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GHB, benzodiazepine GABA-A and GABA-B receptor agonists and antagonists in non-dependent, GHB- dependent and GHB-withdrawn subjects.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

Comparison of the behavioral effects of bretazenil and flumazenil in triazolam-dependent and non-dependent baboons.

Weerts EM, Ator NA, Kaminski BJ, Griffiths RR.

Johns Hopkins University School of Medicine, Department of Psychiatry and Behavioral Sciences, MD 21224, USA. eweerts@jhmi.edu

Eur J Pharmacol. 2005 Sep 5;519(1-2):103-13

Behavioral effects of the benzodiazepine receptor partial agonist bretazenil were compared with those of the benzodiazepine receptor antagonist flumazenil under conditions in which three baboons received continuous intragastric (i.g.) infusion of vehicle and then continuous i.g. infusion of triazolam (1.0 mg/kg/day). In each condition, acute doses of flumazenil (0.01-3.2 mg/kg) and bretazenil (0.01-10.0 mg/kg) were administered every 2 weeks (beginning after 30 days of treatment in the triazolam-dependent condition). Food pellets were available during daily 20-h sessions. Following test injections, 60-min behavioral observations were conducted followed by a fine motor assessment. During chronic vehicle administration, neither drug produced changes in observed behaviors. Bretazenil increased pellets earned and time to complete the fine-motor task (10.0 mg/kg dose). During chronic triazolam dosing, both bretazenil and flumazenil precipitated benzodiazepine withdrawal syndromes, characterized by vomiting, tremors/jerks, and a decrease in pellets earned. Thus, bretazenil can function as an antagonist under conditions of benzodiazepine physical dependence.

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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