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 mimicry 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 resulting anti-idiotope antibodies will be studied as a new typeof ligand in a PCP receptor binding assay. Finally, the antigen binding fragments (Fab and/or Fab prime 2) of the antibodies will be administered in vivo to rats by central routes of administration to determine their behavioral effects and to dogs by both intravenous and intracerebroventricular injection to determine their pharmacokinetic parameters.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02DA000110-05
Application #
3069458
Study Section
Special Emphasis Panel (DABA)
Project Start
1986-07-01
Project End
1991-07-31
Budget Start
1990-08-01
Budget End
1991-07-31
Support Year
5
Fiscal Year
1990
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
Hardin, J S; Wessinger, W D; Proksch, J W et al. (1998) Pharmacodynamics of a monoclonal antiphencyclidine Fab with broad selectivity for phencyclidine-like drugs. J Pharmacol Exp Ther 285:1113-22
Lim, K; Owens, S M; Arnold, L et al. (1998) Crystal structure of monoclonal 6B5 Fab complexed with phencyclidine. J Biol Chem 273:28576-82
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
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; 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
Valentine, J L; Owens, S M (1996) Antiphencyclidine monoclonal antibody therapy significantly changes phencyclidine concentrations in brain and other tissues in rats. J Pharmacol Exp Ther 278:717-24

Showing the most recent 10 out of 22 publications