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Stop Animal Exploitation NOW!
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"Exposing the truth to wipe out animal experimentation"

Government Grants Promoting Cruelty to Animals

University of Texas at San Antonio, San Antonio, TX

CHARLES P. FRANCE - Primate Testing - 2006

Grant Number: 5R01DA009157-12
Project Title: Discriminative effects of benzodiazepine withdrawal
PI Information: PROFESSOR CHARLES P. FRANCE,  [email protected]

Benzodiazepines and related gamma-amino butyric acid (GABA)A modulators are used widely for their anxiolytic, hypnotic and anti- convulsant effects. These same compounds are also abused, both alone and in combination with other classes of drugs (e.g., opioids), and long- term use of benzodiazepines can lead to clinically significant physical dependence. The GABAA receptor complex is the site of action of other drugs of abuse (e.g., ethanol) and GABAergic systems, in general, are thought to indirectly modulate the effects of still other drugs of abuse (e.g., cocaine). Much has been learned over the past 10 years from molecular studies on GABA receptors, yet little of this knowledge has been applied to studies in behaving organisms, particularly with regard to GABA neurobiology and substance abuse. Procedures have been developed under this grant for studying discriminative stimulus effects of GABAA modulators in rhesus monkeys and studies proposed in this application will use those procedures to investigate the neurobiology of drugs that vary in their actions on GABAergic systems. Studies under Aim 1ill will compare GABAergic and other drugs for their ability to prevent and reverse benzodiazepine withdrawal and also to mimic the subjective (discriminative) effects of benzodiazepine in normal subjects. A parallel study (Aim II) will establish a discrimination with flumazenil in monkeys treated daily with the a1-s3lective positive modulator zolpidem to test whether this widely-prescribed sedative/hypnotic produces dependence that can be differentiated from that produced by diazepam.Neuroactive steroids will be studied under Aim III to see whether th eye modify the behavioral effects of other compounds that act at the GABAA receptor complex. This study is founded on positive preliminary data with pregnanolone and a literature showing that neuroactive steroids uncouple benzodiazepine receptors from the GABAA receptor complex in vitro. Blind evaluation of compounds will continue the auspices of the Drug Evaluation Committee of the College on Drug Dependence under Aim IV. Collectively, these studies will provide important quantitative information on the nature of drug/receptor and drug/drug interactions for GABAA modulators and related drugs. These data will promote an understanding of GABAergic neurotransmission and abuse liability for a variety of clinically relevant compounds.

Thesaurus Terms:

benzodiazepine, drug addiction, drug screening /evaluation, drug withdrawal, psychopharmacology GABA receptor, benzodiazepine receptor, diazepam, drug addiction antagonist, drug interaction, drug tolerance, midazolam, neural transmission, neurobiology, neurohormone, receptor coupling, receptor sensitivity, sedative /hypnotic, substance abuse related behavior Macaca mulatta, behavior test

Fiscal Year: 2006
Project Start: 15-MAR-1995
Project End: 31-JAN-2008

Efficacy and the Discriminative Stimulus Effects of Negative GABAA Modulators, or Inverse Agonists, in Diazepam-Treated Rhesus Monkeys

Lance R. McMahon, Lisa R. Gerak, and Charles P. France
Departments of Pharmacology (L.R.M., L.R.G., C.P.F.) and Psychiatry (C.P.F.), the University of Texas Health Science Center at San Antonio, San Antonio, Texas

Received February 17, 2006; accepted May 15, 2006.
JPET 318:907-913, 2006

Subjects. One female and five male adult rhesus monkeys were housed individually on a 14-h light/10-h dark schedule, were maintained at 95% free-feeding weight (range 8.0-11 kg) with a diet comprising primate chow (Harlan Teklad, High Protein Monkey Diet; Harlan Teklad, Madison, WI), fresh fruit, and peanuts, and were provided water in the home cage. Monkeys received 5.6 mg/kg/day diazepam, were trained to discriminate flumazenil, and had received GABAA ligands in previous studies (McMahon and France, 2005 ). The animals used in these studies were maintained in accordance with the Institutional Animal Care and Use Committee, The University of Texas Health Science Center at San Antonio, San Antonio, TX, and with the 1996 Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources on Life Sciences, National Research Council, National Academy of Sciences).

Apparatus. During experimental sessions, monkeys were seated in chairs (model R001; Primate Products, Miami, FL) that provided restraint at the neck and were placed in ventilated, sound-attenuating chambers equipped with two response levers, stimulus lights, and a food cup to which pellets (Bio-Serv, Frenchtown, NJ) could be delivered from a dispenser. An interface (MedAssociates, St. Albans, VT) connected the chambers to a computer that controlled and recorded experimental events.
Discrimination Procedure. Monkeys drank a solution containing diazepam (5.6 mg/kg) 3 h before experimental sessions consisting of multiple 15-min cycles. Each cycle comprised a 10-min timeout period, during which responses had no programmed consequence, followed by a 5-min response period, during which green stimulus lights were illuminated and a fixed ratio (FR) 5 schedule of food presentation was in effect. A maximum of 10 food pellets was available during a cycle; when the maximal number of food pellets was obtained in <5 min, the remainder of the response period was a timeout. The selection of vehicle- and flumazenil-appropriate levers varied among monkeys and remained the same for an individual throughout the study. Responding on the incorrect lever reset the response requirement on the correct lever.

Please email:  CHARLES P. FRANCE,  [email protected]  to protest the inhumane use of animals in this experiment. We would also love to know about your efforts with this cause: [email protected]

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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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