Drug Abuse Experiments on Primates
Spontaneous and precipitated withdrawal after chronic intragastric administration of gamma-hydroxybutyrate (GHB) in baboons
Weerts EM, Goodwin AK, Griffiths RR, Brown PR, Froestl W, Jakobs C, Gibson KM.
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected]
Psychopharmacology (Berl). 2005 May;179(3):678-87. Epub 2005 Jan 12.
RATIONALE: gamma-Hydroxybuyrate (GHB) is a current drug of abuse that may produce physical dependence.
OBJECTIVES: 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.
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