title: Reward and Toxicity of Cocaine Metabolites Generated by Cocaine Hydrolase.
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.
authors: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA, murthy.vishakantha@mayo.edu.
authors: Vishakantha
authors: V
authors: Murthy
authors: Liyi
authors: L
authors: Geng
authors: Yang
authors: Y
authors: Gao
authors: Bin
authors: B
authors: Zhang
authors: Jordan D
authors: JD
authors: Miller
authors: Santiago
authors: S
authors: Reyes
authors: Stephen
authors: S
authors: Brimijoin
mesh_terms: D000818:Animals; D019817:Benzoic Acid / Q000378:metabolism / Q000633:toxicity*; D002091:Butyrylcholinesterase / Q000235:genetics / Q000378:metabolism*; D003042:Cocaine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000633:toxicity; D019970:Cocaine-Related Disorders / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D003213:Conditioning, Psychological; D015316:Genetic Therapy; D057809:HEK293 Cells; D006801:Humans; D006867:Hydrolases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D012201:Reward
chemical_list: D019817:Benzoic Acid; D006867:Hydrolases; D002091:Butyrylcholinesterase; D003042:Cocaine; C034524:ecgonine methyl ester