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

Marilyn E. Carroll, Natalie E. Zlebnik, Justin J. Anker, Thomas R. Kosten, Frank M. Orson, Xiaoyun Shen, Berma Kinsey, Robin J. Parks, Yang Gao, William Stephen Brimijoin

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere43536
JournalPLoS One
Volume7
Issue number8
DOIs
StatePublished - Aug 17 2012

Fingerprint

Gene transfer
cocaine
Hydrolases
Locomotion
hydrolases
Cocaine
gene transfer
locomotion
Vaccines
vaccines
Genes
injection
Butyrylcholinesterase
Rats
Injections
pretreatment
cholinesterase
rats
mice
Tetraisopropylpyrophosphamide

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Combined cocaine hydrolase gene transfer and anti-cocaine vaccine synergistically block cocaine-induced locomotion. / 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, William Stephen.

In: PLoS One, Vol. 7, No. 8, e43536, 17.08.2012.

Research output: Contribution to journalArticle

Carroll, ME, Zlebnik, NE, Anker, JJ, Kosten, TR, Orson, FM, Shen, X, Kinsey, B, Parks, RJ, Gao, Y & Brimijoin, WS 2012, 'Combined cocaine hydrolase gene transfer and anti-cocaine vaccine synergistically block cocaine-induced locomotion', PLoS One, vol. 7, no. 8, e43536. https://doi.org/10.1371/journal.pone.0043536
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, William Stephen. / Combined cocaine hydrolase gene transfer and anti-cocaine vaccine synergistically block cocaine-induced locomotion. In: PLoS One. 2012 ; Vol. 7, No. 8.
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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.",
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