Modification of pharmacokinetic and abuse-related effects of cocaine by human-derived cocaine hydrolase in monkeys
Date
2012-01-20
Authors
Schindler, Charles W.
Justinova, Zuzana
Lafleur, David
Woods, Doug
Roschke, Viktor
Sklair-Tavron, Liora
Redhi, Godfrey H.
Yasar, Sevil
Bergman, Jack
Goldberg, Steven R.
Journal Title
Journal ISSN
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Abstract
Although substantial research effort has focused on developing pharmacological treatments for
cocaine abuse, no effective medications have been developed. Recent studies show that enzymes
that metabolize cocaine in the periphery, forestalling its entry into the brain, can prevent cocaine
toxicity and its behavioral effects in rodents. Here we report on effects of one such enzyme (Albu-
CocH) on the pharmacokinetic and behavioral effects of cocaine in squirrel monkeys. Albu-CocH
was developed from successive mutations of human butyrylcholinesterase (BChE) and has 1000-
fold greater catalytic activity against cocaine than naturally occurring BChE. Pharmacokinetic
studies showed that Albu-CocH (5 mg/kg) had a half-life of 56.6 hours in squirrel monkeys. In
these studies, plasma levels of cocaine following i.v. 1 mg/kg cocaine were reduced two hours
after administration of Albu-CocH, whereas plasma levels of the cocaine metabolite ecgonine
methyl ester were increased. These effects were still evident 72 hrs following Albu-CocH
administration. In behavioral experiments in monkeys, pretreatment with 5 mg/kg Albu-CocH
dramatically decreased self-administration of a reinforcing dose of i.v. cocaine (30 μg/kg/
injection) for over 24 hours. Pretreatment with 5 mg/kg Albu-CocH also attenuated the
reinstatement of extinguished cocaine self-administration by an i.v. priming injection of cocaine
(0.1 or 0.3 mg/kg) and, in separate studies, attenuated the discriminative stimulus effects of
cocaine. The ability of Albu-CocH to attenuate the abuse-related effects of cocaine in squirrel monkeys indicates that further investigation of BChE mutants as potential treatment for cocaine
abuse and toxicity is warranted.
Description
Keywords
cocaine , hydrolase , self-administration , reinstatement , discrimination , squirrel monkeys