GHB for ALCOHOL CRAVINGS

GHB for ALCOHOL CRAVINGS

Clin Neuropharmacol. 2005 March/April;28(2):87-89.

 


Suppression of Craving for gamma-Hydroxybutyric Acid by Naltrexone Administration: Three Case Reports.

Caputo F, Vignoli T, Lorenzini F, Ciuffoli E, Re AD, Stefanini GF, Addolorato G, Trevisani F, Bernardi M; and the Alcoholism Treatment Study Group.

From the *”G. Fontana” Centre for the Study and Multidisciplinary Treatment of Alcohol Addiction, Department of Internal Medicine, Cardioangiology and Hepatology, Alma Mater Studiorum, University of Bologna, Bologna, Italy; daggerUnit for Addiction Treatment, Department of Primary Care, University of Bologna, Bologna, Italy; double daggerDepartment of Internal Medicine, Ospedale degli Infermi, Faenza, Italy; and section signInstitute of Internal Medicine, Catholic University of the Sacred Heart, Roma, Italy. parallelInstitute of Internal Medicine, Catholic University of the Sacred Heart, Roma: Ludovico Abenavoli, Lorenzo Leggio, Giovanni Gasbarrini. Unit for Addiction Treatment, Department of Primary Care, Bologna: Carla Bandini, Carmine D’Angelo, Sara Gubellini, Mariella Lofrumento, Roberta Piazzi, Rosa Alba Russo, Catia Leoni, Claudio Comaschi, Luisa Prata.

Gamma-Hydroxybutyric acid (GHB) is currently used to induce and maintain abstinence from alcohol. Cases of craving and desire to increase doses of GHB have been reported in both clinical trials and nonclinical self-administration. The enhancement of dopamine activity induced by GHB receptor activation might play a role in the euphoric effect and potential craving and the consequent abuse of this drug. Naltrexone (NTX), a mu-opioid antagonist, is effective in inducing and maintaining abstinence from alcohol, reducing relapses in heavy drinking and craving for alcohol in alcohol-dependent outpatients. Taking into account the alcohol antireward property of NTX, we tested its activity in reducing craving for GHB in 3 consecutive cases of alcoholics who manifested craving for this drug. In all patients the combination with NTX suppressed the craving for GHB. The anti-reward effect of NTX likely results from its interference with the GHB-induced dopamine release, leading to a partial blockade of the GHB reinforcing effect responsible of the craving for the drug. A combined therapy with GHB and NTX seems to be able to suppress craving for the former, thus improving the manageability and safety of treatment.

 

 

Drug Alcohol Depend. 2004 Sep 6;75(3):323-5.

 

Ethanol does not alter the binding of the gamma-hydroxybutyric acid (GHB) receptor ligand [3H]NCS-382 in the rat brain.

Mehta AK, Muschaweck NM, Ticku MK.

Department of Pharmacology, MC 7764, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio TX 78229-3900, USA.

We investigated the effect of ethanol on the binding of the gamma-hydroxybutyric acid (GHB) receptor ligand [3H]NCS-382 in the rat cerebral cortex and hippocampus. Ethanol (50-100 mM) did not alter the binding of [3H]NCS-382. Furthermore, acute (3g/kg, p.o.) as well as chronic (9-15 g/kg/day p.o. for 6 days) administration of ethanol also did not have any significant effect on the binding of [3H]NCS-382 in the rat cerebrocortical and hippocampal membranes. These observations suggest that ethanol does not interact directly with the GHB receptor in vitro or in vivo, and GHB receptor may not be involved in the pharmacological effects of ethanol.

 

 

Drug Saf. 2004;27(5):293-306.

 

The Xyrem risk management program.

Fuller DE, Hornfeldt CS, Kelloway JS, Stahl PJ, Anderson TF.

Orphan Medical Inc., Minnetonka, Minnesota 55305, USA.

