Abstract
Mice and rats were tested for reduced sensitivity to cocaine-induced hyper-locomotion after pretreatment with anti-cocaine antibody or cocaine hydrolase (CocH) derived from human butyrylcholinesterase (BChE). In Balb/c mice, direct i.p. injection of CocH protein (1 mg/kg) had no effect on spontaneous locomotion, but it suppressed responses to i.p. cocaine up to 80 mg/kg. When CocH was injected i.p. along with a murine cocaine antiserum that also did not affect spontaneous locomotion, there was no response to any cocaine dose. This suppression of locomotor activity required active enzyme, as it was lost after pretreatment with iso-OMPA, a selective BChE inhibitor. Comparable results were obtained in rats that developed high levels of CocH by gene transfer with helper-dependent adenoviral vector, and/or high levels of anti-cocaine antibody by vaccination with norcocaine hapten conjugated to keyhole limpet hemocyanin (KLH). After these treatments, rats were subjected to a locomotor sensitization paradigm involving a “training phase" with an initial i.p. saline injection on day 1 followed by 8 days of repeated cocaine injections (10 mg/kg, i.p.). A 15-day rest period then ensued, followed by a final “challenge" cocaine injection. As in mice, the individual treatment interventions reduced cocaine-stimulated hyperactivity to a modest extent, while combined treatment produced a greater reduction during all phases of testing compared to control rats (with only saline pretreatment). Overall, the present results strongly support the view that anti-cocaine vaccine and cocaine hydrolase vector treatments together provide enhanced protection against the stimulatory actions of cocaine in rodents. A similar combination therapy in human cocaine users might provide a robust therapy to help maintain abstinence.
Highlights
Recent animal and human studies have yielded promising results with antibody- and enzyme-based approaches to treatment of cocaine addiction by intercepting drug molecules before they reach the brain
To discover whether cocaine hydrolase (CocH) suppresses locomotor effects entirely by selective enzymatic destruction of cocaine, similar experiments were conducted in mice treated with iso-OMPA, an irreversible organophosphate anticholinesterase selective for BChE and BChE-mutants like CocH (Fig. 2)
Locomotor stimulation was again absent in mice pretreated with 1 mg/kg CocH without isoOMPA
Summary
Recent animal and human studies have yielded promising results with antibody- and enzyme-based approaches to treatment of cocaine addiction by intercepting drug molecules before they reach the brain. This line of work began with investigations of anti-cocaine antibodies [1,2], later including monoclonal antibodies [3,4], and vaccines [5,6,7]. By employing novel gene-transfer vectors, helper-dependent adenoviral vectors, it has been possible to generate high circulating levels of CocH or similar enzymes in rats and mice for a year or more after a single treatment [22]. The effective blockade of this ‘‘drug-primed reinstatement behavior’’, an animal model of relapse, supports the concept that drug interception in the peripheral circulation may aid recovering drug users to avoid resumption of drug-taking
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