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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA004136-04
Application #
3209338
Study Section
Pharmacology I Research Subcommittee (DABR)
Project Start
1986-04-01
Project End
1992-03-31
Budget Start
1989-05-01
Budget End
1990-03-31
Support Year
4
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Type
Schools of Medicine
DUNS #
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Shelnutt, S R; Gunnell, M; Owens, S M (1999) Sexual dimorphism in phencyclidine in vitro metabolism and pharmacokinetics in rats. J Pharmacol Exp Ther 290:1292-8
Laurenzana, E M; Owens, S M (1997) Brain microsomal metabolism of phencyclidine in male and female rats. Brain Res 756:256-65
Laurenzana, E M; Owens, S M (1997) Metabolism of phencyclidine by human liver microsomes. Drug Metab Dispos 25:557-63
Sharma, U; Roberts, E S; Kent, U M et al. (1997) Metabolic inactivation of cytochrome P4502B1 by phencyclidine: immunochemical and radiochemical analyses of the protective effects of glutathione. Drug Metab Dispos 25:243-50
Owens, S M (1997) Antibodies as pharmacokinetic and metabolic modifiers of neurotoxicity. NIDA Res Monogr 173:259-72
Shelnutt, S R; Cornett, L E; Owens, S M (1997) Phencyclidine continuous dosing produces a treatment time-dependent regulation of rat CYP2C11 function, protein expression and mRNA levels. J Pharmacol Exp Ther 281:574-81
Shelnutt, S R; Badger, T M; Owens, S M (1996) Phencyclidine metabolite irreversible binding in the rat: gonadal steroid regulation and CYP2C11. J Pharmacol Exp Ther 277:292-8
Laurenzana, E M; Sorrels, S L; Owens, S M (1995) Antipeptide antibodies targeted against specific regions of rat CYP2D1 and human CYP2D6. Drug Metab Dispos 23:271-8
Owens, S M; Gunnell, M; Laurenzana, E M et al. (1993) Dose- and time-dependent changes in phencyclidine metabolite covalent binding in rats and the possible role of CYP2D1. J Pharmacol Exp Ther 265:1261-6
Wessinger, W D; Owens, S M (1991) Chronic administration of phencyclidine: pharmacokinetic comparison of intravenous and subcutaneous infusions in Sprague-Dawley rats. Drug Metab Dispos 19:719-21

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