Sodium oxybate, also known as gamma-hydroxybutyric acid (GHB), was discovered in 1960 and has been described both as a therapeutic agent with high medical value and, more recently, a substance of abuse. The naturally occurring form of this drug is found in various body tissues but has been studied most extensively in the CNS where its possible function as a neurotransmitter continues to be studied. Sodium oxybate has been approved in different countries for such varied uses as general anaesthesia, the treatment of alcohol withdrawal and addiction, and, most recently, cataplexy associated with narcolepsy. During the 1980s, easy access to GHB-containing products led to various unapproved uses, including weight loss, bodybuilding and the treatment of sleeplessness, sometimes with serious long-term effects. The availability of these unapproved and unregulated forms of the drug led to GHB and its analogues being popularized as substances of abuse and subsequent notoriety as agents used in drug-facilitated sexual assault, or ‘date rape’, eventually leading to the prohibition of GHB sales in the US. Legal efforts to control the sale and distribution of GHB and its analogues nearly prevented the clinical development of sodium oxybate for narcolepsy in the US. However, following extensive discussions with a variety of interested parties, a satisfactory solution was devised, including legislative action and the development of the Xyrem Risk Management Program. Amendments to the US Controlled Substances Act made GHB a schedule I drug, but also contained provisions that allow US FDA-approved products to be placed under schedule III. This unique, bifurcated schedule for sodium oxybate/GHB allowed the clinical development of sodium oxybate to proceed and, in July 2002, it was approved by the FDA as an orphan drug for the treatment of cataplexy in patients with narcolepsy as Xyrem(sodium oxybate) oral solution. To promote the safe use of sodium oxybate, as well as alleviate concerns over possible diversion and abuse following product approval, a proprietary restricted drug distribution system was created, called the Xyrem Success Program. Components of the program include a centralized distribution and dispensing system, a physician and patient registry, compulsory educational materials for patients and physicians, a specially trained pharmacy staff, a method for tracking prescription shipments, and an initial post-marketing surveillance program. The system has created a unique opportunity to provide both physician and patient education and ongoing patient counseling, promoting greater drug safety and enhanced patient compliance.

 

 

Psychopharmacology (Berl). 2004 Jul;174(2):220-7.

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Influence of reinforcer type and route of administration on gamma-hydroxybutyrate discrimination in rats.

Baker LE, Pynnonen D, Poling A.

Department of Psychology, Western Michigan University, Kalamazoo, MI 49008, USA. Lisa.Baker@wmich.edu

RATIONALE: Possible effects of reinforcer type on the results of drug discrimination studies have not been examined systematically, but different deprivation operations and differentially effective reinforcers might well influence outcomes. OBJECTIVE: Therefore, this study examined the influence of reinforcer (food or water) as well as route of administration (IP or IG) on gamma-hydroxybutyrate (GHB) discrimination. METHODS: Four separate groups of six rats were trained under a resetting fixed-ratio schedule to discriminate between 300 mg/kg GHB and vehicle under these conditions, then generalization tests were conducted with gamma-butyrolactone (GBL), 1,4-butanediol (1,4-BD), ethanol, and ethanol plus 150 mg/kg GHB. RESULTS: Food maintained significantly higher response rates than water, but there were no significant differences among the four training groups in response accuracy or sessions required to meet the discrimination criterion. Training conditions significantly affected the results of stimulus generalization tests. The IG-Water group was most sensitive to a lower dose of GHB, and only the IP-Water group failed to generalize to orally-administered GHB. Gamma-butyrolactone and 1,4-butanediol fully substituted in all except the IP-Food group. Ethanol did not fully substitute for GHB in any group, and the combination of GHB (150 mg/kg) and ethanol did not have additive effects. CONCLUSIONS: These results demonstrate that methodological variables during drug discrimination training can certainly influence the results of stimulus generalization. Future investigations into the behavioral and/or physiological mechanisms that account for these effects are warranted.

 

 

Brain Res. 2004 Jan 30;997(1):62-6.

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Gamma-hydroxybutyrate and ethanol depress spontaneous excitatory postsynaptic currents in dopaminergic neurons of the substantia nigra.

Brancucci A, Berretta N, Mercuri NB, Francesconi W.

Dipartimento di Fisiologia e Biochimica G. Moruzzi, Universita di Pisa, Pisa, Italy.

