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

PAUL W. CZOTY - Primate Testing - 2007

Grant Number: 1R01DA021658-01A1
Project Title: Cocaine discrimination, self-administration and microdialysis in monkeys
PI Information: PAUL W. CZOTY, pczoty@wfubmc.edu     

Abstract: DESCRIPTION (provided by applicant): Although the subjective effects of cocaine are understood to play an important role in cocaine abuse, studies in humans have revealed an incomplete overlap between discriminative stimulus (SD) and reinforcing (SR) effects of drugs. Moreover, the lack of a clear understanding of the precise roles of dopamine (DA), serotonin (5-HT) and norepinepherine (NE) in these effects has hindered efforts to develop medications for cocaine dependence. The overarching goals of the research in this proposal are to gain a better understanding of the relationship between the SD and SR effects of cocaine and to better elucidate the pharmacological and neurochemical mechanisms that underlie these effects. To accomplish these aims, rhesus monkeys will be trained to discriminate a response-contingent injection of 0.1 mg/kg cocaine from saline, with an opportunity to self-administer 0.1 mg/kg cocaine under a second-order schedule immediately following the discrimination component. Using this procedure, the effects of a range of doses of cocaine, other indirect and direct DA receptor agonists will be characterized, including direct agonists that differ in efficacy at stimulating D1- and D2-like DA receptors (Specific Aim 1). To characterize the extent of overlap of the neurochemical mechanisms involved in production of these abuse-related effects of cocaine, parallel microdialysis studies will measure extracellular DA in the ventral striatum during discrimination and self- administration components of selected doses (Specific Aim 2). Mechanisms by which 5-HT and NE can modulate the behavioral effects of cocaine will be examined in subsequent behavioral and microdialysis studies (Specific Aim 3) that characterize the effects of 5-HT and NE indirect and direct agonists on the SD, SR and neurochemical effects of cocaine. By assessing behavioral and neurochemical effects within a behavioral session in the same monkeys, these innovative studies will: (1) better describe the importance of SD effects to self-administration, (2) more clearly elucidate dopaminergic mechanisms involved in production of the abuse-related effects of cocaine, and (3) provide a unique characterization of pharmacological and neurochemical mechanisms that will aid the development of effective pharmacotherapies for cocaine dependence. Relevance: The proposed studies will provide unique information about the neurobiological mechanisms through which the addictive effects of cocaine are produced. Importantly, the results will provide novel information to aid efforts to develop effective medications for cocaine addiction, and will enhance our understanding and interpretation of data collected in animal models of drug addiction.

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

Thesaurus Terms: cocaine, microdialysis, Macaca mulatta, Primate, brain, central nervous system stimulant, chemotherapy, conflict, dopamine, dopamine receptor, drug abuse, drug addiction, drug interaction, experience, extracellular, human, human subject, lead, model, placebo, play, receptor, role, saline, serotonin, training

Institution:
WAKE FOREST UNIVERSITY HEALTH SCIENCES
MEDICAL CENTER BLVD
WINSTON-SALEM, NC 27157
Fiscal Year: 2007
Department: PHYSIOLOGY AND PHARMACOLOGY
Project Start: 01-JUL-2007
Project End: 30-JUN-2012
ICD: NATIONAL INSTITUTE ON DRUG ABUSE
IRG: ZDG1

The influence of reinforcing effects of cocaine on cocaine-induced increases in extinguished responding in cynomolgus monkeys

Matthew L. Banks,1 Paul W. Czoty,1 and Michael A. Nader1,2
1Department of Physiology and Pharmacology, Wake Forest University School on Medicine, Winston-Salem, NC, USA, 27157
2Department of Radiology, Wake Forest University School on Medicine, Winston-Salem, NC, USA, 27157
Psychopharmacology (Berl). 2007 July; 192(4): 449456

Subjects
Thirteen adult male cynomolgus monkeys (Macaca fascicularis) served as subjects. Five of the monkeys were drug and experimentally-nave at the outset of these studies and lived individually in stainless steel cages. The remaining 8 monkeys had extensive histories of cocaine self-administration and exposure to D1 agonists (Czoty et al. 2004, 2005), and were socially housed. Although monkeys occupied both dominant and subordinate ranks in the social hierarchy, no influence of social rank was observed in this experiment; thus, data are collapsed across ranks. All monkeys were fitted with aluminum collars (Primate Products, Redwood City, Calif., USA) and trained to approach the front of the cage to be guided into a restraint chair (Primate Products) using a specially designed stainless steel pole (Primate Products). Monkeys' were weighed weekly and fed enough food daily (Purina Primate Chow and fresh fruit) to maintain at least 95% of free-feeding weight; water was continuously available in the home cage. All procedures were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Animal Care and Use Committee of Wake Forest University. Environmental enrichment was provided as outlined in the Animal Care and Use Committee of Wake Forest University Nonhuman Primate Environmental Enrichment Plan.

