The long term objective of this project is to develop antibody-based therapy for use in reversing the in vivo toxicity of drugs of abuse in humans.
The specific aims of this project are designed to test the hypothesis that high affinity anti-drug monoclonal antibodies can be used as an antagonist to block and reverse the toxicity of drugs of abuse. Phencyclidine (PCP) has been chosen as a protytic ligand to test this hypothesis since its major sites of action i the central nervous system are far removed from the beneficial effects of most traditional treatment methods such as dialysis. In addition, PCP produces behavioral toxicity in humans that manifests as a wide variety of frightening effects including extreme violence, self-destruction and psychotic behavior, and even death at very high doses. For this project, a monoclonal antibody (MAb) was developed that binds PCP and other dangerous arylcyclohexylamines such as TCP (1-[1-(2-thienyl)cyclohexyl]piperidine) and PCE (N-ethyl-1-phenylcyclohexylamine) with high affinity relative to endogenous sites of action. The antigen binding fragments (Fab) of this MAb will be used to study its in vivo effects on PCP disposition (distribution, protein binding, metabolism and elimination) and on behavioral toxicity in male and female rats and dogs. The experiments in this proposal will proceed in a fashion that will allow a systematic testing of this hypothesis. First, approximately 200 g of monoclonal anti-PCP IgG will be generated in a non-mammalian bioreactor, digested to Fab and then purified to homogeneity. Then, the effect of this anti-PCP Fab on PCP renal elimination will be studied in rats. These studies will be used to determine if the elimination of the Fab is dose-dependent and to determine methods to optimize anti-PCP Fab associated renal elimination of PCP. Next, the effect of the anti-PCP Fab on arylcyclohexylamine toxicity will be studied in male and female rats at highly toxic, acute and chronic doses. Finally, the in vivo effects of anti-PCP Fab on PCP pharmacokinetics and acute toxicity in male and female dogs will be studied. These studies will be used to scale-up the therapy in an animal model that suffers from toxic effects at similar doses to humans. These integrated studies of pharmacokinetic and behavioral changes after immunotherapy will serve as a prototypic system to acquire knowledge that can be applied to antibody-based therapy for a wide variety of drugs with the common features of a high volume of distribution and primary sites of action in the central nervous system.
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|Naef, Lindsay; Srivastava, Lalit; Gratton, Alain et al. (2008) Maternal high fat diet during the perinatal period alters mesocorticolimbic dopamine in the adult rat offspring: reduction in the behavioral responses to repeated amphetamine administration. Psychopharmacology (Berl) 197:83-94|
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