Gamma-hydroxybutyrate (GHB) has been shown to have therapeutical properties in various psychiatric disorders, especially in alcohol abuse, and to mimic different actions of ethanol at the cellular and system level. Using whole-cell patch-clamp recordings on brain slices of 21- to 25-day-old rats, the present study investigated the effects of GHB and ethanol on spontaneous excitatory postsynaptic currents (sEPSCs) in dopaminergic neurons of the substantia nigra pars compacta (SNc). sEPSCs are an index of glutamate release from the excitatory input to dopamine cells, which play a key role in different reward-related behaviors. We found that GHB and ethanol depressed both the frequency and the amplitude of sEPSCs. These effects were GABA(B)-independent and the GHB-induced depression was blocked by the GHB receptor antagonist 6,7,8,9-tetrahydro-5[H]benzocyclohepte-5-ol-4-ylidene acetic acid (NCS-382), pointing to a specific effect of this drug. The effects of ethanol were not affected by NCS-382. This study indicates that GHB and ethanol share the effect of reducing the efficacy of excitatory glutamatergic neurotransmission in the SNc by acting through different mechanisms.

 

 

Ann Neurol. 2003;54 Suppl 6:S3-12.

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GABA, gamma-hydroxybutyric acid, and neurological disease.

Wong CG, Bottiglieri T, Snead OC 3rd.

Institute of Medical Sciences, University of Toronto, Faculty of Medicine and Brain and Behavior Research Program, Hospital for Sick Children, Ontario, Canada.

gamma-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. GABA is converted from glutamic acid by the action of glutamic acid decarboxylase (GAD) of which two isoforms exist GAD65 and GAD67. GABA then is broken down, both within the cell and in the synaptic cleft by GABA transaminase to form succinic semialdehyde. In turn, succinic semialdehyde is converted either to succinic acid by succinic semialdehyde dehydrogenase or into gamma-hydroxybutyric acid (GHB) by succinic semialdehyde reductase. Because GABA modulates the majority of inhibition that is ongoing in the brain, perturbations in GABAergic inhibition have the potential to result in seizures. Therefore, the most common disorder in which GABA is targeted as a treatment is epilepsy. However, other disorders such as psychiatric disease, spasticity, and stiff-person syndrome all have been related to disorders of GABAergic function in the brain. This review covers the roles of GABAergic neurotransmission in epilepsy, anxiety disorders, schizophrenia, stiff-person syndrome, and premenstrual dysphoric disorder. In the final section of this review, the GABA metabolite GHB is discussed in terms of its physiological significance and its role in epilepsy, sleep disorders, drug and alcohol addiction, and an inborn error of GABA metabolism, succinic semialdehyde dehydrogenase deficiency.

 

 

Eur J Pharmacol. 2003 Jun 6;470(3):157-62.

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Interactions of gamma-hydroxy butyrate with ethanol and NCS 382.

Lamb RJ, Munn J, Duiker NJ, Coop A, Wu H, Koek W, France CP.

Department of Psychiatry, University of Texas Health Science Center at San Antonio, Mail Code 7792, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA. lamb@UTHSCSA.edu

We examined the effects of gamma-hydroxy butyrate (GHB) alone and in combination with either ethanol or NCS 382 [(2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene], a purported antagonist at the GHB receptor. These effects were examined on the responding of rats under a fixed-ratio (FR) 10 schedule of sugar solution (14%, w/v; 0.1 ml) presentation. GHB dose-relatedly decreased responding. When GHB was combined with ethanol, the effects of the two drugs were less than additive. NCS 382 did not antagonize the rate-decreasing effects of GHB. These observations are consistent with the notion that many of the behavioral actions of exogenously administered GHB result from GHB’s actions at sites other than the GHB receptor, and are inconsistent with the popular notion that the effects of GHB and ethanol are synergistic.

 

 

Toxicol Sci. 2003 Jun;73(2):270-8. Epub 2003 Apr 15.

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Characterization of the pharmacokinetic and pharmacodynamic interaction between gamma-hydroxybutyrate and ethanol in the rat.

Van Sassenbroeck DK, De Paepe P, Belpaire FM, Buylaert WA.

