference was attenuated by the antagonists SCH23390 (0.2 mg/kg; dopamine D1-like receptors) and MDL72222 (1.0 mg/kg; serotonin3 receptors), but not by raclopride (0.8 mg/kg; dopamine D2-like receptors) or ketanserin (2 mg/kg; preferentially serotonin2 receptors). Our results show that 1-benzylpiperazine possesses rewarding properties in the rat, which suggests the compound to be susceptible to human abuse. The brain dopaminergic and serotonergic systems appear to be involved in the 1-benzylpiperazine reward.
Basic & Clinical Pharmacology & Toxicology 05/2006; 98(4):346-50. · 2.18 Impact Factor
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ABSTRACT: 4-Methylaminorex is a potential psychostimulant drug of abuse that exists as four stereoisomers: cis-4R,5S, cis-4S,5R, trans-4S,5S, and trans-4R,5R. The racemic mixture of the cis-isomers has been encountered in illicit samples, but previous animal studies suggest that also the trans-isomers could have similar stimulant-like properties. We tested whether the stereoisomers possess rewarding properties and compared their potency using the conditioned place preference method in rats. Furthermore, the involvement of the brain dopaminergic system in the 4-methylaminorex reward was tested with the dopamine D1- and D2-receptor antagonists SCH 23390 and raclopride administered systemically, or with the neurotoxin 6-hydroxydopamine injected into the nucleus accumbens. All the four isomers induced place preference, with no apparent differences in their potency. SCH 23990 and raclopride attenuated 4-methylaminorex-induced increase in place preference, and 6-hydroxydopamine also tended to be efficacious. These findings indicate that all the four stereoisomers of 4-methylaminorex possess rewarding properties and thus abuse potential; the trans-isomers are at least as potent as the cis-isomers. Furthermore, the brain dopaminergic system appears to be involved in the 4-methylaminorex-reward.
Pharmacology Biochemistry and Behavior 09/2005; 81(4):715-24. · 2.53 Impact Factor
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ABSTRACT: Anabolic-androgenic steroids (AASs) are widely abused by adolescents, although persistent AAS use can cause several adverse physical and mental effects, including drug dependence. The first aim of the present study was to study the action of nandrolone decanoate on dopaminergic and serotonergic activities in the brains of rats. In order to evaluate the anabolic or toxic effects of the dosing regimens used, selected peripheral effects were monitored as well. Male Wistar rats were treated for 2 weeks. Injections containing nandrolone (5 and 20 mg/kg, i.m.) or vehicle were given once daily, 5 days a week. The levels of dopamine (DA), 5-hydroxytryptamine (5-HT) and their metabolites were assayed from dissected brain regions 3 days after the last injection. Blood was collected for chemical assays before, after 1 week treatment and at decapitation. Both doses of nandrolone significantly increased the levels of 3,4-dihydroxyphenylacetic acid (DOPAC), a metabolite of DA in the cerebral cortex, and the higher dose of nandrolone increased the concentrations of 5-HT in the cerebral cortex compared with the vehicle. In addition, after nandrolone treatment, the levels of hemoglobin and erythrocytes increased, and reticulocyte levels decreased. The results suggest that nandrolone at supraphysiological doses, high enough to induce erythropoiesis, induces changes in the dopaminergic and serotonergic neuronal system in the brains of rats. These phenomena may account to some of the observed central stimulatory properties that have been reported following AAS abuse.
Brain Research 06/2005; 1044(1):67-75. · 2.73 Impact Factor
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ABSTRACT: We describe a rapid GC/MS assay for amphetamine-type stimulant drugs (ATSs) and structurally related common medicaments in blood, serum, oral fluid and urine samples. The drugs were extracted from their matrices and derivatized with heptafluorobutyric anhydride (HFBA) in a single step, using the following procedure: 100 microl (oral fluid) or 200 microl (blood, serum, urine) of the sample were mixed with 50 microl of alkaline buffer and 500 microl of extraction-derivatization reagent (toluene + HFBA + internal standard), centrifuged, and injected into a GC/MS apparatus. As revealed by the validation data this procedure, with its limit of quantitation being set at 20 ng/ml for oral fluid, 25 ng/ml for blood or 200 ng/ml for urine, is suitable for screening, identification and quantitative determination of the ATSs and related drugs in all the matrices examined. Thus, time-consuming and expensive multiple analyses are not needed, unless specifically required.
