title: Long-Term Blockade of Cocaine Self-Administration and Locomotor Activation in Rats by an Adenoviral Vector-Delivered Cocaine Hydrolase.
abstract: A promising approach in treating cocaine abuse is to metabolize cocaine in the blood using a mutated butyrylcholinesterase (BChE) that functions as a cocaine hydrolase (CocH). In rats, a helper-dependent adenoviral (hdAD) vector-mediated delivery of CocH abolished ongoing cocaine use and cocaine-primed reinstatement of drug-seeking for several months. This enzyme also metabolizes ghrelin, an effect that may be beneficial in maintaining healthy weights. The effect of a single hdAD-CocH vector injection was examined in rats on measures of anxiety, body weight, cocaine self-administration, and cocaine-induced locomotor activity. To examine anxiety, periadolescent rats were tested in an elevated-plus maze. Weight gain was then examined under four rodent diets. Ten months after CocH-injection, adult rats were trained to self-administer cocaine intravenously and, subsequently, cocaine-induced locomotion was tested. Viral gene transfer produced sustained plasma levels of CocH for over 13 months of testing. CocH-treated rats did not differ from controls in measures of anxiety, and only showed a transient reduction in weight gain during the first 3 weeks postinjection. However, CocH-treated rats were insensitive to cocaine. At 10 months postinjection, none of the CocH-treated rats initiated cocaine self-administration, unlike 90% of the control rats. At 13 months postinjection, CocH-treated rats showed no cocaine-induced locomotion, whereas control rats showed a dose-dependent enhancement of locomotion. CocH vector produced a long-term blockade of the rewarding and behavioral effects of cocaine in rats, emphasizing its role as a promising therapeutic intervention in cocaine abuse.
authors.affiliation: Research Fellow, Pharmaco-Neuro-Immunology Training Program (J.R.S.) and Department of Biological Science (A.G.), University of Minnesota, Minneapolis, Minnesota; Department of Psychiatry, University of Minnesota Medical School (N.S., M.E.C.), Minneapolis, Minnesota; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota (S.B., Y.G.); Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (R.J.P.) jsmethells@gmail.com.
authors.forename: John R
authors.initials: JR
authors.lastname: Smethells
authors.affiliation: Research Fellow, Pharmaco-Neuro-Immunology Training Program (J.R.S.) and Department of Biological Science (A.G.), University of Minnesota, Minneapolis, Minnesota; Department of Psychiatry, University of Minnesota Medical School (N.S., M.E.C.), Minneapolis, Minnesota; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota (S.B., Y.G.); Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (R.J.P.).
authors.forename: Natashia
authors.initials: N
authors.lastname: Swalve
authors.affiliation: Research Fellow, Pharmaco-Neuro-Immunology Training Program (J.R.S.) and Department of Biological Science (A.G.), University of Minnesota, Minneapolis, Minnesota; Department of Psychiatry, University of Minnesota Medical School (N.S., M.E.C.), Minneapolis, Minnesota; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota (S.B., Y.G.); Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (R.J.P.).
authors.forename: Stephen
authors.identifier: http://orcid.org/0000-0003-1838-5423
authors.initials: S
authors.lastname: Brimijoin
authors.affiliation: Research Fellow, Pharmaco-Neuro-Immunology Training Program (J.R.S.) and Department of Biological Science (A.G.), University of Minnesota, Minneapolis, Minnesota; Department of Psychiatry, University of Minnesota Medical School (N.S., M.E.C.), Minneapolis, Minnesota; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota (S.B., Y.G.); Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (R.J.P.).
authors.forename: Yang
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Research Fellow, Pharmaco-Neuro-Immunology Training Program (J.R.S.) and Department of Biological Science (A.G.), University of Minnesota, Minneapolis, Minnesota; Department of Psychiatry, University of Minnesota Medical School (N.S., M.E.C.), Minneapolis, Minnesota; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota (S.B., Y.G.); Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (R.J.P.).
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Parks
authors.affiliation: Research Fellow, Pharmaco-Neuro-Immunology Training Program (J.R.S.) and Department of Biological Science (A.G.), University of Minnesota, Minneapolis, Minnesota; Department of Psychiatry, University of Minnesota Medical School (N.S., M.E.C.), Minneapolis, Minnesota; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota (S.B., Y.G.); Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (R.J.P.).
authors.forename: Adam
authors.initials: A
authors.lastname: Greer
authors.affiliation: Research Fellow, Pharmaco-Neuro-Immunology Training Program (J.R.S.) and Department of Biological Science (A.G.), University of Minnesota, Minneapolis, Minnesota; Department of Psychiatry, University of Minnesota Medical School (N.S., M.E.C.), Minneapolis, Minnesota; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota (S.B., Y.G.); Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (R.J.P.).
authors.forename: Marilyn E
authors.initials: ME
authors.lastname: Carroll
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000523:psychology; D002265:Carboxylic Ester Hydrolases / Q000097:blood / Q000235:genetics*; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000523:psychology / Q000628:therapy*; D004032:Diet; D004305:Dose-Response Relationship, Drug; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D012201:Reward; D012646:Self Administration; D015430:Weight Gain / Q000187:drug effects
chemical_list: D002265:Carboxylic Ester Hydrolases; C019921:cocaine esterase; D003042:Cocaine