Cocaine abuse is a major medical and public health concern in the United States, with approximately 2.1 million people dependent on cocaine. Pharmacological approaches to the treatment of cocaine addiction have thus far been disappointing, and new therapies are urgently needed. This paper describes an immunological approach to cocaine addiction. Antibody therapy for neutralization of abused drugs has been described previously, including a recent paper demonstrating the induction of anti-cocaine antibodies. However, both the rapidity of entry of cocaine into the brain and the high doses of cocaine frequently encountered have created challenges for an antibody-based therapy. Here we demonstrate that antibodies are efficacious in an animal model of addiction. Intravenous cocaine self-administration in rats was inhibited by passive transfer of an anti-cocaine monoclonal antibody. To actively induce anti-cocaine antibodies, a cocaine vaccine was developed that generated a high-titer, long-lasting antibody response in mice. Immunized mice displayed a significant change in cocaine pharmacokinetics, with decreased levels of cocaine measured in the brain of immunized mice only 30 seconds after intravenous (i.v.) administration of cocaine. These data establish the feasibility of a therapeutic cocaine vaccine for the treatment of cocaine addiction.

Antagonism of cocaine self-administration across a range of doses is feasible after immunization with a cocaine vaccine as long as antibody levels are of a sufficient concentration.

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The flavoprotein mercuric reductase encoded on the transposon Tn501 from Pseudomonas aeruginosa has previously been shown to contain a redox-active cystine at the active site and to share many spectrophotometric, physical, and kinetic properties with the nicotinamide disulfide oxidoreductases [Fox, B., & Walsh, C. T. (1982) J. Biol. Chem. 257, 2498-2503], Oxidized mercuric reductase was unreactive toward iodo[l4C] acetamide, yet the two-electron-reduced form, in which the thiols of the redox-active cystine are free, reacted to give a monoalkylated derivative. The major 14C-labeled peptide from a tryptic digestion of labeled mercuric reductase was purified by high-performance liquid chromatography. The partial amino acid sequence of this peptide is Gly-Thr-Ile-Gly-Gly-Thr-SCMC-Val-Asx-Val-Gly-SCMC-Val-Pro.

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