Long-lasting effects of a PEGylated mutant cocaine esterase (CocE) on the reinforcing and discriminative stimulus effects of cocaine in rats

Gregory T. Collins, Diwahar Narasimhan, Alyssa R. Cunningham, Matthew E. Zaks, Joseph Nichols, Mei Chuan Ko, Roger K. Sunahara, James H. Woods

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1092-1103
Number of pages12
JournalNeuropsychopharmacology
Volume37
Issue number5
DOIs
StatePublished - Apr 2012

Keywords

  • PEG-CCRQ CocE
  • cocaine
  • cocaine esterase
  • drug discrimination
  • methlyphenidate
  • self-administration

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

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