_-hydroxybutyrate (GHB) is a drug of abuse with potent CMS depressant effects. Chronic administration of GHB can produce physical dependence and the withdrawal syndrome reportedly resembles withdrawal from classic sedative-hypnotics (benzodiazepines and alcohol). The mechanisms underlying the pharmacological actions of GHB appear to involve multiple systems including GHB,_amma-aminobutyric acid CGABA), and opioid.
Three specific aims are proposed to further characterize the behavioral pharmacology and physical dependence potential of GHB.
Aim 1 will evaluate the effects of dose and duration of GHB administration on development of physical dependence. A range of GHB doses will each be administered for the same duration and then a GABA-B antagonist will be administered. Signs of withdrawal and effects on food-maintained behavior will be characterized. Second, GHB dose will be held constant and the length of exposure will be varied. The severity of antagonist-precipitated withdrawal behaviors as a function of the length of GHB administration will be determined.
Aim 2 will examine the behavioral effects GHB, benzodiazepine GABA-A and GABA-B receptor agonists and antagonists in non-dependent,GHB- dependent and GHB-withdrawn subjects. The ability of each drug to potentiate GHB effects, precipitate withdrawal and/or alleviate GHB withdrawal will be determined. These studies will determine if chronic GHB administration produces functional changes in GHB, GABA-A and/or GABA-B receptors as evidenced by shifts in the drug dose effect functions.
Aim 3 will characterize the reinforcing effects and pattern of self- administration of GHB, and pro-drugs gamma-butyrolactone(GBL) and 1,4-butendiol (1,4-BD) using a 24-hr self-injection procedure. The relative reinforcing efficacy of each drug will be compared, as measured by the maximum work output or """"""""breaking point"""""""" completed for each injection under a progressive ratio procedure. Physical dependence in the context of self-injection of GHB, GBL and 1,4-BD will also be evalauted. These studies will provide critical information on the behavioral pharmacology and dependence-producing effects of GHB.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
3R01DA014919-05S1
Application #
7498868
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Lynch, Minda
Project Start
2001-09-30
Project End
2011-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
5
Fiscal Year
2007
Total Cost
$17,200
Indirect Cost
Name
Johns Hopkins University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
001910777
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
Goodwin, Amy K; Kaminski, Barbara J; Griffiths, Roland R et al. (2011) Intravenous self-administration of ýý-hydroxybutyrate (GHB) in baboons. Drug Alcohol Depend 114:217-24
Goodwin, A K; Brown, P R; Jansen, E E W et al. (2009) Behavioral effects and pharmacokinetics of gamma-hydroxybutyrate (GHB) precursors gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) in baboons. Psychopharmacology (Berl) 204:465-76
Goodwin, Amy K; Griffiths, Roland R; Brown, P Rand et al. (2006) Chronic intragastric administration of gamma-butyrolactone produces physical dependence in baboons. Psychopharmacology (Berl) 189:71-82
Struys, Eduard A; Verhoeven, Nanda M; Jansen, Erwin E W et al. (2006) Metabolism of gamma-hydroxybutyrate to d-2-hydroxyglutarate in mammals: further evidence for d-2-hydroxyglutarate transhydrogenase. Metabolism 55:353-8
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
Goodwin, Amy K; Froestl, Wolfgang; Weerts, Elise M (2005) Involvement of gamma-hydroxybutyrate (GHB) and GABA-B receptors in the acute behavioral effects of GHB in baboons. Psychopharmacology (Berl) 180:342-51