title: Anti-cocaine antibody and butyrylcholinesterase-derived cocaine hydrolase exert cooperative effects on cocaine pharmacokinetics and cocaine-induced locomotor activity in mice.
abstract: We are investigating treatments for cocaine abuse based on viral gene transfer of a cocaine hydrolase (CocH) derived from human butyrylcholinesterase, which can reduce cocaine-stimulated locomotion and cocaine-primed reinstatement of drug-seeking behavior in rats for many months. Here, in mice, we explored the possibility that anti-cocaine antibodies can complement the actions of CocH to reduce cocaine uptake in brain and block centrally-evoked locomotor stimulation. Direct injections of test proteins showed that CocH (0.3 or 1mg/kg) was effective by itself in reducing drug levels in plasma and brain of mice given cocaine (10mg/kg, s.c., or 20mg/kg, i.p). Administration of cocaine antibody per se at a low dose (8 mg/kg, i.p.) exerted little effect on cocaine distribution. However, a higher dose of antibody (12 mg/kg) caused peripheral trapping (increased plasma drug levels), which led to increased cocaine metabolism by CocH, as evidenced by a 6-fold rise in plasma benzoic acid. Behavioral tests with small doses of CocH and antibody (1 and 8 mg/kg, respectively) showed that neither agent alone reduced mouse locomotor activity triggered by a very large cocaine dose (100mg/kg, i.p.). However, dual treatment completely suppressed the locomotor stimulation. Altogether, we found cooperative and possibly synergistic actions that warrant further exploration of dual therapies for treatment of cocaine abuse.
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA. brimijoin@mayo.edu
authors.forename: Stephen
authors.initials: S
authors.lastname: Brimijoin
authors.forename: Frank
authors.initials: F
authors.lastname: Orson
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Kosten
authors.forename: Berma
authors.initials: B
authors.lastname: Kinsey
authors.forename: Xiao Yun
authors.initials: XY
authors.lastname: Shen
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: White
authors.forename: Yang
authors.initials: Y
authors.lastname: Gao
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D001921:Brain; D002091:Butyrylcholinesterase / Q000235:genetics / Q000378:metabolism*; D003042:Cocaine / Q000037:antagonists & inhibitors* / Q000276:immunology* / Q000378:metabolism / Q000633:toxicity; D019970:Cocaine-Related Disorders / Q000503:physiopathology / Q000628:therapy; D058999:Drug-Seeking Behavior; D006801:Humans; D006867:Hydrolases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009043:Motor Activity; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014612:Vaccines / Q000008:administration & dosage
chemical_list: D000906:Antibodies; D011994:Recombinant Proteins; D014612:Vaccines; D006867:Hydrolases; D002091:Butyrylcholinesterase; D003042:Cocaine