A cocaine hydrolase engineered from human butyrylcholinesterase selectively blocks cocaine toxicity and reinstatement of drug seeking in rats

Stephen Brimijoin; Yang Gao; Justin J. Anker; Luke A. Gliddon; David LaFleur; R. Shah; Qinghai Zhao; M. Singh; Marilyn E. Carroll

doi:10.1038/sj.npp.1301666

A cocaine hydrolase engineered from human butyrylcholinesterase selectively blocks cocaine toxicity and reinstatement of drug seeking in rats

Stephen Brimijoin, Yang Gao, Justin J. Anker, Luke A. Gliddon, David LaFleur, R. Shah, Qinghai Zhao, M. Singh, Marilyn E. Carroll

Pharmacology

Research output: Contribution to journal › Article › peer-review

101 Scopus citations

Abstract

Successive rational mutations of human butyrylcholinesterase (BChE) followed by fusion to human serum albumin have yielded an efficient hydrolase that offers realistic options for therapy of cocaine overdose and abuse. This albumin-BChE prevented seizures in rats given a normally lethal cocaine injection (100 mg/kg, i.p.), lowered brain cocaine levels even when administered after the drug, and provided rescue after convulsions commenced. Moreover, it selectively blocked cocaine-induced reinstatement of drug seeking in rats that had previously self-administered cocaine. The enzyme treatment was well tolerated and may be worth exploring for clinical application in humans.

Original language	English (US)
Pages (from-to)	2715-2725
Number of pages	11
Journal	Neuropsychopharmacology
Volume	33
Issue number	11
DOIs	https://doi.org/10.1038/sj.npp.1301666
State	Published - Oct 2008

Keywords

Addiction relapse
Albumin fusion proteins
Cocaine overdose rescue
Drug self-administration rodent model
Operant conditioning
Protein-based therapeutics for cocaine abuse

ASJC Scopus subject areas

Pharmacology
Psychiatry and Mental health

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10.1038/sj.npp.1301666

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title = "A cocaine hydrolase engineered from human butyrylcholinesterase selectively blocks cocaine toxicity and reinstatement of drug seeking in rats",

abstract = "Successive rational mutations of human butyrylcholinesterase (BChE) followed by fusion to human serum albumin have yielded an efficient hydrolase that offers realistic options for therapy of cocaine overdose and abuse. This albumin-BChE prevented seizures in rats given a normally lethal cocaine injection (100 mg/kg, i.p.), lowered brain cocaine levels even when administered after the drug, and provided rescue after convulsions commenced. Moreover, it selectively blocked cocaine-induced reinstatement of drug seeking in rats that had previously self-administered cocaine. The enzyme treatment was well tolerated and may be worth exploring for clinical application in humans.",

keywords = "Addiction relapse, Albumin fusion proteins, Cocaine overdose rescue, Drug self-administration rodent model, Operant conditioning, Protein-based therapeutics for cocaine abuse",

author = "Stephen Brimijoin and Yang Gao and Anker, {Justin J.} and Gliddon, {Luke A.} and David LaFleur and R. Shah and Qinghai Zhao and M. Singh and Carroll, {Marilyn E.}",

note = "Funding Information: The research in this article was supported by a grant from the Minnesota Partnership for Medical Genomics and Biotechnology and by grant R01-DA023979-01 from NIH/ NIDA. Additional funds were provided by Cogenesys Inc., Rockville, MD, which generated the material under study. Four of the authors (DL, RS, QZ, and MS) are employees of Cogenesys.",

year = "2008",

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doi = "10.1038/sj.npp.1301666",

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AU - Gao, Yang

AU - Anker, Justin J.

AU - Gliddon, Luke A.

AU - LaFleur, David

AU - Shah, R.

AU - Zhao, Qinghai

AU - Singh, M.

AU - Carroll, Marilyn E.

N1 - Funding Information: The research in this article was supported by a grant from the Minnesota Partnership for Medical Genomics and Biotechnology and by grant R01-DA023979-01 from NIH/ NIDA. Additional funds were provided by Cogenesys Inc., Rockville, MD, which generated the material under study. Four of the authors (DL, RS, QZ, and MS) are employees of Cogenesys.

PY - 2008/10

Y1 - 2008/10

N2 - Successive rational mutations of human butyrylcholinesterase (BChE) followed by fusion to human serum albumin have yielded an efficient hydrolase that offers realistic options for therapy of cocaine overdose and abuse. This albumin-BChE prevented seizures in rats given a normally lethal cocaine injection (100 mg/kg, i.p.), lowered brain cocaine levels even when administered after the drug, and provided rescue after convulsions commenced. Moreover, it selectively blocked cocaine-induced reinstatement of drug seeking in rats that had previously self-administered cocaine. The enzyme treatment was well tolerated and may be worth exploring for clinical application in humans.

AB - Successive rational mutations of human butyrylcholinesterase (BChE) followed by fusion to human serum albumin have yielded an efficient hydrolase that offers realistic options for therapy of cocaine overdose and abuse. This albumin-BChE prevented seizures in rats given a normally lethal cocaine injection (100 mg/kg, i.p.), lowered brain cocaine levels even when administered after the drug, and provided rescue after convulsions commenced. Moreover, it selectively blocked cocaine-induced reinstatement of drug seeking in rats that had previously self-administered cocaine. The enzyme treatment was well tolerated and may be worth exploring for clinical application in humans.

KW - Addiction relapse

KW - Albumin fusion proteins

KW - Cocaine overdose rescue

KW - Drug self-administration rodent model

KW - Operant conditioning

KW - Protein-based therapeutics for cocaine abuse

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A cocaine hydrolase engineered from human butyrylcholinesterase selectively blocks cocaine toxicity and reinstatement of drug seeking in rats

Abstract

Keywords

ASJC Scopus subject areas

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