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Behavioral effects and pharmacokinetics of gamma-hydroxybutyrate (GHB) precursors gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) in baboons

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Abstract

Rationale

Gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) are prodrugs for gamma-hydroxybutyrate (GHB). Like GHB, GBL and 1,4-BD are drugs of abuse, but their behavioral effects may differ from GHB under some conditions.

Objectives

The first study compared the behavioral effects of GBL (32–240 mg/kg) and 1,4-BD (32–240 mg/kg) with each other and to effects previously reported for GHB (32–420 mg/kg). A second study determined GHB pharmacokinetics following intragastric administration of GHB, GBL, and 1,4-BD.

Methods

Operant responding for food, observed behavioral effects, and a fine-motor task occurred at multiple time intervals after administration of drug or vehicle. In a separate pharmacokinetics study, blood samples were collected across multiple time points after administration of GHB, GBL, and 1,4-BD.

Results

Like GHB, GBL, and 1,4-BD impaired performance on the fine-motor task, but the onset of motor impairment differed across drugs. GBL and 1,4-BD dose dependently decreased the number of food pellets earned, but at lower doses than previously observed for GHB. Similar to GHB, both GBL and 1,4-BD produced sedation, muscle relaxation, gastrointestinal symptoms, and tremors/jerks. Administration of GBL and 1,4-BD produced higher maximum concentrations of GHB with shorter times to maximum concentrations of GHB in plasma when compared to GHB administration.

Conclusions

GBL and 1,4-BD produced behavioral effects similar to those previously reported with GHB and the time course of effects were related to blood levels of GHB. Given their higher potency and faster onset of effects, the abuse liability of GBL and 1,4-BD may be greater than GHB.

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Acknowledgments

This research was supported by the National Institutes on Drug Abuse R01 DA 14919 (E.M.W.) and NS 40270 (K.M.G.). Protocols were approved by the Johns Hopkins University Animal Care and Use Committee and followed the Guide for Care and Use of Laboratory Animals (National Academy of Sciences, 1996). Facilities were maintained in accordance with USDA and AALAC standards.

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Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD, USA

    A. K. Goodwin & E. M. Weerts

  2. Departments of Molecular and Comparative Pathobiology and Surgery, School of Medicine, Johns Hopkins University, Baltimore, MD, USA

    P. R. Brown

  3. Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands

    E. E. W. Jansen & C. Jakobs

  4. Departments of Pediatrics, Pathology and Human Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    K. M. Gibson

  5. Behavioral Biology Research Center, Johns Hopkins Bayview, 5510 Nathan Shock Dr./Suite 3000, Baltimore, MD, 21224, USA

    A. K. Goodwin

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  1. A. K. Goodwin
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  2. P. R. Brown
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  3. E. E. W. Jansen
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  4. C. Jakobs
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  5. K. M. Gibson
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  6. E. M. Weerts
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Correspondence to A. K. Goodwin.

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Supported by: NIH R01 DA 14919 and NS 40270.

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Goodwin, A.K., Brown, P.R., Jansen, E.E.W. et al. Behavioral effects and pharmacokinetics of gamma-hydroxybutyrate (GHB) precursors gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) in baboons. Psychopharmacology 204, 465–476 (2009). https://doi.org/10.1007/s00213-009-1477-8

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  • DOI: https://doi.org/10.1007/s00213-009-1477-8

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