Heymans Institute of Pharmacology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, B-9000 Ghent, Belgium. diederick.vanassenbroeck@rug.ac.be

It has been reported that ethanol enhances the hypnotic effect of gamma-hydroxybutyrate (GHB). In order to clarify the nature of this interaction we studied the pharmacokinetics and pharmacodynamics of combinations of GHB and ethanol in rats. Intraperitoneal injections of the GHB precursor gamma-butyrolactone (300 mg/kg) together with ethanol (3000 mg/kg) (n = 4) resulted in a longer “sleeping time” than the sum of the individual times (n = 8). Pharmacokinetic analysis of GHB concentrations with a two-compartment model with Michaelis-Menten (M-M) elimination in rats receiving a bolus of GHB (400 mg/kg, i.v.) in addition to steady-state ethanol concentrations (300-3000 microg/ml) (n = 12) or saline (n = 15) showed no marked differences in the area under the curve. The nature of the pharmacodynamic interaction was studied using isobolographs and an interaction model for the loss of the startle and righting reflex and a reaction to a painful tail clamp in rats receiving combinations of steady state concentrations of ethanol (1000-3000 microg/ml) and GHB (200-1400 microg/ml). For the righting reflex, synergy was observed at high ethanol concentrations (>2000 microg/ml) and additivity at lower concentrations. For the startle reflex, it was antagonistic at ethanol concentrations below 1000 microg/ml, and additivity was seen at higher concentrations. For the tail clamp reaction, a slight but significant antagonism was found at all combined concentrations. It is concluded that ethanol prolongs the sleeping time induced by GHB in the rat, which may not be due to a pharmacokinetic interaction. Pharmacodynamic interactions between GHB and ethanol in the rat occur, and the nature varies with the reflex studied and the concentration of ethanol used.

 

Drug Alcohol Depend. 2003 May 1;70(1):85-91.

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Gamma-hydroxybutyric acid versus naltrexone in maintaining alcohol abstinence: an open randomized comparative study.

Caputo F, Addolorato G, Lorenzini F, Domenicali M, Greco G, del RE A, Gasbarrini G, Stefanini GF, Bernardi M.

Department of Internal Medicine, Cardioangiology and Hepatology, ‘G. Fontana’ Centre for the Study and Treatment of Alcohol Addiction, University of Bologna, Via Massarenti no. 9, Bologna, 40138, Italy. fabio-caputo@libero.it

Maintaining abstinence from alcohol is the main goal in the treatment of alcohol dependence. Naltrexone (NTX) and gamma-hydroxybutyric acid (GHB) have proved able to maintain alcohol abstinence in alcoholic subjects. The aim of our study was to evaluate the efficacy of GHB compared with NTX in maintaining abstinence from alcohol after 3 months of treatment. A total of 35 alcohol-dependent outpatients were randomly enrolled in two groups: the GHB group consisted of 18 patients treated with oral doses of GHB (50 mg/kg of body weight t.i.d) for 3 months; the NTX group consisted of 17 patients treated with oral doses of NTX (50 mg/day) for 3 months. At the end of the study, a statistically significant difference (P=0.02) was found in the number of abstinent patients between the GHB and the NTX groups. In patients who failed to be abstinent, no relapses in heavy drinking were observed in the NTX group, while in the GHB group all patients relapsed. The results of the present study show that GHB is more effective than NTX in maintaining abstinence from alcohol in a short-term treatment period; on the other hand, NTX confirmed its ability to reduce alcohol relapses.

 

 

South Med J. 2002 Aug;95(8):926-8.

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Self-medication with gamma-hydroxybutyrate to reduce alcohol intake.

Glisson JK, Norton J.

Department of Neurology and Psychiatry, University of Mississippi Medical Center, Jackson, USA.

We describe a 52-year-old man who self-medicated with gamma-hydroxybutyrate (GHB), a widely available illicit substance, to obtain a decrease in ethanol consumption. He successfully reduced his ethanol intake over a 3-month period, but he was unable to sustain abstinence. Although case reports on the use of GHB to induce euphoria have been published, this is the first report of GHB self-medication to facilitate ethanol abstinence. This report highlights the importance of considering GHB self-medication not only for euphoric and mood altering effects, but also as a potential treatment for ethanol intake reduction.

