Grant Number: 5R37DA010584-10
Project Title: Social Stress: Vulnerability to Cocaine Abuse in
Monkeys
PI Information: PROFESSOR MICHAEL A. NADER,
[email protected]
Abstract: DESCRIPTION (provided by applicant): The overarching goal
of this research is to achieve a better understanding of the individual
differences in the susceptibility and vulnerability to the reinforcing
effects of cocaine using a unique nonhuman primate model of drug abuse.
To accomplish this, we have combined the study of primate social
behavior with intravenous drug self-administration and the noninvasive
brain imaging procedure positron emission tomography (PET) to examine
how environmental and pharmacological variables influence the behavioral
and reinforcing effects of cocaine. In the previous funding period we
found that social housing altered dopamine (DA) D2 receptor function in
male cynomolgus monkeys and these changes were associated with
differential vulnerability to self-administer cocaine between dominant
and subordinate monkeys. These studies were the first to examine
intravenous cocaine self-administration in socially housed monkeys and
found that social status and environmental context can have profound
effects on cocaine reinforcement. We also found that chronic exposure to
cocaine could attenuate the effects of social rank on DA receptor
function and result in similar rates of self-administration among the
socially housed monkeys. The studies proposed in this competing renewal
application are designed to evaluate further the interactions between
DA, social rank and the reinforcing effects of cocaine. Specifically, we
propose to 1) examine further the plasticity of the DA system during
cocaine abstinence and following social group reorganization and assess
the impact of these manipulations on cocaine reinforcement; 2) determine
the effects of social consequences of self-administering cocaine on the
reinforcing effects of the drug and on measures of impulsivity; and 3)
examine further the interactions between acute and chronic environmental
stressors and enrichment on DA receptor function and on the reinforcing
effects of cocaine, as a function of social rank. The use of novel and
homologous nonhuman primate models of cocaine abuse, as proposed, should
aid in understanding how environmental and pharmacological variables
contribute to vulnerability, maintenance, relapse and choice behavior
involving drugs of abuse. Such information will lead to better treatment
and prevention strategies.
Public Health Relevance:
This Public Health Relevance is not available.
Thesaurus Terms:
cocaine, drug abuse, reinforcer, social status, substance abuse related
behavior
biological model, dopamine, dopamine receptor, drug /alcohol abstinence,
environmental stressor, ethology, impulsive behavior, neural plasticity,
operant conditioning, psychological stressor, psychopharmacology,
receptor expression, self medication, social behavior, social change,
social dominance
Macaca fascicularis, behavioral /social science research tag, positron
emission tomography
Institution: WAKE FOREST UNIVERSITY HEALTH SCIENCES
MEDICAL CENTER BLVD
WINSTON-SALEM, NC 27157
Fiscal Year: 2006
Department: PHYSIOLOGY AND PHARMACOLOGY
Project Start: 01-SEP-1996
Project End: 30-JUN-2010
ICD: NATIONAL INSTITUTE ON DRUG ABUSE
IRG: ZRG1Cocaine Self-Administration
Produces a Progressive Involvement of Limbic, Association, and
Sensorimotor Striatal Domains
Linda J. Porrino, David Lyons, Hilary R. Smith, James B. Daunais, and
Michael A. Nader
Center for the Neurobiological Investigation of Drug
Abuse, Department of Physiology and Pharmacology, Wake Forest University
School of Medicine, Winston-Salem, North Carolina 27157
Behavioral/Systems/Cognitive
The Journal of Neuroscience, April 7, 2004, 24(14):3554-3562;
doi:10.1523/JNEUROSCI.5578-03.2004
Subjects.
Fourteen experimentally naive adult male rhesus monkeys (Macaca
mulatta) weighing between 7.6 and 11.5 kg (mean � SD; 9.5 � 1.04) at the
start of the study served as subjects. Monkeys were housed individually
in stainless steel cages with water ad libitum; animals had physical and
visual contact with each other. Their body weights were maintained at
90�95% of free-feeding weights by banana-flavored pellets earned during
the experimental sessions and by supplemental feeding of Lab Diet Monkey
Chow, provided no sooner than 30 min after the session. All procedures
were performed in accordance with established practices as described in
National Institutes of Health Guide for Care and Use of Laboratory
Animals. In addition, all procedures were reviewed and approved by the
Animal Care and Use Committee of Wake Forest University.
