Modification of pharmacokinetic and abuse‐related effects of cocaine by human‐derived cocaine hydrolase in monkeys

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.

Accelerating Cocaine Metabolism as an Approach to the Treatment of Cocaine Abuse and Toxicity

“…When rats and squirrel monkeys are pre-treated with Albu-CocH, cocaine plasma levels are reduced and EME levels are increased [64,65]. Albu-CocH is also able to reduce cocaine brain levels [66].…”

“…Albu-CocH has been shown to antagonize cocaine self-administration in rats responding on a progressive ratio schedule [67] and in squirrel monkeys responding on a fixed-ratio schedule [65]. In both rats and squirrel monkeys, Albu-CocH was also able to decrease cocaine-induced reinstatement of cocaine self-administration that had undergone extinction [65,66]. Finally, in squirrel monkeys, Albu-CocH is able to antagonize the discriminative stimulus effects of cocaine [65].…”

“…In both rats and squirrel monkeys, Albu-CocH was also able to decrease cocaine-induced reinstatement of cocaine self-administration that had undergone extinction [65,66]. Finally, in squirrel monkeys, Albu-CocH is able to antagonize the discriminative stimulus effects of cocaine [65]. In the effects on squirrel monkey self-administration, Albu-CocH had a duration of action of over 24 h. After 24 h these effects were diminished.…”

“…For example, while dopamine antagonists can reduce self-administration in rodents, slightly larger doses can also reduce operant responding for food [88]. Since a mutant BChE would be restricted to the periphery, it would be unlikely to affect other behaviors and in fact does not seem to affect food reinforced behavior [65]. Clearly, the side-effect profiles of the treatments reviewed here, as well as PD treatments, will be important considerations in their eventual use in humans.…”

Introduction: Biologics to Treat Substance Use Disorders: Vaccines, Monoclonal Antibodies, and Enzymes

“…For example, administration of a mutated butyrylcholinesterase linked to serum albumin dramatically reduces both the toxicological and behavioral effects of cocaine in rodents and nonhuman primates. These effects are attributable to a rapid degradation of cocaine in plasma (and a corresponding rise in a hydrolysis product of cocaine, ecgonine methyl ester) (reviewed in Brimijoin 2011 ; Schindler et al 2013 ). A Phase II facilitation of abstinence study of this product (TV 1380) in cocaine-dependent subjects has recently been completed (www.clinicaltrials.gov).…”