The objective of this research project is to develop a better understanding of drug dependence through investigations of the dependence producing properties of phencyclidine (PCP), a commonly abused drug in the U.S.. Drug dependence is a potential long-term consequence of chronic drug use. For some drugs, dependence is obvious because gross signs of abstinence (e.g., nausea, vomiting, tremors, convulsions, etc.) occur when chronic drug administration is stopped. Such signs of physical dependence are characteristic of withdrawal after chronic administration of drugs such as opiates, barbiturates and ethanol. The avoidance of these unpleasant abstinence effects is thought to play a significant role in the maintenance of drug self- administration and may contribute to relapse to drug use by former users. In contrast, there are other popular drugs of abuse, such as PCP, cocaine and marijuana, for which physical dependence in humans has not been unequivocally demonstrated. Nevertheless, laboratory animal studies employing operant behavior have clearly demonstrated disruptions in behavior after chronic administration of these drugs is stopped. It seems likely that such behavioral manifestations of dependence (which have been considered evidence of """"""""behavioral dependence""""""""), could, like physical dependence, also play a significant role in maintaining drug abuse. We have developed behavioral models of PCP dependence in rats using short-term, low dose exposure paradigms. Using these behavioral dependence models, we have examined some of the pharmacological, pharmacokinetic, biochemical and behavioral determinants of PCP dependence. The current proposal will extend the previous studies by attempting to define the receptor-mediated correlates of behavioral dependence on PCP. Quantitative behavioral methods which emulate the well-established techniques used for studying the physical dependence properties of abused drugs (i.e., the primary dependence and the substitution models) will be used to accomplish these goals. In addition, we will further explore changes in PCP-receptor number and affinity to determine their relationship to behavioral dependence. Receptor changes will be monitored during the development of tolerance, dependence, and subsequent recovery from abstinence-induced PCP withdrawal. A better understanding of the behavioral syndrome observed in animals when chronic PCP is withdrawn could have general applicability toward understanding the abuse of other drugs which, like PCP, do not produce overt physiological signs of withdrawal in humans. Identifying the behavioral and biochemical mechanisms contributing to behavioral dependence on PCP may lead to improved drug abuse treatment strategies. Basic research employing this integrated approach should also contribute to a better understanding of brain-behavior relationships.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA004278-06
Application #
2117114
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1986-12-01
Project End
1995-08-31
Budget Start
1993-09-01
Budget End
1995-08-31
Support Year
6
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Burke, T F; Buzzard, S; Wessinger, W D (1995) [3H]MK-801 binding to well-washed rat brain membranes following cessation of chronic phencyclidine treatment. Pharmacol Biochem Behav 51:435-8
Wessinger, W D (1995) Sexual dimorphic effects of chronic phencyclidine in rats. Eur J Pharmacol 277:107-12
Wessinger, W D (1994) Tolerance to and dependence on MK-801 (dizocilpine) in rats. Pharmacol Biochem Behav 49:1049-56
Wessinger, W D; Owens, S M (1991) Chronic administration of phencyclidine: pharmacokinetic comparison of intravenous and subcutaneous infusions in Sprague-Dawley rats. Drug Metab Dispos 19:719-21
Wessinger, W D; Owens, S M (1991) Phencyclidine dependence: the relationship of dose and serum concentrations to operant behavioral effects. J Pharmacol Exp Ther 258:207-15
Massey, B W; Wessinger, W D (1990) Alterations in rat brain [3H]-TCP binding following chronic phencyclidine administration. Life Sci 47:PL139-43
Owens, S M; McMillan, D E; Hardwick, W C et al. (1990) Phencyclidine pharmacokinetics and concentration-response relationships in the pigeon. Pharmacol Biochem Behav 35:797-801
Massey, B W; Wessinger, W D (1990) Effects of terminating chronic phencyclidine on schedule-controlled behavior in rats. Pharmacol Biochem Behav 36:117-21
Wessinger, W D; Owens, S M (1990) Influence of phencyclidine (PCP) pharmacokinetics on PCP dependence after i.v. and s.c. routes of administration. NIDA Res Monogr 105:431-2
Wessinger, W D (1987) Behavioral dependence on phencyclidine in rats. Life Sci 41:355-60