The long term goal of this clinician scientist development award is to understand how early events, immediately after drug use, can affect the outcome of substance abuse. In these studies, the investigators will examine the interrelationships among pharmacokinetic, neurochemical and behavioral responses for two prototypic stimulant drugs of abuse (methamphetamine and phencyclidine). The study of the common and diverse mechanisms of stimulant effects in animal models of real-life human drug use should lead to more rational treatment plans in acute care settings and to a better understanding of the long-term consequences of stimulant abuse. To accomplish these goals, the investigators will perform a separate series of identical studies for each of the drugs. First, a systematic pharmacokinetic study of plasma and tissue concentrations will be conducted to determine the rate and extent of central nervous system (CNS) drug penetration. Second, dose-response relationships for neurochemical and behavioral responses will be determined. In these studies, rapid in vivo electrochemical changes in CNS dopamine levels in freely moving animals will be measured. These data will then be used to develop a combined pharmacokinetic- pharmacodynamic model of drug response for each drug. Third, the effects of route (iv vs. intraperitoneal) and rate of administration on neurochemical and behavioral responses will be measured. These studies should provide a neurochemical basis for why drug abusers usually prefer rapid routes of administration (iv and smoking) over other modes of administration (e.g, oral). Fourth, the combined models of abuse will be tested and extended using newly invented therapeutic agents. High affinity drug- specific antibodies will be used to rapidly reduce brain concentrations. The effects of this therapy on neurochemical and behavioral responses to each of the prototypic drugs will be analyzed. Scientific growth will be aided through collaboration with a well established mentor, consultant, and other scientists. Specific training will be obtained in the areas of analytical and behavioral pharmacology, statistics, computer modeling, and neuroscience.
