title: Cocaine esterase prevents cocaine-induced toxicity and the ongoing intravenous self-administration of cocaine in rats.
abstract: Cocaine esterase (CocE) is a naturally occurring bacterial enzyme, is a very efficient protein catalyst for the hydrolysis of cocaine, and has previously been shown to protect rodents from the lethal effects of cocaine. The current studies were aimed at evaluating the capacity of a longer acting mutant form (CocE T172R/G173Q; DM CocE) of CocE to protect against the lethal effects of cocaine, and alter ongoing intravenous cocaine self-administration in rats. A dose-response analysis revealed a dose-dependent suppression of cocaine-reinforced responding with 1.0 mg of CocE T172R/G173Q producing saline-like rates of responding. The effects of 1.0 mg of CocE T172R/G173Q on cocaine-reinforced responding were then compared with responding when saline was available for injection, whereas the selectivity of CocE T172R/G173Q's effects was assessed by evaluating the effects of 1.0 mg of CocE T172R/G173Q on (-)-2beta-carbomethoxy-3beta-phenyltropane (WIN-35065-2)- and food-reinforced responding. Although 1.0 mg of CocE T172R/G173Q suppressed responding maintained by 0.1 mg/kg/injection cocaine, a significant increase in responding was observed when responding was maintained by 1.0 mg/kg/injection cocaine, resulting in a 10-fold rightward shift in the dose-response curve for cocaine self-administration at a dose that did not significantly alter responding maintained by either WIN-35065-2 or food. These findings demonstrate that a long-acting form of CocE is effective at abruptly reducing the ongoing self-administration of low doses of cocaine, and provides a robust antagonism of cocaine's reinforcing effects. Furthermore, these studies provide strong evidence for the potential usefulness of a suitable, stable, and long-acting form of CocE as a pharmacotherapy for cocaine abuse in humans.
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0632, USA.
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Collins
authors.forename: Remy L
authors.initials: RL
authors.lastname: Brim
authors.forename: Diwahar
authors.initials: D
authors.lastname: Narasimhan
authors.forename: Mei-Chuan
authors.initials: MC
authors.lastname: Ko
authors.forename: Roger K
authors.initials: RK
authors.lastname: Sunahara
authors.forename: Chang-Guo
authors.initials: CG
authors.lastname: Zhan
authors.forename: James H
authors.initials: JH
authors.lastname: Woods
mesh_terms: D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism*; D003042:Cocaine / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000523:psychology*; D003216:Conditioning, Operant / Q000187:drug effects; D018765:Dopamine Uptake Inhibitors / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D012646:Self Administration; D015819:Substance Abuse, Intravenous / Q000188:drug therapy* / Q000523:psychology*
chemical_list: D018765:Dopamine Uptake Inhibitors; D002265:Carboxylic Ester Hydrolases; C019921:cocaine esterase; D003042:Cocaine