title: Physical dependence on gamma-hydroxybutrate (GHB) prodrug 1,4-butanediol (1,4-BD): time course and severity of withdrawal in baboons.
abstract: 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 100mg/kg/day to 400mg/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 to 2300 μmol/L and levels of 1,4-BD in plasma ranged from 13.1 to 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.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, USA. Electronic address: Goodwin@jhu.edu.
authors.forename: Amy K
authors.initials: AK
authors.lastname: Goodwin
authors.forename: K Michael
authors.initials: KM
authors.lastname: Gibson
authors.forename: Elise M
authors.initials: EM
authors.lastname: Weerts
mesh_terms: D000818:Animals; D002072:Butylene Glycols / Q000008:administration & dosage / Q000097:blood*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D007263:Infusions, Parenteral; D008297:Male; D048530:Papio anubis; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism*; D012720:Severity of Illness Index; D012978:Sodium Oxybate / Q000097:blood*; D013375:Substance Withdrawal Syndrome / Q000097:blood* / Q000175:diagnosis* / Q000523:psychology; D019966:Substance-Related Disorders / Q000097:blood / Q000175:diagnosis / Q000523:psychology; D013997:Time Factors
chemical_list: D002072:Butylene Glycols; D011355:Prodrugs; D012978:Sodium Oxybate; C039681:1,4-butanediol
keywords: GABA-B receptor antagonists; GHB; Operant behavior; Withdrawal
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