Behavioral apparatus.
Cocaine self-administration and food-reinforced responding occurred in
ventilated and sound-attenuated operant chambers (1.5 x 0.74 x 0.76 m;
Med Associates, East Fairfield, VT) designed to accommodate a primate
chair (Model R001, Primate Products, Redwood City, CA). The chamber
contained an intelligence panel (48 x 69 cm), which consisted of two
retractable levers (5 cm wide) and three stimulus lights. The levers
were positioned within easy reach of the monkey sitting in the primate
chair. One gram of food pellets was delivered from a feeder located on
the top of the chamber. A peristaltic infusion pump (7531�10,
Cole-Parmer Co., Chicago, IL) was used to deliver drug injections at a
rate of 1 ml/10 sec to those animals self-administering cocaine.
Operation of the chambers and data acquisition were accomplished with a
Power Macintosh computer system with an interface (Med Associates).
Surgical procedures.
All monkeys, including controls, were surgically prepared, under sterile
conditions, with indwelling intravenous catheters and vascular access
ports (Model GPV, Access Technologies, Skokie, IL). Monkeys were
anesthetized with a combination of ketamine (15 mg/kg, i.m.) and
butorphanol (0.03 mg/kg, i.m.), and an incision was made near the
femoral vein. After blunt dissection and isolation of the vein, the
proximal end of the catheter was inserted into the vein for a distance
calculated to terminate in the inferior vena cava. The distal end of the
catheter was threaded subcutaneously to an incision made slightly off
the midline of the back. The vascular access port was placed within a
pocket formed by blunt dissection near this incision. Monkeys were given
24�48 hr recovery times before returning to food-reinforced responding.
Approximately 5 d before the terminal procedure, each monkey was
implanted with a chronic indwelling catheter into the adjacent femoral
artery for collection of timed arterial blood samples during the 2DG
procedure. The surgical procedures were identical to those described for
the venous catheters. For monkeys in the initial exposure groups (see
below), this catheter was implanted at the same time as the venous
catheter.
Self-administration procedures.
Monkeys were initially trained to respond on one of two levers by
reinforcing each response on the correct lever with a 1 gm
banana-flavored pellet. Over a period of 3 weeks, the interval between
availability of food pellets was gradually increased until a 3 min
interval was achieved [i.e., fixed-interval 3 min schedule (FI 3-min)].
Under the final schedule conditions, the first response on the lever
after 3 min resulted in the delivery of a food pellet; sessions ended
after 30 food presentations. At the end of each session, the response
levers were retracted, houselights and stimulus lights were
extinguished, and animals remained in the darkened chamber for 30 min
before they were returned to their home cages. All monkeys responded
under the FI 3-min schedule of food presentation for at least 20
sessions and until stable performance was obtained (�20% of the mean for
three consecutive sessions, with no trends in response rates). When
food-maintained responding was stable, the feeder was unplugged, and the
effects of extinction on responding were examined for five consecutive
sessions, after which responding was reestablished and maintained by
food presentation.
Neuropsychopharmacology (2002) 27
3546.10.1038/S0893-133X(01)00427-4
Effects of Cocaine Self-administration on Striatal
Dopamine Systems in Rhesus Monkeys: Initial and Chronic Exposure
Michael A Nader Ph.D, James B Daunais Ph.D, Tonya Moore MS, Susan H
Nader BA, Rodney J Moore Ph.D, Hilary R Smith BA, David P Friedman Ph.D
and Linda J Porrino Ph.D
Department of Physiology and Pharmacology, Wake Forest
University School of Medicine, Winston-Salem, NC 27157
METHODS
Behavioral Manipulations
Subjects
Twenty-four experimentally naive adult male rhesus monkeys (Macaca
mulatta), weighing 7.611.5 kg at the start of the study, served as
subjects. Monkeys were individually housed in stainless steel cages with
water ad libitum; animals had visual and auditory contact with each
other. Their body weights were maintained at approximately 9095% of
free-feeding weights, by banana-flavored pellets earned during the
experimental sessions and by supplemental feeding of Lab Diet Monkey
Chow, no sooner than 30 min post session. Each monkey was weighed once a
week and, if necessary, their diets were adjusted to maintain weights.
