Grant Number: 5R01DA015723-03
Project Title: Opioids:Relative Reinforcing Strength and
Dependence
PI Information: ASSISTANT PROFESSOR CAROL A. PARONIS,
[email protected]
Abstract: DESCRIPTION (provided by applicant):
Considerable effort has been dedicated to understanding physiological
and behavioral aspects of opioid dependence, yet little is known
regarding how opioid dependence alters the reinforcing effects of
heroin. Since 1968, when it was first demonstrated that prior dependence
is not required for animals to initiate self-administration of abused
drugs, very few studies have examined self-administration behavior in
opioid-dependent subjects. The proposed research is designed to address
questions of whether and how reinforcing effects of opioids are altered
as a function of dependence, including dependence that results from
identified pharmacotherapies for heroin addiction, e.g., buprenorphine.
We have developed innovative self-administration procedures in which
full dose-effect functions for the relative reinforcing strength of IV
heroin can be rapidly determined. In these novel choice procedures,
subjects learn to distribute their behavior throughout the session on
the basis of the relative reinforcing strong features of an IV solution
that is available for self-injection and an alternative reinforcer
(food). These procedures are especially designed to divorce the
reinforcing strength of drugs from other behavioral effects. In proposed
studies, the self-administration of heroin and other opioid agonists
will be determined under varying conditions of response cost to evaluate
contextual influences on relative reinforcing strength. Next, studies
will be conducted to determine how the relative reinforcing strength of
heroin is modulated by acute treatment and chronic treatment with
morphine-like drugs. Preliminary data indicate that the reinforcing
strength of heroin in nondependent subjects can be predictably altered
by treatment with other opioids or by changes in response cost,
confirming the utility of these procedures for studies of the relative
reinforcing strength of self-administered heroin. Following completion
of these studies, alteration in the reinforcing strength of heroin will
be gauged in relation to aspects of tolerance and dependence that
develop during chronic treatment. Lastly, planned experiments will
address the modification of heroin's reinforcing effects by nonopioid
drugs, specifically GABA-A agonists. These studies are designed to
empirically address questions raised by high rates of benzodiazepine
abuse by opioid-addicted populations. Overall, the proposed studies will
provide significant advances for evaluating contextual or
pharmacological modifications of the reinforcing strength of heroin in
nondependent and opioid-dependent individuals. Results of these studies
will improve our ability to assess the effectiveness with which
agonist-based medications may combat its addictive power.
Thesaurus Terms:
drug addiction, heroin, opiate alkaloid, psychopharmacology, reinforcer
benzodiazepine, buprenorphine, disease /therapy duration, dosage, drug
abuse chemotherapy, drug habituation, drug tolerance, gamma
aminobutyrate, intravenous administration, intravenous drug abuse,
narcotic antagonist, neurotransmitter agonist, self medication,
substance abuse related behavior
Macaca mulatta, behavioral /social science research tag
Institution: MC LEAN HOSPITAL (BELMONT, MA)
115 MILL ST
BELMONT, MA 02478
Fiscal Year: 2006
Department:
Project Start: 14-MAY-2004
Project End: 31-MAR-2009
ICD: NATIONAL INSTITUTE ON DRUG ABUSE
IRG: BRLE
Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on October 16, 2003; DOI: 10.1124/jpet.103.052795
Modification by Dopaminergic Drugs of Choice Behavior
under Concurrent Schedules of Intravenous Saline and Food Delivery in
Monkeys
Maciej Gasior, Carol A. Paronis, and Jack Bergman
Behavioral Pharmacology Laboratory/Alcohol and Drug Abuse Research
Center, McLean Hospital, Belmont, Massachusetts
Received April 8, 2003; accepted September 25, 2003.
Subjects.
Three female (Mm 211, Mm 258, and Mm 331) and one male (Mm 263) adult
rhesus monkeys (Macaca mulatta), weighing 6 to 9.5 kg, were studied in
daily experimental sessions 5 to 6 days/week. Two monkeys (Mm 211 and Mm
331) were previously exposed to cocaine in i.v. self-administration
experiments, and two monkeys (Mm 258 and Mm 263) had previously
participated in experiments with a variety of opioid or dopaminergic
drugs. Subjects were individually housed in stainless steel cages
between experimental sessions in a temperature- and humidity-controlled
room with a 12-h light/dark cycle (7:00 AM lights on). Each monkey had
unlimited access to tap water and received a nutritionally balanced diet
(5045 High Protein Monkey Diet; PMI Nutrition International, Inc.,
Brentwood, MO) supplemented regularly with fresh fruit, trail mix, and
vitamins. The protocol for animal use in these studies was approved by
the Institutional Animal Care and Use Committee. Subjects in this study
were maintained in accordance with guidelines provided by the Committee
on Care and Use of Laboratory Animals of the Institute of Laboratory
Animals Resources, National Institutes of Health. This facility is
licensed by the U.S. Department of Agriculture.
Each monkey initially was trained to lever press under a fixed ratio
schedule of food presentation. After food-maintained performance was
well established, each monkey was prepared with a chronic venous
catheter after the general surgical procedure described by Herd et al.
(1969 ). Briefly, under isoflurane anesthesia and in aseptic conditions,
one end of a hydrophilically coated polyurethane catheter (inside
diameter, 1.0 mm; outside diameter, 1.7 mm) was inserted through a
femoral vein and passed to the level of the right atrium. The distal end
of the catheter was attached to a titanium vascular access port (model
TI200 AC-5H; Access Technologies, Skokie, IL) that was subcutaneously
located in the midscapular region.
Apparatus.
During experimental sessions, each monkey was seated in a Plexiglas
chair within a ventilated, sound-attenuating chamber. Two response
levers were mounted on a panel attached to the front of the chair. Each
press of either lever with a force of at least 0.25 N produced an
audible click of a relay and was recorded as a response. Colored lamps
(red or white) behind the levers could be illuminated to serve as visual
stimuli. A motor-driven feeder outside the chamber could deliver food
pellets to a food receptacle on the chair via flexible tubing. A
motor-driven syringe pump outside the chamber could deliver intravenous
injections via an external catheter line and noncoring Huber needle
through the silicone rubber septum of the monkey's vascular access port.
Sterile 0.9% saline (1-2 ml) was used to flush residual drug solution
from the port and catheter after experimental sessions. Both the syringe
and feeder were operated by automatic programming equipment. Each
operation of the syringe pump or feeder lasted 200 ms and delivered a
constant volume from the syringe or one food pellet, respectively.
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