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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

NANCY A. ATOR - Primate Testing - 2007

Grant Number: 5R01DA004133-21         $348,813
Project Title: Functional Analysis of GABAerglc Sedative/Anxiolytics
PI Information: Name Email Title
  ATOR, NANCY A. ator@jhmi.edu PROFESSOR

Abstract: DESCRIPTION (provided by applicant): Anxiolytics and sedative-hypnotics are among the most widely prescribed of all psychoactive medications. Misuse, abuse, and physiological dependence associated with their use are of continuing concern. Over the past 20 years, drug discrimination analysis has provided an animal model for classification of the subjective effects of psychoactive drugs relevant to preclinical drug abuse liability assessments. It also has proven uniquely sensitive and selective as a behavioral assay for examining functional in vivo relevance of novel chemical structures, novel receptor binding profiles, and novel cellular activity for centrally acting drugs. The aims of the present application are predicated on the evidence from our previous work that drug discrimination analysis is uniquely powerful for analyzing the relationship between the biochemical and behavioral effects of psychoactive drugs. Specific Aim 1 is to characterize the relation between in vitro profiles for GABAA modulators that bind the benzodiazepine (Bz) site and their in vivo profiles of discriminative stimulus effects. Advances in understanding the structure of the GABAA-receptor complex have led to development of novel compounds that preferentially bind GABAA receptor subtypes, have lower efficacy in modulating GABA, or both. The hope is that such compounds will be better treatments for anxiety and sleep disorders, produce less tolerance with chronic use, and have less abuse liability and dependence potential. The in vitro work on these compounds provides a platform for making predictions about specific behavioral effects, which we will test. Specific Aim 2 is to test predictions about the relation between chronic Bz administration and the effects of glutamatergic ligands administered during and after the chronic Bz. In vitro data and data from studies of convulsant thresholds in mice strongly suggest that the withdrawal syndrome that emerges after discontinuation of chronic Bz use may be due less to reduced GABAergic functioning as to overfunctioning of the ionotropic glutamatergic system. The proposed studies will exploit the sensitivity of drug discrimination training for neuronal substrates of drug action to explore the predictions of the glutamate hypothesis of the Bz withdrawal syndrome. These data will be critical to our understanding of mechanisms of Bz dependence and their relation to Bz tolerance. One of the studies under Specific Aim 2 will extend our work on physiological dependence on Bz ligands to provide a direct test of the use of non-competitive antagonists for the N-methyl-D-aspartate receptor to ameliorate Bz withdrawal.

Public Health Relevance:
T
his Public Health Relevance is not available.

Thesaurus Terms:
GABA receptor, benzodiazepine, benzodiazepine receptor, drug addiction, glutamate, pentobarbital, psychopharmacology, sedative /hypnotic, tranquilizer
NMDA receptor, diazepam, discrimination learning, drug withdrawal, ketamine, lorazepam, neuropharmacology, operant conditioning, psychological reinforcement, receptor binding, substance abuse related behavior
baboon, behavior test, behavioral /social science research tag, laboratory rat

Institution: JOHNS HOPKINS UNIVERSITY
  W400 Wyman Park Building
  BALTIMORE, MD 212182680
Fiscal Year: 2007
Department: PSYCHIATRY AND BEHAVIORAL SCIENCES
Project Start: 01-MAY-1992
Project End: 30-JUN-2009
ICD: NATIONAL INSTITUTE ON DRUG ABUSE
IRG: IFCN

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. ator@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: NANCY A. ATOR, ator@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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