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 µ 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. |
