The problem of drug addiction continues to plague society. In particular, cocaine, amphetamines, and nicotine represent the major substances of abuse leading to dependence and significant behavior modification. A number of pharmacotherapies and psychosocial programs have been implemented over the years to aid in cessation, detoxification and relapse prevention with limited success. Cocaine abuse remains prevalent, people continue to smoke, a variety of amphetamines litter the recreational drug market, and the abuse of heroin is on the rise especially among adolescents, all with alarming statistics. In this regard, alternative therapies are crucial, either as stand-alone treatments or to complement those already in existence, if progress is to be made in treating substance dependence. This proposal provides the foundation of an immunopharmacological therapy for drug addiction based on catalytic monoclonal antibodies (mAbs) that degrade drugs of abuse. The specific aims encompass 1) anti-cocaine catalytic mAb investigations in a rat locomotor model for testing efficacy, pharmacokinetics, and improvements in catalytic activity using cutting-edge recombinant DNA and structure-based strategies. Some mAbs nave been prepared and are ready for study. As improved catalysts become available from antibody engineering, they will be characterized and then tested in rats. 2) Synthesis of haptens to elicit catalytic mAbs specific for the degradation of amphetamines and nicotine. The novel hapten designs are derived using a "bait and switch" approach developed in our laboratory. Preliminary studies of mAbs against MDMA ("ecstasy") are in progress. Rationales are presented for the requirements of catalytic mAbs with regard to drug dependence in humans and their eventual realization as clinical therapeutics. Although the complete elimination of drug addiction may be an ideal, catalytic mAbs along with other pharmacological agents and counseling programs to alleviate addiction problems would prove beneficial for society. [unreadable] [unreadable]