Johns Hopkins University, Baltimore, MD

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Stop Animal Exploitation NOW!
S. A. E. N.
"Exposing the truth to wipe out animal experimentation"

Government Grants Promoting Cruelty to Animals

Johns Hopkins University, Baltimore, MD

ELISE M. WEERTS - Primate Testing - 2007

Grant Number: 5R01DA014919-05 $354,138
Project Title: Behavioral Pharmacology and GHB Physical Dependence
PI Information: Name Email Title
  WEERTS, ELISE M. eweerts@jhmi.edu ASSOCIATE PROFESSOR

Abstract: DESCRIPTION (provided by applicant): Gamma-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, Gamma-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GHB, benzodiazepine GABA-A and GABA-B receptor agonists and antagonists in non-dependent, GHB- dependent and GHB-withdrawn subjects.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 evaluated. These studies will provide critical information on the behavioral pharmacology and dependence-producing effects of GHB.

Public Health Relevance:
This Public Health Relevance is not available.

Thesaurus Terms:
baboon, behavior, psychopharmacology, receptor
acid, alcohol, ataxia, barbiturate, benzodiazepine, benzodiazepine receptor, binding site, brain, butyrolactone, central nervous system depressant, cocaine, conditioning, drug abuse, drug screening /evaluation, enzyme, food, food processing /preparation, human, model, muscle relaxation, narcolepsy, opioid receptor, pharmacology, quality of life, rape, receptor expression, sedative /hypnotic, sensory depression, syndrome, triazolam

Institution: JOHNS HOPKINS UNIVERSITY
  W400 Wyman Park Building
  BALTIMORE, MD 212182680
Fiscal Year: 2007
Department: PSYCHIATRY AND BEHAVIORAL SCIENCES
Project Start: 30-SEP-2001
Project End: 31-MAR-2011
ICD: NATIONAL INSTITUTE ON DRUG ABUSE
IRG: BRLE

Chronic intragastric administration of gamma-butyrolactone produces physical dependence in baboons.

Goodwin AK, Griffiths RR, Brown PR, Froestl W, Jakobs C, Gibson KM, Weerts EM.

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Psychopharmacology (Berl). 2006 Nov;189(1):71-82. Epub 2006 Sep 20

RATIONALE: Abuse of gamma-hydroxybutyrate (GHB) and its precursors is a public health concern. Gamma-butyrolactone (GBL) is found in commercially available products and, when ingested, is metabolized to GHB. OBJECTIVE: The goal was to evaluate the physical dependence potential and behavioral effects of GBL. METHODS: Vehicle and then GBL were administered continuously (24 h per da y) in baboons (Papio anubis, n=5) via intragastric catheters. GBL dosing was initiated at 100 mg/kg/day and then progressively increased stepwise by increments of 100 mg/kg to a final dose of 600 mg/kg. The number of food pellets earned, fine-motor task performance, and observed behaviors were used as dependent measures. Precipitated withdrawal was evaluated after administration of GABA-B and benzodiazepine receptor antagonists during chronic GBL dosing (400-600 mg/kg). Spontaneous withdrawal was evaluated after discontinuation of chronic GBL 600 mg/kg. Blood GHB levels were determined during chronic dosing of each GBL dose by isotope dilution assay.

RESULTS: Chronic GBL dose-dependently decreased food-maintained behavior, disrupted performance on the fine-motor task, and produced signs of sedation and muscle relaxation. The GABA-B antagonist SGS742 [56 mg/kg, intramuscular (IM)] precipitated a withdrawal syndrome, whereas the benzodiazepine antagonist flumazenil (5 mg/kg, IM) produced little or no effect. Signs of physical dependence were also demonstrated when chronic GBL dosing was discontinued. Analysis of plasma indicated GBL was metabolized to GHB; levels were 825 to 1,690 micromol l(-1) GHB and 2,430 to 3,785 micromol l(-1) GHB after week 1 of 400 and 600 mg/kg/day, respectively.

CONCLUSIONS: These data indicate that, like GHB, chronic GBL dosing produced physical dependence that likely involved the GABA-B receptor.

Please email: ELISE M. WEERTS, eweerts@jhmi.edu to protest the inhumane use of animals in this experiment. We would also love to know about your efforts with this cause: saen@saenonline.org

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Rats, mice, birds, amphibians and other animals have been excluded from coverage by the Animal Welfare Act. Therefore research facility reports do not include these animals. As a result of this situation, a blank report, or one with few animals listed, does not mean that a facility has not performed experiments on non-reportable animals. A blank form does mean that the facility in question has not used covered animals (primates, dogs, cats, rabbits, guinea pigs, hamsters, pigs, sheep, goats, etc.). Rats and mice alone are believed to comprise over 90% of the animals used in experimentation. Therefore the majority of animals used at research facilities are not even counted.

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