The long-term objective of this project is to use immunological approaches to describe the receptor-mediated effects of phencyclidine (PCP). This unique and promising approach involves the construction of the PCP receptor and ligand system with anti-drug and anti-idiotypic antibodies, respectively. This approach in other receptor studies has shown that appropriately modeled anti-drug antibodies can mimic the recognition pattern of the receptor. These anti-drug antibodies can then be used to stimulate formation of antibodies against the binding site of the anti-drug antibody (i.e., anti-idiotypic antibodies). These anti-idiotypic antibodies should contain an internal peptide image of the primary antibody binding site, which should bind to the neuroreceptor. Therefore, the goal of this research is to develop an immunological model for the PCP receptor and ligand system. The appropriate drug and orientation for molecular mimcry of the neuroreceptor will be determined in preliminary studies by production of rabbit antibodies against different orientations of the PCP molecule and against its more potent analogue, TCP (1-[1-(2-thienyl)cyclohexyl]piperidine), coupled to protein. The choice of an appropriate hapten will be based on RIA cross-reactivity studies with PCP and its analogues and cross-reactivity with the recently discovered endogenous peptide ligand for the PCP receptor. Next, mouse monoclonal anti-drug antibodies will be produced, followed by the production of rat monoclonal anti-idiotype antibodies. The anti-idiotope antibodies will be used for inhibition studies in a PCP receptor binding assay and both monoclonal antibodies will be used for immunohistochemical mapping of cross-reacting sites in the central nervous system. Finally, the in vivo behavioral effects after central nervous system routes of administration and pharmacokinetic parameters after i.c.v. and i.v. administration of the monoclonal antibodies fragments will be studied.
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