 

 

Alcohol Alcohol. 2002 Mar-Apr;37(2):128-31.

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Gamma-hydroxybutyric acid versus alcohol preference in Sardinian alcohol-preferring rats.

Serra S, Colombo G, Melis S, Vacca G, Carai MA, Gessa GL.

Neuroscienze S.c.a r.l., Via Palabanda 9, I-09123 Cagliari, Italy.

Previous experiments demonstrated that the selectively bred Sardinian alcohol-preferring (sP) rats possess a genetically based proclivity to consume pharmacologically relevant doses of gamma-hydroxybutyric acid (GHB). The present study was aimed at comparing the reinforcing properties of GHB and ethanol, measuring the propensity of sP rats to consume GHB and ethanol when both drugs were concomitantly available. Initially, two groups of sP rats (ethanol-naive and ethanol-experienced, respectively) were forced to consume GHB in order to help them discover the reinforcing properties, which could then prevail over the unpleasant taste of the GHB solution. Subsequently GHB (at concentrations increasing from 1 to 6% w/v) was offered in free choice with water and all rats consumed pharmacologically relevant amounts of GHB. Finally, under the free-choice regimen between GHB (presented to each rat at its preferred concentration), ethanol and water, daily ethanol intake averaged approximately 6 g/kg (i.e. the amount of ethanol usually consumed by sP rats), whereas GHB intake declined by approximately 75%. In the few rats showing a high intake of GHB, ethanol intake was not altered. No difference in GHB drinking behaviour was ever recorded between ethanol-naive and ethanol-experienced rats. The results of the present study demonstrate that freely available GHB is not capable of altering ethanol preference and consumption in sP rats and suggest that the postulated reciprocal substitutability of the two drugs does not completely include the reinforcing properties, at least in sP rats and when oral self-administration of GHB is considered. The results also provide a model of the low abuse liability of GHB observed in human alcoholics.

 

 

Alcohol Alcohol. 2002 Jan-Feb;37(1):67-73.

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Double-blind controlled trial of gamma-hydroxybutyrate and clomethiazole in the treatment of alcohol withdrawal.

Nimmerrichter AA, Walter H, Gutierrez-Lobos KE, Lesch OM.

Anton-Proksch-Institute Vienna, Dominikanerbastei 21/49, A-1010 Vienna, Austria.

The aim of this double-blind, comparative study was to assess the efficacy and safety of gamma-hydroxybutyrate (GHB) in ameliorating the symptoms of alcohol withdrawal. Newly admitted alcohol-dependent patients (n = 98) were randomized to receive either clomethiazole 1000 mg daily (CLO group) (n = 33), or 50 mg GHB/kg body wt (n = 33) or 100 mg GHB/kg body wt (n = 32). This dose was administered for 5 days, halved on day 6, and on days 7 and 8 only placebo was given. As CLO is available as capsules and GHB as syrup, a double-dummy method was used to try to ensure blindness. The groups were matched in terms of baseline demographic and alcohol-related variables. There was no difference between the three treatments in ratings of alcohol withdrawal symptoms nor requests for additional medication. After tapering off the active medication, there was no increase in withdrawal symptoms, indicating that physical tolerance did not develop to either GHB or CLO within the 5-day treatment period. The most frequently reported side-effect of GHB was transient vertigo, particularly after the evening double dose.

 

 

J Psychoactive Drugs. 2001 Apr-Jun;33(2):135-42.

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Long-term therapy using GHB (sodium gamma hydroxybutyrate) for treatment-resistant chronic alcoholics.

Maremmani I, Lamanna F, Tagliamonte A.

Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology, University of Pisa, Italy.

Thirty-five alcohol-dependent patients according to DSM-IV criteria who also met criteria for treatment resistance were treated with doses of gamma hydroxybutyrate (GHB) ranging between 25 and 100 mg/kg/die in an open one-year study. The results show that no patients discontinued the program during the first month of treatment. Sixty percent of these patients successfully completed the protocol; 11.4% showed complete abstinence (full responder patients); 14.3% strongly reduced their alcohol intake (partial responder patients) and 34.3% of the patients were still under treatment after one year. Forty percent of the patients were non-responders. The retention rate under treatment of the studied sample was statistically higher than that found during the last treatment of the same subjects. No significant differences were found between full responder and partial responder patients regarding changes in clinical features, alcohol intake or social adjustment. Patients still in treatment after one year significantly differed from non-responder patients on all the variables investigated. A six-times/daily fractionated administration of the GHB dose was the only significant predictor of the retention rate.