Journal of Chromatography B 11/2004; 810(1):57-68. · 2.89 Impact Factor
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ABSTRACT: 4-Methylaminorex, a potential psychostimulant drug of abuse, exists as four stereoisomers: cis-4R,5S, cis-4S,5R, trans-4S,5S, and trans-4R,5R, which were shown previously to possess stereospecific effects. This study characterized their pharmacokinetic and tissue distribution profiles, and metabolic turnover to norephedrine and norpseudoephedrine, in male Wistar rats. The rats received each isomer intravenously, intraperitoneally, or orally, followed by blood sample collection via cannula (pharmacokinetic study), or tissue sample collection at predetermined time points (tissue distribution study). The samples were analyzed for cis- and trans-isomers, and when appropriate for norephedrine and norpseudoephedrine, with gas chromatography/mass spectrometry. Trans-4S,5S-, cis-4R,5S-, and cis-4S,5R-isomers behaved comparably kinetically (volume of distribution 1.7-2.3 l/kg, distribution half-life 3.8-7.0 min, elimination half-life 35-42 min, and bioavailability 32-57% intraperitoneally or 4-16% orally), whereas trans-4R,5R-isomer differed from the others, with a longer elimination half-life (118-169 min) and higher bioavailability (100% intraperitoneally or 83% orally). The highest isomer concentrations were observed in the kidney followed most frequently by the liver, brain, muscle, and last by fat and blood. The elimination half-lives of the stereoisomers from the tissues were generally similar to those in blood. No pharmacologically significant amounts of norephedrine or norpseudoephedrine were detected in blood or the brain. In conclusion, differences between the stereoisomers of 4-methylaminorex in the pharmacokinetics and tissue distribution are described. However, these differences are not compatible with, and thus may not account for, the distinct behavioral and neurochemical effects of the stereoisomers demonstrated previously. Furthermore, metabolic turnover to norephedrine and norpseudoephedrine does not seem to contribute significantly to 4-methylaminorex pharmacology.
Journal of Pharmacology and Experimental Therapeutics 07/2004; 309(3):1198-205. · 3.83 Impact Factor
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ABSTRACT: Alcohol-preferring AA (Alko Alcohol) and alcohol-avoiding ANA (Alko Non-Alcohol) rats have well-documented differences in their voluntary ethanol consumption and brain opioidergic systems. The aim of the present study was to investigate whether these rat lines differ in their susceptibility to morphine-induced behavioural and neurochemical sensitization. The rats were given 15 injections of morphine (10 mg/kg, s.c.) or saline every other day. Locomotor activity and release of dopamine in the nucleus accumbens were monitored after a challenge with additional morphine injections (10 mg/kg) 1 and 5 weeks after withdrawal from the repeated treatment. Morphine increased locomotion more in the previously morphine-treated rats than in the saline-treated controls. Furthermore, AA rats were more sensitive to this effect of morphine than ANA rats. Accumbal morphine-induced dopamine release was significantly higher in the morphine-treated AA than ANA rats after the first challenge injection 1 week from withdrawal, but no differences were observed after the second challenge. The brain and plasma concentrations of morphine were similar among the lines suggesting that the differences in the effects of morphine cannot be explained in terms of differential pharmacokinetics of morphine in these lines. These data show that AA rats are more susceptible to morphine-induced behavioural sensitization than ANA rats. Furthermore, it suggests that mesolimbic dopamine has at best only a transient role in the expression of opioid-induced behavioural sensitization. The relationship between the mechanisms underlying the differential sensitivity of these rat lines to the effects of repeated morphine and voluntary ethanol drinking remains to be determined.
European Journal of Neuroscience 05/2003; 17(8):1655-63. · 3.63 Impact Factor
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ABSTRACT: It has previously been demonstrated that the 5-HT(3) receptors located in the mesolimbic brain areas are able to modulate the dopaminergic effects of various abused drugs, including cocaine (COC).
The present experiments investigated the role of 5-HT(3) receptors in the actions of selected monoamine uptake inhibitors.
