title: Long-lasting effects of a PEGylated mutant cocaine esterase (CocE) on the reinforcing and discriminative stimulus effects of cocaine in rats.
abstract: Recent mutagenesis studies have identified a mutant G4C/S10C/T172R/G173Q cocaine esterase (CCRQ CocE) with an in vitro duration of action of >40 days. Although the in vivo duration of CCRQ CocE's action was <24 h, modification of this enzyme with polyethylene glycol (PEG) polymers resulted in a CocE (PEG-CCRQ CocE) capable of preventing cocaine-induced lethality for up to 72 h. The current studies were aimed at providing a detailed characterization of the effectiveness, selectivity, and duration of PEG-CCRQ CocE's actions in cocaine self-administration and discrimination assays in rats. Pretreatment with PEG-CCRQ CocE produced dose-dependent rightward shifts in the dose-response curves for cocaine self-administration and discrimination, with the highest dose of PEG-CCRQ CocE capable of producing an initial shift of cocaine's reinforcing and interoceptive effects of >30-fold to the right, with significant inhibition of these effects observed for up to 72 h. Although PEG-CCRQ CocE also produced slight reductions in the rates of methylphenidate- and food-reinforced responding, these effects were short-lived, lasting <24 h. Finally, when taken together with the finding that PEG-CCRQ CocE failed to alter the cocaine-like interoceptive effects of either methylphenidate or d-amphetamine, these results suggest that PEG-CCRQ CocE possesses a high degree of pharmacologic specificity for cocaine and a prolonged in vivo duration of action. In conclusion, these studies provide strong evidence to support the further development of long-lasting, highly efficient CocEs, such as PEG-CCRQ CocE, as a potential therapeutic option for the treatment of cocaine abuse in humans.
authors: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA. gcollins@mclean.harvard.edu
authors: Gregory T
authors: GT
authors: Collins
authors: Diwahar
authors: D
authors: Narasimhan
authors: Alyssa R
authors: AR
authors: Cunningham
authors: Matthew E
authors: ME
authors: Zaks
authors: Joseph
authors: J
authors: Nichols
authors: Mei-Chuan
authors: MC
authors: Ko
authors: Roger K
authors: RK
authors: Sunahara
authors: James H
authors: JH
authors: Woods
mesh_terms: D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects*; D004192:Discrimination, Psychological / Q000187:drug effects*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005518:Food Preferences / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012055:Reinforcement Schedule; D012054:Reinforcement, Psychology; D012646:Self Administration; D013395:Sucrose / Q000008:administration & dosage; D013549:Sweetening Agents / Q000008:administration & dosage; D013997:Time Factors
chemical_list: D018765:Dopamine Uptake Inhibitors; D013549:Sweetening Agents; D008774:Methylphenidate; D013395:Sucrose; D007649:Ketamine; D002265:Carboxylic Ester Hydrolases; C019921:cocaine esterase; D003042:Cocaine