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

Charles W. Schindler, Zuzana Justinova, David Lafleur, Doug Woods, Viktor Roschke, Hussein Hallak, Liora Sklair-Tavron, Godfrey H. Redhi, Sevil Yasar, Jack Bergman, Steven R. Goldberg

Research output: Contribution to journalArticle

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 2 hours after administration of Albu-CocH, whereas plasma levels of the cocaine metabolite ecgonine methyl ester were increased. These effects were still evident 72 hours following Albu-CocH administration. In behavioral experiments in monkeys, pre-treatment 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. Pre-treatment 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.

Original languageEnglish (US)
Pages (from-to)30-39
Number of pages10
JournalAddiction Biology
Volume18
Issue number1
DOIs
StatePublished - Jan 2013

Fingerprint

Hydrolases
Cocaine
Haplorhini
Pharmacokinetics
Butyrylcholinesterase
Saimiri
Cocaine-Related Disorders
Self Administration
Injections
Aptitude
Enzymes
Therapeutics
Half-Life
Rodentia
Pharmacology

Keywords

  • Cocaine
  • discrimination
  • hydrolase
  • reinstatement
  • self-administration
  • squirrel monkeys

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Psychiatry and Mental health
  • Pharmacology

Cite this

Schindler, C. W., Justinova, Z., Lafleur, D., Woods, D., Roschke, V., Hallak, H., ... Goldberg, S. R. (2013). Modification of pharmacokinetic and abuse-related effects of cocaine by human-derived cocaine hydrolase in monkeys. Addiction Biology, 18(1), 30-39. https://doi.org/10.1111/j.1369-1600.2011.00424.x

Modification of pharmacokinetic and abuse-related effects of cocaine by human-derived cocaine hydrolase in monkeys. / Schindler, Charles W.; Justinova, Zuzana; Lafleur, David; Woods, Doug; Roschke, Viktor; Hallak, Hussein; Sklair-Tavron, Liora; Redhi, Godfrey H.; Yasar, Sevil; Bergman, Jack; Goldberg, Steven R.

In: Addiction Biology, Vol. 18, No. 1, 01.2013, p. 30-39.

Research output: Contribution to journalArticle

Schindler, CW, Justinova, Z, Lafleur, D, Woods, D, Roschke, V, Hallak, H, Sklair-Tavron, L, Redhi, GH, Yasar, S, Bergman, J & Goldberg, SR 2013, 'Modification of pharmacokinetic and abuse-related effects of cocaine by human-derived cocaine hydrolase in monkeys', Addiction Biology, vol. 18, no. 1, pp. 30-39. https://doi.org/10.1111/j.1369-1600.2011.00424.x
Schindler, Charles W. ; Justinova, Zuzana ; Lafleur, David ; Woods, Doug ; Roschke, Viktor ; Hallak, Hussein ; Sklair-Tavron, Liora ; Redhi, Godfrey H. ; Yasar, Sevil ; Bergman, Jack ; Goldberg, Steven R. / Modification of pharmacokinetic and abuse-related effects of cocaine by human-derived cocaine hydrolase in monkeys. In: Addiction Biology. 2013 ; Vol. 18, No. 1. pp. 30-39.
@article{e467db60a14d42ce8ea7baa3351a0734,
title = "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 2 hours after administration of Albu-CocH, whereas plasma levels of the cocaine metabolite ecgonine methyl ester were increased. These effects were still evident 72 hours following Albu-CocH administration. In behavioral experiments in monkeys, pre-treatment 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. Pre-treatment 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.",
keywords = "Cocaine, discrimination, hydrolase, reinstatement, self-administration, squirrel monkeys",
author = "Schindler, {Charles W.} and Zuzana Justinova and David Lafleur and Doug Woods and Viktor Roschke and Hussein Hallak and Liora Sklair-Tavron and Redhi, {Godfrey H.} and Sevil Yasar and Jack Bergman and Goldberg, {Steven R.}",
year = "2013",
month = "1",
doi = "10.1111/j.1369-1600.2011.00424.x",
language = "English (US)",
volume = "18",
pages = "30--39",
journal = "Addiction Biology",
issn = "1355-6215",
publisher = "Wiley-Blackwell",
number = "1",

}

TY - JOUR

T1 - Modification of pharmacokinetic and abuse-related effects of cocaine by human-derived cocaine hydrolase in monkeys

AU - Schindler, Charles W.

AU - Justinova, Zuzana

AU - Lafleur, David

AU - Woods, Doug

AU - Roschke, Viktor

AU - Hallak, Hussein

AU - Sklair-Tavron, Liora

AU - Redhi, Godfrey H.

AU - Yasar, Sevil

AU - Bergman, Jack

AU - Goldberg, Steven R.

PY - 2013/1

Y1 - 2013/1

N2 - 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 2 hours after administration of Albu-CocH, whereas plasma levels of the cocaine metabolite ecgonine methyl ester were increased. These effects were still evident 72 hours following Albu-CocH administration. In behavioral experiments in monkeys, pre-treatment 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. Pre-treatment 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.

AB - 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 2 hours after administration of Albu-CocH, whereas plasma levels of the cocaine metabolite ecgonine methyl ester were increased. These effects were still evident 72 hours following Albu-CocH administration. In behavioral experiments in monkeys, pre-treatment 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. Pre-treatment 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.

KW - Cocaine

KW - discrimination

KW - hydrolase

KW - reinstatement

KW - self-administration

KW - squirrel monkeys

UR - http://www.scopus.com/inward/record.url?scp=84871772754&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84871772754&partnerID=8YFLogxK

U2 - 10.1111/j.1369-1600.2011.00424.x

DO - 10.1111/j.1369-1600.2011.00424.x

M3 - Article

C2 - 22264200

AN - SCOPUS:84871772754

VL - 18

SP - 30

EP - 39

JO - Addiction Biology

JF - Addiction Biology

SN - 1355-6215

IS - 1

ER -