title: Long-term reduction of cocaine self-administration in rats treated with adenoviral vector-delivered cocaine hydrolase: evidence for enzymatic activity.
abstract: A new pharmacokinetic approach treating cocaine addiction involves rapidly metabolizing cocaine before it reaches brain reward centers using mutated human butyrylcholinesterase (BChE) or cocaine hydrolase (CocH). Recent work has shown that helper-dependent adenoviral (hdAD) vector-mediated plasma CocH reduced the locomotor-activating effects of cocaine and prevented reinstatement of cocaine-seeking behavior up to 6 months in rats. The present study investigated whether hdAD-CocH could decrease ongoing intravenous cocaine (0.4 mg/kg) self-administration. The hdAD-CocH vector was injected into self-administering rats, and after accumulation of plasma CocH, there was a dramatic reduction in cocaine infusions earned under a fixed ratio 1 schedule of reinforcement that lasted for the length of the study (>2 months). Pretreatment with the selective BChE and CocH inhibitor iso-OMPA (1.5 mg/kg) restored cocaine intake; therefore, the decline in self-administration was likely due to rapid CocH-mediated cocaine metabolism. Direct measurements of cocaine levels in plasma and brain samples taken after the conclusion of behavioral studies provided strong support for this conclusion. Further, rats injected with hdAD-CocH did not experience a deficit in operant responding for drug reinforcement and self-administered methamphetamine (0.05 mg/kg) at control levels. Overall, these outcomes suggest that viral gene transfer can yield plasma CocH levels that effectively diminish long-term cocaine intake and may have potential treatment implications for cocaine-dependent individuals seeking to become and remain abstinent.
authors.affiliation: 1] Deprtment of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, USA [2] Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Natalie E
authors.initials: NE
authors.lastname: Zlebnik
authors.affiliation: Deprtment of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Brimijoin
authors.affiliation: Deprtment of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Deprtment of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: Amy T
authors.initials: AT
authors.lastname: Saykao
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Parks
authors.affiliation: Deprtment of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: Marilyn E
authors.initials: ME
authors.lastname: Carroll
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D019969:Amphetamine-Related Disorders / Q000201:enzymology / Q000628:therapy; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000008:administration & dosage; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D019970:Cocaine-Related Disorders / Q000201:enzymology / Q000628:therapy*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D006867:Hydrolases / Q000235:genetics* / Q000378:metabolism*; D008694:Methamphetamine / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D012055:Reinforcement Schedule; D012646:Self Administration; D013770:Tetraisopropylpyrophosphamide / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000697:Central Nervous System Stimulants; D002800:Cholinesterase Inhibitors; D008694:Methamphetamine; D013770:Tetraisopropylpyrophosphamide; D006867:Hydrolases; D003042:Cocaine