Pharmacotherapies useful in the treatment of cocaine abuse have proven very difficult to identify. The traditional receptor antagonist approach does not appear appropriate for cocaine for a number of reasons. This proposal is designed to evaluate five protein-based medications that may be effective in blocking the behavioral and toxic effects of cocaine. Three of these medications are antibodies that have been raised against cocaine in mice. A fourth medication is butyrylcholinesterase, the enzyme that breaks down cocaine in the blood. The fifth medication is a novel catalytic antibody, Mab 15A10, which may combine the properties of binding and metabolizing. Each of these medications is postulated to act to reduce the rate of cocaine entry into the brain, either by a process of sequestration, or by a process of rapid breakdown, or both. This decrease in rate of brain entry should decrease both the toxicity and the abuse liabililty of cocaine. The test procedures for toxicity involve evaluation of the ability of several doses of each of these medications to block cocaine-induced blood pressure increases in rats and mice. As a control, a drug with a similar structure and action as cocaine, but without the esteratic bridge where BChE and Mab 15A10 act, will be evaluated in parallel with cocaine. The duration of cocaine antagonism, a critical aspect of a medication, will be evaluated using the blood pressure assay in mice. The test procedure for treatment of the abuse of cocaine is intravenous self-administration studies in rats. Here too, dose-response curves with cocaine and WIN 35065 will be established, and attempts to shift these curves to the right will be made with administration of each of the five medications. Studies in which the ability of BChE and Mab 15A10 to produce increases in the cocaine metabolite, egconine methyl ester are planned to demonstrate that both of these medications increase the rate of cocaine metabolism.
