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


OBJECTIVE
The goal was to evaluate the physical dependence potential and behavioral effects of GBL.


METHODS
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.


RESULTS
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.


CONCLUSIONS
These data indicate that, like GHB, chronic GBL dosing produced physical dependence that likely involved the GABA-B receptor.
Goodwin
Amy K
AK
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Griffiths
Roland R
RR
Brown
P Rand
PR
Froestl
Wolfgang
W
Jakobs
Cornelis
C
Gibson
K Michael
KM
Weerts
Elise M
EM
D015107:4-Butyrolactone / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002408:Catheters, Indwelling; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005442:Flumazenil / Q000494:pharmacology; D005502:Food; D018756:GABA Antagonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D058788:GABA-B Receptor Antagonists; D008297:Male; D009048:Motor Skills / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009943:Organophosphorus Compounds / Q000494:pharmacology; D048530:Papio anubis; D011963:Receptors, GABA-A / Q000378:metabolism; D018080:Receptors, GABA-B / Q000378:metabolism; D012890:Sleep / Q000187:drug effects; D012978:Sodium Oxybate / Q000097:blood / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000097:blood / Q000378:metabolism / Q000503:physiopathology*; D019966:Substance-Related Disorders / Q000097:blood / Q000378:metabolism / Q000503:physiopathology*; D013997:Time Factors
D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D058788:GABA-B Receptor Antagonists; D009943:Organophosphorus Compounds; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; C079148:(3-aminopropyl)(n-butyl)phosphinic acid; D005442:Flumazenil; D012978:Sodium Oxybate; D015107:4-Butyrolactone