Phencyclidine abuse has persisted at a constant rate throughout the 1980s. There is increased public concern for the practice of smoking PCP with cocaine base (space base). There is increased scientific interest in PCP as an NMDA receptor antagonist. PCP-like drugs may prevent damage to the cerebral cortex resulting from stroke, cardiac arrest, asphyxia and brain injury. Progress on this grant has focused on developing a behavioral profile of PCP in monkeys. The models of PCP self-administration have extended the PCP self-administration research to other drugs and other routes of administration (i.e., cocaine smoking). There are two overall goals of this competing renewal application. The first is to devise strategies for preventing and reducing drug self-administration and the aversive effects of withdrawal. Environmental strategies (arranging contingencies of other rewarding events in the environment and applying a behavioral economic analysis) and pharmacological strategies (pretreatment with drugs that have shown to be promising candidates for the clinical management of drug abuse) will be tested for their effects on PCP self- administration and withdrawal. The second is to expand the oral PCP model to new areas of research, such as development of an animal model of relapse and the application of behavioral economics to drug abuse. The PCP model will also be extended to other drugs and routes of administration. There are four specific aims. The first two are extensions of current work and the last two represent new directions.
The first aim i s to examine environmental and pharmacological methods for reducing self-administration of orally-delivered PCP. A behavioral economic analysis will compare FR size (price) of PCP and an alternative reinforcer to consumption of these substances, and cross-price elasticity coefficients will be obtained as a quantitative index of change in demand for drug due to price and the availability of the alternative substance. Behavioral history with an alternative reinforcer will also be evaluated. Pharmacological methods will include injections of buprenorphine and antidepressants (fluoxetine, sertraline) before self-administration sessions.
The second aim i s to test environmental and pharmacological strategies for reducing behavioral disruptions resulting from PCP withdrawal. The behavioral economics of presenting a nondrug alternative reinforcer during PCP withdrawal as well as a history of exposure to that substance will be investigated. Pharmacological treatments to be tested are buprenorphine, sertraline or fluoxetine. The sensitive behavioral dependence model developed with PCP will also be used to study withdrawal effects from self-administration of buprenorphine and MK-801 (a potent NMDA antagonist).
The third aim i s to develop a model of relapse and investigate environmental and pharmacological factors that initiate and suppress relapse. Environmental factors will be the presence and absence of alternative reinforcers such a food and preferred liquids. Pharmacological factors will be other drugs of abuse (e.g., opiates, ethanol) and pharmacotherapeutic drugs (e.g., buprenorphine).
The fourth aim i s to extend the oral self-administration of PCP to other drugs and routes of administration. Buprenorphine and a related NMDA antagonist, MK-801 will be smoking. Heart rate, blood pressure and activity (by telemetry) will be continuously monitored during PCP self-administration, withdrawal, relapse, and reinitiation of drug- taking behavior. The effects of environmental and pharmacological interventions on these measures will be analyzed. The significance of comparing a range of environmental and pharmacological interventions across critical phases of the addition process, is that it will provide important information on the most effective intervention strategy for a specific behavioral event (e.g., maintenance, withdrawal and relapse). The health related consequence of this research is that it will provide animal models of prevention and reduction of drug abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA002486-15
Application #
2116581
Study Section
Special Emphasis Panel (SRCD (32))
Project Start
1980-01-01
Project End
1995-12-31
Budget Start
1994-01-01
Budget End
1994-12-31
Support Year
15
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Psychiatry
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Carroll, Marilyn E; Lynch, Wendy J (2016) How to study sex differences in addiction using animal models. Addict Biol 21:1007-29
Carroll, Marilyn E; Collins, Molly; Kohl, Emily A et al. (2016) Sex and menstrual cycle effects on chronic oral cocaine self-administration in rhesus monkeys: Effects of a nondrug alternative reward. Psychopharmacology (Berl) 233:2973-84
Carroll, Marilyn E; Smethells, John R (2015) Sex Differences in Behavioral Dyscontrol: Role in Drug Addiction and Novel Treatments. Front Psychiatry 6:175
Carroll, Marilyn E; Kohl, Emily A; Johnson, Krista M et al. (2013) Increased impulsive choice for saccharin during PCP withdrawal in female monkeys: influence of menstrual cycle phase. Psychopharmacology (Berl) 227:413-24
Brand, Theresa; Anderson, George M (2011) The measurement of platelet-poor plasma serotonin: a systematic review of prior reports and recommendations for improved analysis. Clin Chem 57:1376-86
Carroll, Marilyn E; Anker, Justin J (2010) Sex differences and ovarian hormones in animal models of drug dependence. Horm Behav 58:44-56
Carroll, Marilyn E; Mach, Jami L; La Nasa, Rachel M et al. (2009) Impulsivity as a behavioral measure of withdrawal of orally delivered PCP and nondrug rewards in male and female monkeys. Psychopharmacology (Berl) 207:85-98
Newman, Jennifer L; Perry, Jennifer L; Carroll, Marilyn E (2008) Effects of altering reinforcer magnitude and reinforcement schedule on phencyclidine (PCP) self-administration in monkeys using an adjusting delay task. Pharmacol Biochem Behav 90:778-86
Newman, Jennifer L; Perry, Jennifer L; Carroll, Marilyn E (2007) Social stimuli enhance phencyclidine (PCP) self-administration in rhesus monkeys. Pharmacol Biochem Behav 87:280-8
Newman, Jennifer L; Thorne, Joseph J; Batulis, David K et al. (2006) Effects of menstrual cycle phase on the reinforcing effects of phencyclidine (PCP) in rhesus monkeys. Pharmacol Biochem Behav 85:584-91

Showing the most recent 10 out of 44 publications