Gamma-hydroxybutyrate (GHB) is currently under investigation as a potential treatment for narcolepsy and alcohol dependence. Although GHB is currently classified as a Schedule I substance under the controlled substances act, illicit use of GHB, and its precursors gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD), is on the rise. The ability of GHB and its precursors to produce physical dependence has not been evaluated in controlled studies in humans or laboratory animals. The goal of the proposed research is to evaluate the physical dependence potential of GHB, GBL and 1,4-BD.
Two specific aims are proposed:
Aim 1 is to characterize the behavioral effects of GHB, GBL, 1,4-BD after acute and chronic intragastric drug administration in baboons.
Aim 2 is to characterize physical dependence and the withdrawal syndrome for GHB and its precursors GBL and 1,4-BD in baboons. First, GHB, GBL and 1,4-BD will be administered alone and then in combination with the GHB antagonist NCS-382. Changes in food-maintained behavior, observed behaviors, and fine motor coordination, when compared to controls, will be evaluated. Next a high dose of GHB, GBL or 1,4-BD will be administered chronically via continuous i.g. infusion and changes in food-maintained behavior, observed behaviors, and fine motor coordination, when compared to vehicle control, will be evaluated. Then, the GHB antagonist NCS-382 will be administered to baboons that have been chronically treated with GHB, GBL or 1,4-BD. Evidence for a precipitated withdrawal syndrome will be determined based on changes in food-maintained behavior, observed behaviors, and fine motor coordination when compared those same behaviors recorded during the vehicle baseline and following administration of the antagonist alone. Finally, chronic treatment with GHB, GBL or 1,4-BD will be abruptly discontinued. The presence and time-course of a spontaneous withdrawal syndrome will be determined based on comparison with the same behavioral measures determined during a) the vehicle baseline condition and b) during the chronic drug dosing condition. The results of these studies will provide critical information on the behavioral pharmacology and physical dependence potential of GHB and its precursors.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA014919-02
Application #
6523637
Study Section
Special Emphasis Panel (ZDA1-RXL-E (08))
Program Officer
Lynch, Minda
Project Start
2001-09-30
Project End
2004-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
2
Fiscal Year
2002
Total Cost
$327,000
Indirect Cost
Name
Johns Hopkins University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Goodwin, Amy K; Gibson, K Michael; Weerts, Elise M (2013) Physical dependence on gamma-hydroxybutrate (GHB) prodrug 1,4-butanediol (1,4-BD): time course and severity of withdrawal in baboons. Drug Alcohol Depend 132:427-33
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Weerts, Elise M; Ator, Nancy A; Kaminski, Barbara J et al. (2005) Comparison of the behavioral effects of bretazenil and flumazenil in triazolam-dependent and non-dependent baboons. Eur J Pharmacol 519:103-13
Weerts, Elise M; Goodwin, Amy K; Griffiths, Roland R et al. (2005) Spontaneous and precipitated withdrawal after chronic intragastric administration of gamma-hydroxybutyrate (GHB) in baboons. Psychopharmacology (Berl) 179:678-87