 

Drug Alcohol Depend. 1998 Dec 1;53(1):7-10.

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Gamma-hydroxybutyric acid in the treatment of alcoholism: dosage fractioning utility in non-responder alcoholic patients.

Addolorato G, Cibin M, Caputo F, Capristo E, Gessa GL, Stefanini GF, Gasbarrini G.

Institute of Internal Medicine, Catholic University Sacro Cuore, Rome, Italy.

Gamma-hydroxybutyric acid (GHB) has recently been introduced in clinical practice for alcoholism management, due to its utility in inducing abstinence from alcohol. In the present study we investigated the usefulness of greater dosage fractioning of GHB in non-responder alcoholics to the usual three administrations per day. A total of 154 alcoholics were admitted to the study and were treated with GHB (50 mg/Kg orally administered three times per day) for 8 weeks (phase 1); the patients who continued to drink alcohol in phase 1 were administered the same dose of GHB divided into six times per day for another 8 weeks (phase 2). Of the 154 patients, 115 completed phase 1; 78 (67.8%) of these began and maintained abstinence (group A) while 37 subjects (32.2%) continued to drink alcohol (group B) showing a craving significantly higher than group A at the end of phase 1 (P < 0.001); in these patients the major fractioning of the drug in phase 2 caused a significant reduction in craving (P < 0.005) and 26 (70.2%) began and maintained abstinence. Moreover no significant differences in final craving score between group A and B was observed. Within the limits of an open study, our data show that non-responder subjects to the conventional fractioning of GHB seem to benefit from the greater fractioning of the drug and seem to indicate the need for a slow-release form of GHB with a prolonged action.

 

Life Sci. 2002 Mar 22;70(18):2101-12.

 

Gamma-hydroxybutyrate increases tryptophan availability and potentiates serotonin turnover in rat brain.

Gobaille S, Schleef C, Hechler V, Viry S, Aunis D, Maitre M.

Laboratoire de Neurobiologie Moleculaire des Interactions Cellulaires, Faculte de Medecine and INSERM U-338, Strasbourg, France.

Gamma-hydroxybutyrate (GHB) is both a therapeutic agent and a recreative drug. It has sedative, anxiolytic and euphoric effects. These effects are believed to be due to GHB-induced potentiation of cerebral GABAergic and dopaminergic activities, but the serotonergic system might also be involved. In this study, we examine the effects of pharmacological doses of GHB on the serotonergic activity in rat brain. Administration of 4.0 mmol/kg i.p. GHB to rats induces an accumulation of tryptophan and 5-HIAA (5-hydroxyindole acetic acid) in the frontal cortex, striatum and hippocampus without causing significant change in the tissue serotonin content. In the extracellular space, GHB induced a slight decrease in serotonin release. The tryptophan and 5-HIAA accumulation induced by GHB is mimicked by the GHB receptor agonist para-chlorophenyl-transhydroxycrotonate (NCS-356) and blocked by NCS-382 (6,7,8,9-tetrahydro-5-[H]-benzocycloheptene-5-ol-4-ylidene acetic acid) a selective GHB receptor antagonist. GHB induces the accumulation of either a derivative of or [3H]-tryptophan itself in the extracellular space, possibly by increasing tryptophan transport across the blood-brain barrier. The blood content of certain neutral amino-acids, including tryptophan, is also increased by peripheral GHB administration. Some of the effect of GHB could be reproduced by baclofen and reduced by the GABAB antagonist CGP 35348. Taken together, these results indicate that the GHB-induced stimulation of tissue serotonin turnover may be due to an increase in tryptophan transport to the brain and in its uptake by serotonergic cells. As the serotonergic system may be involved in the regulation of sleep, mood and anxiety, the stimulation of this system by high doses of GHB may be involved in certain neuropharmacological events induced by GHB administration.

 

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