Spontaneous and precipitated withdrawal after chronic intragastric administration of gamma-hydroxybutyrate (GHB) in baboons.
BACKGROUND
gamma-Hydroxybuyrate (GHB) is a current drug of abuse that may produce physical dependence.


OBJECTIVE
The present study characterized the behavioral effects of chronic GHB in baboons (n = 4), and evaluated whether signs of withdrawal occurred (1) after administration of the GABA-B antagonist CGP36742 during chronic GHB administration (precipitated withdrawal) and (2) following discontinuation of chronic GHB administration (spontaneous withdrawal).


METHODS
Water (vehicle) and then GHB was continuously infused via intragastric (IG) catheters. GHB administration was initiated at 350 mg/kg per day, and the dose was increased by 100 mg/kg over 4 days to 750 mg/kg per day. Food pellets were available 20 h/day under a fixed ratio (FR5 or 10) schedule of reinforcement. Observation sessions and a 2-min fine motor task were conducted during vehicle and GHB administration. CGP36742 (32 and 56 mg/kg, IM) was administered during vehicle and chronic GHB administration. After a total of 32-36 days GHB administration was abruptly discontinued. Blood samples were collected during all interventions and analyzed for GHB content.


RESULTS
Chronic GHB decreased food-maintained behavior, disrupted performance of the fine motor task, and produced ataxia, muscle relaxation, tremors and jerks. At the end of GHB administration, plasma levels of GHB ranged from 486 to 2080 micromol/L. Administration of CGP36742 during chronic GHB administration produced increases in aggression, self-directed behaviors, vomit/retch, tremors and/or jerks, which is consistent with a precipitated withdrawal syndrome. Similar signs were observed when GHB administration was discontinued. Seizures were not observed.


CONCLUSIONS
These data indicate that chronic GHB administration produced physical dependence and that activation of the GABA-B receptor may be important for GHB physical dependence.
Weerts
Elise M
EM
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. eweerts@jhmi.edu
Goodwin
Amy K
AK
Griffiths
Roland R
RR
Brown
P Rand
PR
Froestl
Wolfgang
W
Jakobs
Cornelis
C
Gibson
K Michael
KM
D000818:Animals; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology; D058788:GABA-B Receptor Antagonists; D007263:Infusions, Parenteral / Q000379:methods*; D008297:Male; D009943:Organophosphorus Compounds / Q000494:pharmacology; D048530:Papio anubis; D018080:Receptors, GABA-B / Q000378:metabolism; D012978:Sodium Oxybate / Q000008:administration & dosage* / Q000097:blood*; D013375:Substance Withdrawal Syndrome / Q000097:blood*
D058788:GABA-B Receptor Antagonists; D009943:Organophosphorus Compounds; D018080:Receptors, GABA-B; C079148:(3-aminopropyl)(n-butyl)phosphinic acid; D012978:Sodium Oxybate