Harvard Medical School, Boston, MA

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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

Harvard Medical School, Boston, MA

ROGER D. SPEALMAN - Primate Testing - 2006

Grant Number: 5R01DA011928-09
Project Title: Nonhuman Primate Models of Speedball Abuse
PI Information: PROFESSOR AND CHAIR ROGER D. SPEALMAN, roger_spealman@hms.harvard.edu 

Abstract: DESCRIPTION (provided by applicant):
The dual abuse of cocaine and heroin (commonly called "speedballs") is a pernicious form of drug addiction that has increased worldwide along with the increased availability of cocaine and heroin. Speedball abusers show a higher rate of failure in treatment, a greater incidence of psychopathology, and increased risk of HIV infection compared to abusers of the individual drugs. Despite the prevalence and detrimental consequences of speedball abuse, comparatively little is known about its neuropharmacological basis or treatment. Our previous research using nonhuman primate models of the subjective and reinforcing effects of drugs has revealed a distinctive pattern of interactions between cocaine and heroin, which appears to be mediated via mu and delta opioid and D1-like and D2-like dopamine receptor mechanisms. Our proposed research will build on these findings by investigating the role of specific receptor subtypes within these receptor families. In rhesus monkeys trained to discriminate IV cocaine from vehicle or to self-administer IV cocaine under a modified progressive-ratio schedule, we will use selective agonists and antagonists to investigate the contribution of subtypes of mu and delta receptors in heroin-induced enhancement of the discriminative stimulus and reinforcing effects of cocaine. In rhesus monkeys trained to discriminate IV heroin from vehicle or to self-administer IV heroin under a modified progressive-ratio schedule, we will use a similar strategy to investigate the contribution of D1-like and subtypes of D2-like receptors in cocaine-induced attenuation of the discriminative stimulus effects of heroin and cocaine-induced enhancement of the reinforcing effects of heroin. Quantitative pharmacological analyses, including in vivo apparent pA2 and isobolographic analysis, along with a novel behavioral economic model termed labor-supply will provide an objective framework for interpretation of drug interactions. The results of our proposed research will provide needed information about neuropharmacological mechanisms underlying speedball addiction and potential targets for medication development.

Thesaurus Terms:
cocaine, dopamine receptor, drug abuse, drug interaction, heroin, neuropharmacology, opioid receptor
disease /disorder model, dopamine agonist, dopamine antagonist, intravenous drug abuse, pharmacokinetics, reinforcer, self medication
Macaca mulatta, injection /infusion

Institution: HARVARD UNIVERSITY (MEDICAL SCHOOL)
MEDICAL SCHOOL CAMPUS
BOSTON, MA 02115
Fiscal Year: 2006
Department: PSYCHIATRY
Project Start: 01-AUG-1998
Project End: 30-JUN-2008
ICD: NATIONAL INSTITUTE ON DRUG ABUSE
IRG: BBBP

Journal of Pharmacology And Experimental Therapeutics Fast Forward

First published on November 21, 2003; DOI: 10.1124/jpet.103.060962

Opioid Partial Agonist Effects of 3-O-Methylnaltrexone in Rhesus Monkeys

Donna M. Platt, James K. Rowlett, Sari Izenwasser, and Roger D. Spealman

Harvard Medical School (D.M.P., J.K.R., R.D.S.), New England Primate Research Center, Southborough, Massachusetts; and Department of Psychiatry and Behavioral Sciences (S.I.), University of Miami School of Medicine, Miami, Florida

Received October 6, 2003; accepted November 20, 2003.

Drug Discrimination

Subjects and Surgical Procedure.
Four adult male rhesus monkeys (Macaca mulatta), weighing 8.4 to 12.1 kg, were studied in daily experimental sessions (Monday to Friday). Due to circumstances unrelated to the present experiment, one monkey (M-164) died during the course of the study and did not receive all drug treatments. Between sessions, monkeys lived in individual home cages where they had unlimited access to water. The monkeys were maintained at 85 to 90% of their free-feeding body weight by adjusting their access to food in the home cage (Teklad, supplemented with fresh fruit and vegetables). All animals were maintained in accordance with the guidelines of the Committee on Animals of the Harvard Medical School and the Guide for Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council, Department of Health, Education, and Welfare Publication No. (NIH) 85-23, revised 1996. Research protocols were approved by the Harvard Medical School Institutional Animal Care and Use Committee.


