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 A better understanding of the behavioral syndrome observed in animals when chronic PCP is withdrawn could have general applicability toward understanding the abuse of other drugs which, like PCP, do not produce overt physiological signs of withdrawal in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.
