Long-term blockade of cocaine self-administration and locomotor activation in rats by an adenoviral vector-delivered cocaine hydrolase

John R. Smethells, Natashia Swalve, William Stephen Brimijoin, Yang Gao, Robin J. Parks, Adam Greer, Marilyn E. Carroll

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

A promising approach in treating cocaine abuse is to metabolize cocaine in the blood using a mutated butyrylcholinesterase (BChE) that functions as a cocaine hydrolase (CocH). In rats, a helper-dependent adenoviral (hdAD) vector-mediated delivery of CocH abolished ongoing cocaine use and cocaine-primed reinstatement of drug-seeking for several months. This enzyme also metabolizes ghrelin, an effect that may be beneficial in maintaining healthy weights. The effect of a single hdAD-CocH vector injection was examined in rats on measures of anxiety, body weight, cocaine self-administration, and cocaine-induced locomotor activity. To examine anxiety, periadolescent rats were tested in an elevated-plus maze. Weight gain was then examined under four rodent diets. Ten months after CocH-injection, adult rats were trained to self-administer cocaine intravenously and, subsequently, cocaine-induced locomotion was tested. Viral gene transfer produced sustained plasma levels of CocH for over 13 months of testing. CocH-treated rats did not differ from controls in measures of anxiety, and only showed a transient reduction in weight gain during the first 3 weeks postinjection. However, CocH-treated rats were insensitive to cocaine. At 10 months postinjection, none of the CocH-treated rats initiated cocaine self-administration, unlike 90% of the control rats. At 13 months postinjection, CocH-treated rats showed no cocaine-induced locomotion, whereas control rats showed a dose-dependent enhancement of locomotion. CocH vector produced a long-term blockade of the rewarding and behavioral effects of cocaine in rats, emphasizing its role as a promising therapeutic intervention in cocaine abuse.

Original languageEnglish (US)
Pages (from-to)375-381
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume357
Issue number2
DOIs
StatePublished - May 1 2016

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Self Administration
Hydrolases
Cocaine
Locomotion
Cocaine-Related Disorders
Anxiety
Weight Gain
Body Weights and Measures
Butyrylcholinesterase

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Long-term blockade of cocaine self-administration and locomotor activation in rats by an adenoviral vector-delivered cocaine hydrolase. / Smethells, John R.; Swalve, Natashia; Brimijoin, William Stephen; Gao, Yang; Parks, Robin J.; Greer, Adam; Carroll, Marilyn E.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 357, No. 2, 01.05.2016, p. 375-381.

Research output: Contribution to journalArticle

Smethells, John R. ; Swalve, Natashia ; Brimijoin, William Stephen ; Gao, Yang ; Parks, Robin J. ; Greer, Adam ; Carroll, Marilyn E. / Long-term blockade of cocaine self-administration and locomotor activation in rats by an adenoviral vector-delivered cocaine hydrolase. In: Journal of Pharmacology and Experimental Therapeutics. 2016 ; Vol. 357, No. 2. pp. 375-381.
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