Wake Forest University, Winston Salem, NC

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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

LINDA J. PORRINO - Primate Testing - 2006

Grant Number: 5P50DA006634-150012
Project Title: FUNCTIONAL SUBSTRATES OF COCAINE SELF-ADMINISTRATION
PI Information: PROFESSOR LINDA J. PORRINO, lporrino@wfubmc.edu 

Abstract: The clinical course of cocaine abuse has been characterized as progressing though a number of temporal stages that advance from initial experimentation to addiction. This clinical course is paralleled by changes in the neurobiological response to cocaine, as well as residual changes in structure and function that can persist despite long periods of abstinence. The purpose of this project is to expand our understanding of the neuroadaptations accompanying chronic cocaine use, especially those critical for the expression of craving triggered by environmental and internal stimuli associated with drug availability. We will use neuroimaging methods designed to evaluate the entire brain simultaneously in order to evaluate the influence of cocaine exposure across a range of brain targets that may be critical to these behavioral changes. This project makes use of both rodent and non-human primate models of cocaine self-administration. The following questions will be addressed: 1) What is the temporal course of the development of the changes in functional activity that accompany the presentation of cocaine-predictive stimuli as a factor of duration of cocaine exposure, length of abstinence and pattern of drug administration? 2) What is the anatomical distribution of changes in functional activity within the limbic and neo-cortices that accompany the presentation of cocaine-predictive cues after long term self-administration? These studies will employ non-human primates because of the close homology of primate cortex with humans. 3) How do changes in the effects of cocaine-predictive cues on functional activity develop over the course of self-administration experience? These studies will utilize non-invasive imaging with positron emission tomography to assess rates of glucose utilization repeatedly in the same animal. This approach will permit the establishment of the temporal course of functional changes in the same animal at a number of time points. Because we will be using a within subjects design, it will also be possible to examine the time course in each individual animal, thus permitting an evaluation of individual differences in the response to chronic cocaine exposure. In short, the goal of these studies is to characterize the sites of changes in functional activity that result from chronic cocaine exposure investigating the factors important for the initiation and progression of these changes over the course of cocaine self-administration experience. These data will provide a clearer picture of the neuroadaptations that can influence behavior days, weeks or even years after abstinence.

Public Health Relevance:
This Public Health Relevance is not available.

Thesaurus Terms:
cocaine, craving, drug abuse, neuroanatomy, neuropharmacology, neurophysiology, self medication
brain imaging /visualization /scanning, dopamine, drug addiction, drug administration rate /duration, drug habituation, glucose metabolism, pathologic process, psychopharmacology
Macaca mulatta, behavioral /social science research tag, laboratory rat, positron emission tomography

Institution:
WAKE FOREST UNIVERSITY HEALTH SCIENCES
MEDICAL CENTER BLVD
WINSTON-SALEM, NC 27157
Fiscal Year: 2006
Department:
Project Start:
Project End:
ICD: NATIONAL INSTITUTE ON DRUG ABUSE
IRG: ZDA1

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:  LINDA J. PORRINO, lporrino@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

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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.

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