Apparatus
The apparatus consisted of a ventilated, sound-attenuating experimental chamber (1.5 0.74 0.76 m; Med Associates, East Fairfield, VT). Two retractable response levers (5 cm wide) were located on one side of the chamber with a horizontal row of three stimulus lights 14 cm above each lever and a food receptacle located between the levers. The receptacle was connected with a Tygon tube to a pellet dispenser (Gerbrands Corp., Arlington, MA) located on the top of the chamber for delivery of 1-g banana-flavored food pellets (Bio-Serv, Frenchtown, NJ). An infusion pump (Cole-Parmer, Inc., Chicago, IL) was located on the top of the chamber. Experimental sessions were conducted 5-7 days/week while monkeys were seated in a primate restraint chair within the operant conditioning chamber.

Catheter Implantation
All subjects were surgically prepared with a chronic indwelling venous catheter into a major vein (femoral, internal or external jugular or brachial) and subcutaneous vascular access port (Access Technologies, Skokie, Ill., USA) under sterile conditions as previously described (Czoty et al. 2004). To prolong patency, each port and catheter was flushed with a solution of heparinized saline (100 U/ml) each day.

Procedure
Experiment 1: Effects of noncontingent cocaine on response allocation during concurrent availability of saline and food. Subjects (n=8) in this experiment had extensive experience self-administering cocaine under a concurrent FR 50 schedule of cocaine and food presentation described previously (Czoty et al. 2005). Briefly, 50 consecutive responses on one lever produced an injection of cocaine; completion of an FR 50 on the other lever produced a food pellet. Responses emitted on the alternate lever before completion of an FR 50 reset the response requirement. Sessions ended after 30 total reinforcers had been earned or 60 min had elapsed, whichever came first. Under this schedule, response-contingent cocaine (0.003-0.1 mg/kg) presentation resulted in dose-dependent increases in the percentage of responses emitted on the injection lever (Czoty et al. 2005). In the present studies, saline was substituted for a dose of cocaine that resulted in >90% injection-lever responding (0.03 or 0.1 mg/kg per injection). When response allocation stabilized, such that < 5% of the total responses were allocated to the injection lever for three consecutive days, a noncontingent injection of cocaine (0.01-0.56 mg/kg, i.v.) was administered immediately before the session. Each dose was administered in mixed order across monkeys and the entire cocaine dose-response curve was determined under the saline, food choice conditions before re-establishing cocaine self-administration.

Experiment 2: Effects of cocaine self-administration on reinstatement of extinguished food-reinforced responding. Cocaine-nave subjects (n=5) were trained to respond under an FR 50 schedule of food presentation on the right lever. Sessions began with illumination of the white light above the lever; completion of 50 responses resulted in the white light being extinguished, illumination of the red light for 10 sec and delivery of a food pellet, followed by a 10-sec timeout period in which the chamber was dark and responding had no scheduled consequences. The left lever was not extended into the chamber. Sessions lasted until 30 reinforcers had been obtained or 60 min had elapsed. Once response rates and number of reinforcers were deemed stable, the food pellet dispenser was unplugged and food-maintained responding was extinguished. Under these conditions, 50 responses still produced changes in stimulus lights but no food pellet was delivered. Responding was deemed extinguished when the number of reinforcers earned was less than 20% of those earned during baseline sessions for three consecutive sessions. Next, food pellets (1 or 5) or cocaine injections (0.03-1.0 mg/kg, IV) were administered non-contingently immediately prior to the session. It is important to note that, because catheters were flushed with heparinized saline immediately before each extinction session, data from non-cocaine priming sessions represent the effects of a priming injection of saline. Food pellets were delivered into the food receptacle via manual operation of the pellet dispenser. After a food or cocaine prime was examined during an extinction session, at least one baseline extinction session was conducted before the next prime was administered. The order of presentation of these stimuli was randomized across subjects.

When the effects of noncontingent cocaine and food had been determined, monkeys were exposed to cocaine self-administration on the opposite (left) lever in the presence of the white light; the right lever remained retracted during cocaine self-administration sessions. Cocaine- and food-reinforced responding were maintained on opposite levers so that the contingencies for the different reinforcers would be associated with topographically different responses. With the white light illuminated, responding was maintained under an FR 50 schedule of 0.03 mg/kg per injection cocaine for 11 0.6 sessions (range: 10-13 sessions). The dose was chosen based on previous results within our laboratory that this is the lowest dose that maintains responding above saline (control) levels (Czoty et al., 2005) and the duration of self-administration was chosen to conservatively assure that acquisition of cocaine self-administration had occurred, which we previously established to be within 7 sessions (e.g., Nader et al., 2002). At the end of that period, food-reinforced responding was re-established on the original (right) lever while the left lever remained retracted. When food-maintained responding was stable, responding was extinguished and the effects of noncontingent food and cocaine were re-determined as described above.

Please email:  PAUL W. CZOTY, pczoty@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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