Wake Forest University, Winston Salem, NC

Home Page
About SAEN
Articles and Reports
Contact Us
Events and Campaigns
Fact Sheets
Financial Information
How You Can Help
Make a Donation, Please!
Media Coverage
Newsletters
Petitions
Picture Archive
Press Releases
Resources and Links
Grass Roots Org. List

Stop Animal Exploitation NOW!
S. A. E. N.
"Exposing the truth to wipe out animal experimentation"

Government Grants Promoting Cruelty to Animals

Wake Forest University, Winston Salem, NC

MICHAEL A. NADER - Primate Testing - 2006 -2

Grant Number: 5R37DA010584-10
Project Title: Social Stress: Vulnerability to Cocaine Abuse in Monkeys
PI Information: PROFESSOR MICHAEL A. NADER, mnader@wfubmc.edu

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: ZRG1

Cocaine 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 9095% 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 (753110, 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 2448 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 3546.10.1038/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 7.611.5 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 9095% 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.

Please email:  MICHAEL A. NADER, mnader@wfubmc.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

Return to Grants
Return to Wake Forest University, Winston Salem, NC
Return to Facility Reports and Information
Return to Resources and Links

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.

We welcome your comments and questions


This site is hosted and maintained by:
The Mary T. and Frank L. Hoffman Family Foundation
Thank you for visiting all-creatures.org.
Since date.gif (991 bytes)