The ability of the 5-HT(3) receptor antagonist MDL 72222 (MDL; 0.1 and 1.0 mg/kg) to modify the neurochemical and behavioral changes induced by COC (20 mg/kg), mazindol (MAZ; 10 mg/kg), and methylphenidate (MP; 5.0 or 10, and 20 mg/kg) was assessed with an in vivo microdialysis technique, a conditioned place preference method, and motor activity measurements.
MDL robustly attenuated the elevation of extracellular dopamine levels in the nucleus accumbens, acquisition of place preference, and motor activity induced by COC and MAZ, but not those induced by MP, the only drug with no significant effect on 5-HT. In contrast, expression of COC-induced place preference was not attenuated by MDL.
These results show that COC- and MAZ-induced reward-related neurochemical and behavioral effects, preferentially those implicated in development of conditioned reward, are modified by the 5-HT(3) blockade. In contrast to COC and MAZ, the changes induced by MP, which has less effect on the serotonergic system, remain unchanged. Thus it appears that involvement of a serotonergic component in the mechanism of action of a drug could be a prerequisite for effective antagonism by 5-HT(3) receptor blockers.
Psychopharmacologia 03/2002; 159(4):341-50. · 4.08 Impact Factor
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ABSTRACT: 4-Methylaminorex is a stimulant drug of abuse that exists as four stereoisomers: cis-4R,5S, cis-4S,5R, trans-4S,5S, and trans-4R,5R. These isomers have previously been shown to differ markedly in various respects. In the present study we assessed the effects of the isomers of 4-methylaminorex (2.5, 5.0, and 10 mg/kg i.p.) on extracellular dopamine and 5-hydroxytryptamine (5-HT) levels in the nucleus accumbens, as well as behavior in the rats simultaneously. The relative concentrations of the isomers in the brain were also measured. The samples were collected by in vivo microdialysis and then analyzed for neurotransmitters with high-performance liquid chromatography/electrochemical detection and for cis- and trans-4-methylaminorex with gas chromatography/mass spectrometry. The behavioral effects of the isomers were assessed from videotapes recorded during the microdialysis experiments. All isomers elevated the extracellular levels of both dopamine and 5-HT, with the exception of trans-4R,5R. The rank order of potency for elevating dopamine was trans-4S,5S > cis-4S,5R approximately cis-4R,5S > trans-4R,5R, and for elevating 5-HT cis-4S,5R > trans-4S,5S approximately cis-4R,5S > trans-4R,5R. Analysis of the behavioral data, together with the neurochemical data, suggests that behavioral effects of the isomers of 4-methylaminorex are related to drug-induced dopamine release and, in the case of higher doses of the most efficacious isomers, to 5-HT as well. The brain concentrations of the isomers did not reflect their neurochemical efficacy, which implies that their differences are pharmacodynamic rather than pharmacokinetic.
Journal of Pharmacology and Experimental Therapeutics 02/2002; 300(2):450-9. · 3.83 Impact Factor
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ABSTRACT: Rationale: It has previously been demonstrated that the 5-HT3 receptors located in the mesolimbic brain areas are able to modulate the dopaminergic effects of various abused drugs, including
cocaine (COC). Objectives: The present experiments investigated the role of 5-HT3 receptors in the actions of selected monoamine uptake inhibitors. Methods: The ability of the 5-HT3 receptor antagonist MDL 72222 (MDL; 0.1 and 1.0mg/kg) to modify the neurochemical and behavioral changes induced by COC
(20mg/kg), mazindol (MAZ; 10mg/kg), and methylphenidate (MP; 5.0 or 10, and 20mg/kg) was assessed with an in vivo microdialysis
technique, a conditioned place preference method, and motor activity measurements. Results: MDL robustly attenuated the elevation of extracellular dopamine levels in the nucleus accumbens, acquisition of place preference,
and motor activity induced by COC and MAZ, but not those induced by MP, the only drug with no significant effect on 5-HT.
In contrast, expression of COC-induced place preference was not attenuated by MDL. Conclusions: These results show that COC- and MAZ-induced reward-related neurochemical and behavioral effects, preferentially those implicated
in development of conditioned reward, are modified by the 5-HT3 blockade. In contrast to COC and MAZ, the changes induced by MP, which has less effect on the serotonergic system, remain
unchanged. Thus it appears that involvement of a serotonergic component in the mechanism of action of a drug could be a prerequisite
for effective antagonism by 5-HT3 receptor blockers.
