Combined cocaine hydrolase gene transfer and anti-cocaine vaccine synergistically block cocaine-induced locomotion

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 spontaneou...

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Bibliographic Details
Published in:PloS one 2012-08, Vol.7 (8), p.e43536
Main Authors: Carroll, Marilyn E, Zlebnik, Natalie E, Anker, Justin J, Kosten, Thomas R, Orson, Frank M, Shen, Xiaoyun, Kinsey, Berma, Parks, Robin J, Gao, Yang, Brimijoin, Stephen
Format: Article
Language:English
Subjects:
Addictions
Adenoviridae - genetics
Anesthetics, Local - immunology
Anesthetics, Local - toxicity
Animals
Antibodies - administration & dosage
Antibodies - immunology
Attention deficit hyperactivity disorder
Biology
Butyrylcholinesterase - genetics
Butyrylcholinesterase - metabolism
Cocaine
Cocaine - immunology
Cocaine - toxicity
Combined Modality Therapy
Combined treatment
Combined vaccines
Departments
Drug abuse
Drug dosages
Enzymes
Experiments
Gait Disorders, Neurologic - chemically induced
Gait Disorders, Neurologic - physiopathology
Gait Disorders, Neurologic - therapy
Gene transfer
Gene Transfer Techniques
Genetic Vectors - genetics
Humans
Hydrolase
Hydrolases
Hyperactivity
Immunoglobulins
Immunology
Injection
Laboratory animals
Locomotion
Locomotor activity
Male
Medicine
Mice
Mice, Inbred BALB C
Motor Activity - genetics
Motor Activity - immunology
Motor Activity - physiology
Neurosciences
Pathology
Psychiatry
Rats
Rats, Wistar
Rodents
Saline solutions
Studies
Therapy
Time Factors
Treatment Outcome
Vaccination
Vaccines
Vaccines - administration & dosage
Vaccines - immunology
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0043536