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

Goodwin, Amy K.; Griffiths, Roland R.; Brown, Paul; Froestl, Wolfgang; Jakobs, Cornelis; Gibson, K. Michael; Weerts, Elise M.

doi:10.1007/s00213-006-0534-9

Cited by 21 publications

(40 citation statements)

References 44 publications

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“…Furthermore, chronic administration of GHB caused cross-tolerance to baclofen, but not to flunitrazepam (a GABA A agonist) [23]. Similarly, withdrawal from GHB has been shown to be a GABA B -mediated effect in primates [15]. These data all point to baclofen being effective at replicating many effects of GHB, and thus being a putative treatment for GHB withdrawal.…”

Section: Ghb and Gaba Bmentioning

confidence: 95%

“…Lack of activation of GABA A receptors by GHB may explain why benzodiazepines are unsatisfactory [14]. In contrast, blocking the GABA B receptor was recently shown to trigger GHB withdrawal in primates [15] indicating a GABA B agonist could be a more specific treatment for GHB withdrawal. In this report, we describe the successful treatment of a patient with severe GHB withdrawal symptoms using the GABA B receptor agonist, baclofen.…”

Section: Introductionmentioning

confidence: 99%

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Baclofen and Gamma-Hydroxybutyrate Withdrawal

LeTourneau

Hagg

2008

Neurocrit Care

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Section: Ghb and Gaba Bmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Baclofen and Gamma-Hydroxybutyrate Withdrawal

LeTourneau

Hagg

2008

Neurocrit Care

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“…GBL (GHB precursor) was administered to baboons in an increasing dosing regimen (100e600 mg/kg). GABA B and benzodiazepine receptor antagonists (SGS742 and flumazenil, respectively) were used to precipitate withdrawal (Goodwin et al, 2006). Cessation of GBL-administration resulted in increased scores on withdrawal outcome measures (e.g., fine-motor tasks, lip smacking, grooming, lip drooping, tremors), demonstrating that GHB administration alone can produce physical dependence.…”

Section: Can Ghb Induce a State Of Dependence?mentioning

confidence: 99%

Preclinical assessment of abuse liability of biologics: In defense of current regulatory control policies

Gauvin

Zimmermann

Baird

2015

Regulatory Toxicology and Pharmacology

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“…Both GHB and the GHB pro-drug gamma-butyrolactone (GBL) produced physical dependence in baboons in previous studies, and administration of a GABA-B antagonist precipitated a withdrawal syndrome (Goodwin et al, 2006; Weerts et al, 2005). Withdrawal symptoms included vomiting, retching, tremors, jerks, postural changes, increased self-directed behavior, increased aggression, decreased operant responding for food pellets, and increased duration to complete a fine-motor task.…”

Section: Introductionmentioning

confidence: 96%

Physical dependence on gamma-hydroxybutrate (GHB) prodrug 1,4-butanediol (1,4-BD): Time course and severity of withdrawal in baboons

Goodwin

Gibson

Weerts

2013

Drug and Alcohol Dependence

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Background 1,4-butanediol (1,4-BD) is a gamma-hydroxybutyrate (GHB) pro-drug, with multiple commercial uses, and a drug of abuse. Although there are case reports of a withdrawal syndrome following 1,4-BD use, no studies have evaluated the physical dependence potential of 1,4-BD and characterized the time course of withdrawal. Methods Vehicle and then 1,4-BD were administered continuously 24 h/day via intragastric catheters in male baboons (Papio anubis, n=3). Dosing was initiated at 100 mg/kg and increased by 100 mg/kg/day to 400 mg/kg. After a stabilization period, doses of 500 and then 600 mg/kg/day were each maintained for 3-4 weeks. Plasma levels of 1,4-BD and GHB were determined for each dose condition. Physical dependence was assessed via administration of a GABA-B antagonist (precipitated withdrawal test) during administration of the 600 mg/kg dose and via abrupt termination of chronic 1,4-BD administration (spontaneous withdrawal test). Outcome measures included the number of food pellets earned, performance on a fine-motor task, observed behaviors, and plasma levels of GHB and 1,4-BD. Results Following maintenance of 1,4-BD 600 mg/kg for 3 weeks, the number of food pellets earned was significantly decreased. At the end of chronic 1,4-BD dosing, the levels of GHB in plasma ranged from 1290- 2300 μmol/L and levels of 1,4-BD in plasma ranged from 13.1 -37.9 μmol/L. Signs of physical dependence were observed following precipitated and spontaneous withdrawal tests. Seizures were not observed. Conclusions These data indicate chronic 1,4-BD produced physical dependence in baboons and the withdrawal syndrome can be characterized as mild to intermediate.

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

Abstract: These data indicate that, like GHB, chronic GBL dosing produced physical dependence that likely involved the GABA-B receptor.

Cited by 21 publications

References 44 publications

Baclofen and Gamma-Hydroxybutyrate Withdrawal

Baclofen and Gamma-Hydroxybutyrate Withdrawal

Preclinical assessment of abuse liability of biologics: In defense of current regulatory control policies

Physical dependence on gamma-hydroxybutrate (GHB) prodrug 1,4-butanediol (1,4-BD): Time course and severity of withdrawal in baboons

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