Psychopharmacologia 01/2002; 159(4):341-350. · 4.08 Impact Factor
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ABSTRACT: The effects of a 5-HT3 receptor antagonist MDL 72222 on cocaine- and amphetamine-induced increases in extracellular dopamine in the nucleus accumbens and the dorsal striatum were studied with microdialysis technique using halothane anaesthesized rats. Dopamine and its metabolites were measured by HPLC with electrochemical detection. Cocaine elevated extracellular dopamine in the nucleus accumbens and to a lesser extent in the dorsal striatum, but it did not affect dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid. Pretreatment with MDL 72222 (25-100 μg/kg) dose-dependently attenuated cocaine-induced elevation of dopamine in both of the nuclei studied. Amphetamine elevated extracellular dopamine and reduced DOPAC and homovanillic acid equally in the nucleus accumbens and in the dorsal striatum. MDL 72222 also attenuated the amphetamine-induced elevation of extracellular dopamine concentration in both brain areas studied, but first at a dose of 100 μg/kg. The different potencies of the interactions of the 5-HT3 receptor antagonist with cocaine and amphetamine could be related to the different mechanisms by which these drugs primarily elevate extracellular dopamine.
Pharmacology & Toxicology 04/1996; 78(5):317 - 321.
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ABSTRACT: KANKAANPÄÄ, A., E. MERIRINNE, P. LILLSUNDE AND T. SEPPÄLÄ. The acute effects of amphetamine derivatives on extracellular serotonin and dopamine levels in rat nucleus accumbens. 〈Default ¶ Font>PHARMACOL BIOCHEM BEHAV 59(4) 1003–1009, 1998.—The acute effects of amphetamine derivatives on extracellular concentration of serotonin (5-HT) and dopamine in the nucleus accumbens were studied with in vivo microdialysis using conscious, freely moving rats. 5-HT, dopamine, and their major metabolites were measured by HPLC with electrochemical detection. Amphetamine (1.0–9.0 mg/kg) elevated dopamine levels considerably, but failed to affect the levels of 5-HT, except at the highest dose administered. 3,4-Methylenedioxyamphetamine (MDA, 1.0–9.0 mg/kg) and 3,4-methylenedioxymethamphetamine (MDMA, 1.0–9.0 mg/kg) elevated both 5-HT and dopamine levels dose dependently. The failure of 2,5-dimethoxy-4-methylamphetamine (DOM, 0.5–1.0 mg/kg) to affect the 5-HT levels suggests that extracellular levels of 5-HT play a minor role in hallucinogenic activity. The strong effects of MDA and MDMA on levels of 5-HT indicate that their actions on serotonergic mechanisms are different from those of the hallucinogens. In addition, methylenedioxyamphetamines may act via dopaminergic mechanisms similar to those of amphetamine.
Pharmacology Biochemistry and Behavior.
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ABSTRACT: γ-Hydroxybutyrate (GHB) is an increasingly popular drug of abuse that causes stimulation, euphoria, anxiolysis or hypnosis, depending on the dose used. Low doses of the drug are used recreationally, and also implicated in drug-facilitated sexual assaults. Because of the unusually steep dose–response curves, accidental GHB overdosing, leading to coma, seizures or death can occur. Being a controlled substance, GHB is often substituted with its non-scheduled precursors γ-butyrolactone (GBL) and 1,4-butanediol (BD), which are rapidly metabolized into GHB in the body. Here we describe an assay for GHB, GBL and BD in blood and/or urine samples. GHB and BD were extracted from diluted 200 μL aliquots of samples with t-butylmethylether (plus internal standard benzyl alcohol) in test tubes preloaded with NaCl. After acidification and centrifugation the solvent phase was transferred to a test tube preloaded with Na2SO4, incubated for 30 min, centrifuged again, and evaporated in vacuum. The residue was mixed with N-methyl-N-trimethylsilyl-trifluoroacetamide (MSTFA) in acetonitrile, and injected into a GC–MS. When analyzing GBL, the salting-out step was omitted, and analysis was performed with a GC–FID apparatus. As revealed by the validation data this procedure is suitable for quantitative determination of GHB and its precursors in blood and/or urine samples.
Forensic Science International.
