Grant Number: 3R01DA002486-26S1
Project Title: A PRIMATE MODEL OF DRUG ABUSE: INTERVENTION
PI Information: PROFESSOR OF PSYCHIATRY AND NEUROSCIENCE, MARILYN
E. CARROLL, [email protected]
Goals of the proposed research are to use a rhesus monkey model of drug
abuse, to study factors affecting vulnerability to drug abuse and to
evaluate behavioral and pharmacological treatment interventions. Routes
of administration that have been developed in this laboratory will
include oral drug self-administration and smoking.
When using the oral
route of self-administration, liquid deliveries are contingent upon
lip-contact responses. Smoke deliveries are contingent upon inhalation
responses. Vulnerability factors to be examined are sex and phase of the
menstrual cycle as well as patterns/duration of access to drugs. Initial
work indicates that escalation from drug use to abuse is dependent upon
the amount and duration of access.
The proposed work will extend these
findings to monkeys, other drugs, and measures of reinforcing efficacy.
In addition, the question of whether differential access to one drug
affects acquisition of self-administration of a second drug will be
examined. Well-accepted measures of the reinforcing efficacy of drugs,
behavioral economic demand curve analyses and PR schedules will be used
to determine how these predisposing factors ultimately affect the
reinforcing potential of selected drugs.
The drugs that will be studied
are cocaine, ethanol, heroin, methadone and phencyclidine (PCP).
Behavior maintained by food and/or liquid saccharin will be used as a
control for drug-selective effects. The behavioral economic measures
will also be used quantify the extent to which these drug and nondrug
substances substitute for each other. These studies will inform us about
the effectiveness of substituting nondrug items for drugs in treatment,
as well for predicting polydrug abuse by how well one form of drug abuse
substitutes for another.
The use of nondrug reinforcers as a behavioral
treatment will also be compared in male and female monkeys and during 3
phases of the menstrual cycle. Potential treatment medications will also
be examined in male monkeys using a behavioral economic approach.
different types of drugs that have produced promising preliminary
results are proposed: bremazocine, an agonist at the kappa opioid
receptor, baclofen, a GABAB agonist, and ketoconazole, an inhibitor of
corticosterone synthesis. Finally, the behavioral (alternative
reinforcer) and pharmacological treatments will be combined and compared
to the effects of each given alone.
The results of the proposed 11
experiments will provide valuable information about major vulnerability
factors and several behavioral and pharmacological treatment approaches
for drug abuse. It is hoped that this information will lead to earlier
and more effective prevention and treatment of drug abuse.
behavior therapy, disease /disorder proneness /risk, drug abuse
chemotherapy, nonhuman therapy evaluation, substance abuse related
behavior, substance abuse related disorder analgesic, buprenorphine,
cocaine, corticosterone, disease /disorder model, drug addiction
antagonist, drug interaction, ethanol, gender difference, heroin,
ketoconazole, menstrual cycle, methadone, muscle relaxant, oral
administration, phencyclidine, psychological reinforcement,
psychopharmacology, reinforcer, self medication, smoking Macaca mulatta,
behavioral /social science research tag
Institution: UNIVERSITY OF MINNESOTA TWIN CITIES
450 MCNAMARA ALUMNI CENTER, MINNEAPOLIS, MN 554552070
Fiscal Year: 2006
Project Start: 01-JAN-1980
Project End: 31-MAR-2007
ICD: NATIONAL INSTITUTE ON DRUG ABUSE
J Pharmacol Exp Ther. 2002 Jun;301(3):993-1002
Vol. 301, Issue 3, 993-1002, June 2002
Effects of Bremazocine on Self-Administration of
Smoked Cocaine Base and Orally Delivered Ethanol, Phencyclidine,
Saccharin, and Food in Rhesus Monkeys: A Behavioral Economic Analysis
Kelly P. Cosgrove and Marilyn E. Carroll
Department of Psychiatry, University of Minnesota, Minneapolis,
Sixteen adult male rhesus monkeys (Macaca mulatta) served as
Eight monkeys (M-A1, M-B4, M-E, M-G2, M-I, M-J1,
M-J2, and M-X) self-administered orally delivered ethanol, PCP, or
saccharin concurrently with water under an FR schedule.
had previous experience orally self-administering these substances. Six
monkeys (M-B4, M-C2, M-G2, M-I, M-J2, and M-Y) that had previously
self-administered food were assigned to the group that self-administered
Six monkeys that had previously self-administered smoked
cocaine base (M-L, M-L2, M-O, M-M3, M-S, and M-S4) were assigned to the
Monkeys were maintained at 85% of their free feeding
weights, and the 85% weights ranged from 9.0 to 13.0 kg across monkeys.
The animals were weighed every 2 weeks to monitor body weight, and food
allotments were adjusted to maintain them at their 85% weights.
monkeys' diet consisted of Teklad monkey chow (Bartonville, IL), fresh
fruit on a daily basis, and trail mix or other small snacks were
provided several times per week for enrichment at least 1 h after the
daily session. Other forms of enrichment (television, Kong toys) were
provided nonsystematically, several times per week, and they did not
interfere with the daily session responding for food or liquids.
had visual, auditory, and olfactory contact with each other throughout
the study. They were monitored at least every other day by the
Animals were individually housed in temperature- and
humidity-controlled colony rooms on a 12-h light/dark cycle with lights
on at 7:00 AM. Use of the animals for this protocol was approved by the
University of Minnesota Institutional Animal Care and Use Committee
(protocol number 0112A14081). Laboratory facilities were accredited by
the American Association for the Accreditation of Laboratory Animal
Care, and principles of laboratory animal care (National Research
Council, 1996) were followed.
Monkeys were housed in individual, custom-made stainless steel cages (83
cm in width × 76 cm in height × 100 cm in depth) (Lab Products, Maywood,
NJ) consisting of three solid walls, a barred front door, a grid floor,
and a primate perch. One side wall was modified to allow for attachment
of an operant panel from the exterior of the cage.
Through cutouts in
the side wall, response devices on the panel were inserted into the
cage. These included two solenoid-operated brass drinking spouts, a
primate lever, and stimulus lights above the spouts and lever. The two
brass drinking spouts (1.2 cm in diameter) extended 2.7 cm into the cage
and were located at the level of the monkey's mouth (45 cm above the
cage floor). The drinking spouts were activated by lip contact
Upon completion of the required number of lip contact
responses, under an FR schedule, a solenoid valve opened allowing 0.6 ml
of liquid to flow through Tygon tubing from a 2000-ml Nalgene reservoir
suspended above the cage panel through the drinking spout. Lip removal
closed the solenoid valve and terminated the liquid delivery.
lever was located in the middle of the panel approximately 20 cm above
the cage floor. A recessed food receptacle was located directly
underneath the primate lever. Upon completion of lever FR requirements,
one primate chow biscuit (7.0 g) was released into the food receptacle
from a primate universal magazine feeder (Gerbrands Inc., Arlington, MA)
that was mounted on the exterior of the cage and connected by a chute to
the food receptacle.