The long-term objective of this project is to use immunopharmacological reagents (both heterologous and monoclonal) to study the receptor-mediated effects of phencyclidine (PCP). This unique and promising method involves the construction of the PCP receptor and neuroligand system with anti-drug and anti- idiotypic antibodies, respectively. This approach is other receptor studies has shown that appropriately modeled anti-drug antibodies can mimic the recognition pattern of the receptor, and these antibodies can be used to stimulate formation of antibodies against the binding site of the anti-drug antibody (i.e., anti- idiotypic antibodies). Some of these anti-idiotypes should contain an internal image of the primary antibody binding site, which in turn should bind to the neuroreceptor. In some studies, appropriately modeled anti-drug antibodies have even detected the presence of endogenous neuroligands. For this project, antibodies have already been generated which can mimic the arylcyclohexylamine recognition pattern of the PCP receptor and these antibodies are being used to detect and purify an immunoreactive PCP-like endogenous ligand using large scale liquid chromatography and affinity chromatography techniques. The monoclonal antibodies against this anti-PCP hapten will be used to generate monoclonal anti-idiotypic antibodies (hopefully, the internal image of the PCP receptor). These anti-PCP and anti-idiotypic antibodies will be characterized by using radioimmunoassay and receptor binding techniques and use for immunohistochemical mapping of endogenous ligands and PCP receptors in the central nervous system. The in vivo behavioral effects of these antibodies will be studied after central nervous system administration. In other studies, a battery of anti-arylcyclohexylamine antibodies will be used to characterize PCP metabolite covalent binding in animal and human tissue specimens. The cross-reacting PCP metabolite-protein conjugates will then be used to screen for human anti-PCP antibodies in a population of chronic PCP abusers, and in previous PCP users exhibiting late-appearing, long-lasting, schizophrenic effects. Finally, the pharmacokinetics of the smallest antibody antigen binding fragment, FV, will be determined. Knowledge gained from these studies should be important for understanding the receptor mediated effects of PCP and the possible long-term effects of PCP abuse in humans.
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