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.

Three 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.

Thesaurus Terms:
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
Department: PSYCHIATRY
Project Start: 01-JAN-1980
Project End: 31-MAR-2007
ICD: NATIONAL INSTITUTE ON DRUG ABUSE
IRG: ZRG1

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, Minnesota

Animals

Sixteen adult male rhesus monkeys (Macaca mulatta) served as experimental subjects.

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.

These monkeys 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 food pellets.

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 cocaine group.

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.

The 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.

Animals had visual, auditory, and olfactory contact with each other throughout the study. They were monitored at least every other day by the veterinary staff.

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.

Apparatus
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 responses.

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.

A primate 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.