The long-term objectives for the applicant are to better understand the neurolological and metabolic consequences of phencyclidine (PCP) abuse and to develop immunotherapeutic methods for the treatment of drug abuse. The first objective is designed to test the hypothesis that PCP metabolites can lead to long-term, detrimental effects through irreversible binding to critical macromolecules in the central nervous system and at peripheral sites. For these experiments, an animal model will to provide a source of tissues for in vitro studies of the molecular mechanism(s) underlying the vulnerability to PCP metabolite covalent binding. The in vitro experiments will include studies of specific isoenzyme pathways and other potential targets of covalent binding in normal animals and in animals which are genetically deficient in the isoenzyme pathways responsible for generating the electrophillic metabolites. The research plan will include a series of complimentary biochemical, immunological, physical/chemical, tissue culture and neuroreceptor binding studies. When considered together, these molecular and whole animal data should allow us to better predict the neurobiological consequences of PCP abuse. In a second project, high affinity anti-PCP monoclonal antibodies (MAb) will be used as a treatment to block and/or reverse the acute toxicity of PCP. For these experiments, the Fab (antigen binding fragments) of anti-PCP MAb will be used to systematically study the ability of antibodies to affect the pharmacokinetics and acute toxicity of PCP in rats. First, about 613.5 grams of monoclonal anti-PCP Fab will be generated and purified. Then, using toxic doses of PCP, the effects of these anti-PCP Fab on PCP pharmacokinetics will be determined. Finally, with the knowledge gained in these pharmacokinetic studies, rational strategies will be developed to test the ability of these antibody antagonists to block and reverse the effects of toxic doses of PCP. Knowledge gained from these studies could lead to an important treatment for PCP toxicity in humans. During this funding period the applicant will continue to develop as a research scientist in the areas of immunology, experimental therapeutics, pharmaceutical biotechnology and neuroscience. Scientific growth will be aided through collaboration and consultations with other scientist and visits to other research facilities. Specific training will be obtained in the areas of molecular biology, tissue culture and neuroscience.
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