 

Monkeys were prepared with chronic indwelling venous catheters (polyvinyl chloride; i.d. 0.64 mm, o.d. 1.35 mm) using the general surgical procedures described by Carey and Spealman (1998 ). Under isoflurane anesthesia and aseptic conditions, one end of a catheter was passed to the level of the right atrium by way of a brachial, femoral, or jugular vein. The distal end of the catheter was passed subcutaneously and exited in the mid-scapular region. Catheters were flushed daily with heparinized saline (150-200 U/ml) and were sealed with stainless steel obturators when not in use. Monkeys wore custom-made nylon-mesh jackets (Lomir Biomedical, Toronto, ON, Canada) at all times to protect the catheter.

Apparatus.
Experimental sessions were conducted in ventilated and sound-attenuating chambers. Monkeys were seated in custom-made primate chairs (Crist Instrument Co., Hagerstown, MD). Two response levers (model ENV-610M; MED Associates, Georgia, VT) were mounted 16 cm apart on the wall of the chamber in front of the monkey. Each press of a lever with a minimum downward force of approximately 0.25 N produced an audible click and was recorded as a response. Food pellets (Formula 0094, 1 g; Bioserve, Frenchtown, NJ) could be delivered to a tray located between the levers. Colored lights mounted above the levers could be illuminated to serve as visual stimuli.

Procedure.
Monkeys were trained to discriminate heroin from saline under a 10-response fixed-ratio (FR 10) schedule of food reinforcement (Platt et al., 2001 ). The training dose of heroin in the present study was 0.056 mg/kg for all monkeys. After an i.v. injection of heroin, 10 consecutive responses on one lever produced a food pellet, whereas after an i.v. injection of saline, 10 consecutive responses on the other lever produced a pellet. For two of the monkeys, responding on the right lever after an injection of heroin resulted in delivery of a food pellet. For the other two monkeys, responding on the left lever after injection of heroin resulted in pellet delivery. Delivery of each pellet was followed by a 10-s time-out period. Responses on the incorrect lever (e.g., the saline-appropriate lever after heroin injection) reset the FR requirement.

Journal of Pharmacology And Experimental Therapeutics Fast Forward

First published on November 18, 2004; DOI:10.1124/jpet.104.076646

BEHAVIORAL PHARMACOLOGY

Self-Administration of Cocaine-Opioid Combinations by Rhesus Monkeys: Evaluation of the Role of Receptor Efficacy Using Labor Supply Analysis
 
James K. Rowlett, Joshua S. Rodefer1, and Roger D. Spealman

Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts
 
Received August 24, 2004; accepted November 17, 2004.

Apparatus.
Monkeys were housed individually in stainless steel primate cages that also served as the experimental chambers. A removable panel was placed on the front of each cage and contained four stimulus lights (MED Associates, St. Albans, VT; two red and two white; 3 cm, 1.1 W) and a response lever (MED Associates). Each monkey was fitted with a nylon mesh jacket (Lomir Biomedical Inc., Malone, NY) that was connected to a 1-m stainless steel flexible tether (Lomir Biomedical). The monkey's catheter was routed through the tether and attached to a fluid swivel (Lomir Biomedical) on top of the cage. The swivel was attached to an injection pump (MED Associates) located on top of the cage that could infuse drug solutions at a rate of 0.2 ml/s. The stimulus lights, response levers, and infusion pump were connected to interfaces (MED Associates) and PC-compatible computers located in an adjacent room.
Procedure. Monkeys were trained to self-administer cocaine under a progressive-ratio schedule of i.v. drug injection according to the schedule parameters described by Rowlett et al. (2002 ).

Experimental sessions began daily at 12:00 noon. At the beginning of the session, the white stimulus lights above the lever were illuminated to signal the start of a trial. The white lights were extinguished upon completion of the response requirement, and the red stimulus lights were illuminated for 1 s, coinciding with a 1-s infusion of drug or saline. Each trial ended with either an injection or the expiration of a 30-min limited hold. Trials were separated by a 30-min timeout period, during which all the lights were extinguished and responding had no programmed consequences.

Experimental sessions consisted of five components made up of four trials each, for a possible maximum of 20 trials per session. The response requirement remained constant during each of the four trials within a component and doubled across successive components of the session. For example, a session with an IRR of 100 consisted of the following five components with increasing response requirements (four trials each): 100, 200, 400, 800, and 1600. The session ended when a monkey self-administered a maximum of 20 injections or when the response requirement was not completed for two consecutive trials. The number of trials per response requirement was chosen so that completing the maximum number of injections could be delivered in 10 h or less each day.

Please email: ROGER D. SPEALMAN, roger_spealman@hms.harvard.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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