In addition, they were given fresh fruit or peanuts two to three times
per week. Monkeys lived in temperature- and humidity-controlled colony
rooms with lighting on from 6 A.M. to 8 P.M. All procedures were
performed in accordance with established practices as described in the
National Institutes of Health Guide for Care and Use of Laboratory
Animals. In addition, all procedures were reviewed and approved by the
Animal Care and Use Committee of Wake Forest University.
Surgery
Intravenous Catheters Each monkey was surgically prepared, under
sterile conditions, with an indwelling intravenous catheter and vascular
access port (Model GPV, Access Technologies, Skokie, IL). Monkeys were
anesthetized with a combination of ketamine (15 mg/kg, i.m.) and
butorphanol (0.03 mg/kg, i.m.) and an incision was made near the femoral
vein. After blunt dissection and isolation of the vein, the proximal end
of the catheter was inserted into the vein for a distance calculated to
terminate in the vena cava. The distal end of the catheter was threaded
subcutaneously to an incision made slightly off the midline of the back.
The vascular access port was placed within a pocket formed by blunt
dissection near the incision. Prior to each experimental session, the
back of the animal was cleaned with 95% ETOH and betadine scrub and a 22
gauge Huber Point Needle (Model PG20-125) was inserted into the port
leading to the venous catheter, connecting an infusion pump, containing
the cocaine solution, to the catheter. The pump was operated for
approximately 3 s, filling the port with the dose of cocaine that was
available during the experimental session. At the end of each session,
the port was filled with heparinized saline (100 Units/ml) to help
prevent clotting.
Intraarterial Catheters - Approximately five days before the
terminal procedure, each monkey was implanted with a chronic indwelling
catheter into the femoral artery. The procedures were identical to those
described for the venous catheters. For monkeys in the "initial" cocaine
self-administration groups (see below), this catheter was implanted at
the same time as the venous catheter. On the final session, a terminal
glucose metabolism study was conducted (see Lyons et al. 1996 for
details). In this procedure, monkeys were injected with
2-[14C]deoxyglucose (2-DG) approximately 2 min after the end of the
session and blood samples were obtained through the arterial catheter
over a 45 min period. No metabolism data will be presented.
Apparatus
Cocaine self-administration and food-reinforced responding occurred in
ventilated and sound-attenuated chambers (150 74 76 cm, Med
Associated, East Fairfield, VT) designed to accommodate a primate chair
(Model R001, Primate Products, Redwood City, CA). An intelligence panel
(48 69 cm), located on the right side of the chamber, contained two
retractable levers (5 cm wide) with three small stimulus lights
centrally located 14 cm above each lever. The levers were positioned to
be within easy reach of the monkey sitting in the primate chair. One
gram food pellets were delivered into a food receptacle located on the
intelligence panel, between the two levers. A peristaltic infusion pump
(7531-10, Cole-Parmer Co., Chicago, IL) for delivering drug injections
at a rate of approximately 1 ml/10 s, was located on the top of the
chamber. Operation of the chambers and data acquisition were
accomplished with a computer system (Power Macintosh and Med Associates
interface).
Procedures
Each monkey was fitted with an aluminum collar (Model B008, Primate
Products) and trained to approach the front of the cage when the
investigator was present. A stainless steel rod (Model R011, Primate
Products) with a latch on the end was attached to the collar and the
monkey was guided into the primate restraint chair. The monkey, seated
in the primate chair, was then wheeled into the experimental chamber.
Monkeys were initially trained to respond on the left lever by
reinforcing each response with a 1g banana-flavored pellet. Over
approximately three weeks, the interval between food pellet availability
was gradually increased until a 3-min interval was obtained (i.e., a
fixed-interval 3-min schedule; FI 3-min). Under the final schedule
conditions, the first response on the lever after 3 min resulted in food
pellet delivery; sessions ended after 30 food presentations. All monkeys
continued to respond under the FI 3-min schedule of food presentation
for at least 20 sessions and until stable performance was obtained (20%
of the mean for three consecutive sessions, with no trends in response
rates). When food-maintained responding was stable, the feeder was
unplugged and the effects of extinction on responding were examined for
five consecutive sessions. After this extinction period, responding was
re-established and maintained by food presentation. Because saline was
not studied after cocaine self-administration had been established (see
below), rates of responding during extinction of food-maintained
responding were used to confirm that cocaine was functioning as a
reinforcer. |