Reward and Toxicity of Cocaine Metabolites Generated by Cocaine Hydrolase

Vishakantha Murthy, Liyi Geng, Yang Gao, Bin Zhang, Jordan D. Miller, Santiago Reyes, Stephen Brimijoin

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Butyrylcholinesterase (BChE) gene therapy is emerging as a promising concept for treatment of cocaine addiction. BChE levels after gene transfer can rise 1000-fold above those in untreated mice, making this enzyme the second most abundant plasma protein. For months or years, gene transfer of a BChE mutated into a cocaine hydrolase (CocH) can maintain enzyme levels that destroy cocaine within seconds after appearance in the blood stream, allowing little to reach the brain. Rapid enzyme action causes a sharp rise in plasma levels of two cocaine metabolites, benzoic acid (BA) and ecgonine methyl ester (EME), a smooth muscle relaxant that is mildly hypotensive and, at best, only weakly rewarding. The present study, utilizing Balb/c mice, tested reward effects and cardiovascular effects of administering EME and BA together at molar levels equivalent to those generated by a given dose of cocaine. Reward was evaluated by conditioned place preference. In this paradigm, cocaine (20 mg/kg) induced a robust positive response but the equivalent combined dose of EME + BA failed to induce either place preference or aversion. Likewise, mice that had undergone gene transfer with mouse CocH (mCocH) showed no place preference or aversion after repeated treatments with a near-lethal 80 mg/kg cocaine dose. Furthermore, a single administration of that same high cocaine dose failed to affect blood pressure as measured using the noninvasive tail-cuff method. These observations confirm that the drug metabolites generated after CocH gene transfer therapy are safe even after a dose of cocaine that would ordinarily be lethal.

Original languageEnglish (US)
Pages (from-to)819-826
Number of pages8
JournalCellular and molecular neurobiology
Volume35
Issue number6
DOIs
StatePublished - Aug 24 2015

Keywords

  • Addiction
  • Adeno-associated viral vector
  • Butyrylcholinesterase
  • Cocaine
  • Cocaine hydrolase
  • Ecgonine methyl ester
  • Gene therapy
  • Place conditioning

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology

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