University of Texas at San Antonio, San Antonio, TX

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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

University of Texas at San Antonio, San Antonio, TX

CHARLES P. FRANCE - Primate Testing - 2006

Grant Number: 5R01DA005018-20
Project Title: Discriminative stimulus effects of opioid withdrawal
PI Information: PROFESSOR CHARLES P. FRANCE, france@uthscsa.edu 

Abstract: DESCRIPTION (provided by applicant): Opioid abuse remains a significant public health problem despite continued research and the availability of new drugs for treatment. In addition to the ongoing problem of heroin abuse is a growing concern about the recreational use of potent, efficacious opioid analgesics such as oxycodone. This is a competing continuation of a grant that has developed novel drug discrimination procedures for studying opioid dependence and withdrawal; those procedures have been used in concert with other measures of opioid activity to examine a range of pharmacologic and behavioral parameters that contribute to the abuse and dependence liability of morphine and related opioids. Studies proposed in this renewal exploit these discrimination procedures to focus on the neuropharmacology of opioid dependence and withdrawal as well as the role of opioid withdrawal in drug taking. AIM I characterizes the neuropharmacology of opioid withdrawal in rhesus monkeys by examining monoaminergic drugs for their ability to modulate discriminative stimulus and other effects (directly observable and HPA activation) of opioid withdrawal in monkeys. These studies build upon published data from this laboratory showing that dopamine uptake blockers attenuate discriminative stimulus and not other indices of withdrawal. AIM II combines a well-established drug discrimination procedure with i.v. self administration in monkeys to examine the effects of withdrawal on self administration of cocaine and mu agonists that vary in efficacy. AIM III provides a comprehensive set of descriptive data from rhesus monkeys on the behavioral pharmacology of several prescription opioids that are believed to be increasingly abused, including oxycodone, oxymorphone, hydrocodone and hydromorphone. While it is assumed that these opioids have exclusively morphine-like actions, there are limited data available to support that view. The four opioids will be compared to morphine using measures of drug discrimination, antinociception, and respiration. Finally, studies under AIM IV investigate the relationship between opioid tolerance and dependence, on the one hand, and constitutive activity and inverse agonism at opioid receptors, on the other hand, using drug discrimination procedures in pigeons with varying degrees of morphine tolerance and dependence. These studies should provide insight to the lasting neurobiological changes that can occur as a consequence of chronic drug treatment. Collectively these studies will apply drug discrimination and other procedures to important question regarding opioid dependence, withdrawal and abuse and will provide information that will facilitate the development of new therapeutics for opioid abuse.

Thesaurus Terms:
discrimination learning, drug withdrawal, neuropharmacology, opiate alkaloid, psychopharmacology, substance abuse related behavior
dopamine transporter, drug habituation, drug tolerance, ligand, naltrexone, neuroendocrine system, opioid receptor, pharmacokinetics, self medication
Macaca mulatta, behavioral /social science research tag, pigeon

Institution:
UNIVERSITY OF TEXAS HLTH SCI CTR SAN ANT
SAN ANTONIO, TX 78229
Fiscal Year: 2006
Department: PHARMACOLOGY
Project Start: 01-MAY-1995
Project End: 30-JUN-2008
ICD: NATIONAL INSTITUTE ON DRUG ABUSE
IRG: ZRG1
 
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,  france@uthscsa.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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