Lasting reduction of cocaine action in neostriatum--a hydrolase gene therapy approach.

Full Abstract

We previously found that a quadruple mutant cocaine hydrolase derived from human butyrylcholinesterase [termed cocaine esterase (CocE)] can suppress or reverse cocaine toxicity and abolish drug-primed reinstatement in rats. Here, we examined whether gene transfer of CocE reduces cocaine actions in brain reward centers. Early experiments used a standard, early region 1-deleted adenoviral vector, which, after intravenous delivery of 10(10) plaque-forming units, caused plasma cocaine hydrolase activity to rise 25,000-fold between day 4 and day 7. During this period, under a protocol that typically induces FosB expression in the caudate nucleus, these rats and unprotected controls given only empty vector or saline were subjected to repeated twice-daily injections of cocaine (30 mg/kg i.p.). Immunohistochemistry of the neostriatum on day 7 showed many FosB-reactive nuclei in unprotected rats but few if any in rats pretreated with active vector, which resembled rats never exposed to cocaine. Western blots confirmed this result. In contrast there was a more localized protection against cocaine-elicited FosB induction when hydrolase vector was injected directly into the ventral striatum, which generated high transgene expression in many neurons of the target area. Similar results were obtained with systemic and local injection of a more efficient helper-dependent adenoviral vector, which transduced high levels of hydrolase for at least 2 months, with lesser expression continued up to 1 year. Behavioral tests are now warranted to determine whether such effects can reduce drug-seeking behavior and lower the probability of relapse.

Author information

Author/s: Gao, Yang (Y); Brimijoin, Stephen (S);

Affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA.

Grants: R01-DA023979 (Agency:NIDA NIH HHS)

Journal and publication information

Publication Type: Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther), published in United States. (Language: eng)

Reference: 2009-Aug; vol 330 (issue 2) : pp 449-57

Dates: Created 2009/07/21; Completed 2009/08/19;

PMID: 19478136, status: MEDLINE (last retrieval date: 8/21/2009, IMS Date: )

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