title: Novel cocaine vaccine linked to a disrupted adenovirus gene transfer vector blocks cocaine psychostimulant and reinforcing effects.
abstract: Immunotherapy is a promising treatment for drug addiction. However, insufficient immune responses to vaccines in most subjects pose a challenge. In this study, we tested the efficacy of a new cocaine vaccine (dAd5GNE) in antagonizing cocaine addiction-related behaviors in rats. This vaccine used a disrupted serotype 5 adenovirus (Ad) gene transfer vector coupled to a third-generation cocaine hapten, termed GNE (6-(2R,3S)-3-(benzoyloxy)-8-methyl-8-azabicyclo [3.2.1] octane-2-carboxamido-hexanoic acid). Three groups of rats were immunized with dAd5GNE. One group was injected with (3)H-cocaine, and radioactivity in the blood and brain was determined. A second group was tested for cocaine-induced locomotor sensitization. A third group was examined for cocaine self-administration, extinction, and reinstatement of responding for cocaine. Antibody titers were determined at various time-points. In each experiment, we added a control group that was immunized with dAd5 without a hapten. The vaccination with dAd5GNE produced long-lasting high titers (>10(5)) of anti-cocaine antibodies in all of the rats. The vaccination inhibited cocaine-induced hyperlocomotor activity and sensitization. Vaccinated rats acquired cocaine self-administration, but they showed less motivation to self-administer cocaine under a progressive-ratio schedule than control rats. When cocaine was not available in a session, control rats exhibited 'extinction burst' responding, whereas vaccinated rats did not. Moreover, when primed with cocaine, vaccinated rats did not reinstate responding, suggesting a blockade of cocaine-seeking behavior. These data strongly suggest that our dAd5GNE vector-based vaccine may be effective in treating cocaine abuse and addiction.
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, USA. sunmee@scripps.edu
authors.forename: Sunmee
authors.initials: S
authors.lastname: Wee
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Hicks
authors.forename: Bishnu P
authors.initials: BP
authors.lastname: De
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Rosenberg
authors.forename: Amira Y
authors.initials: AY
authors.lastname: Moreno
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Kaminsky
authors.forename: Kim D
authors.initials: KD
authors.lastname: Janda
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Crystal
authors.forename: George F
authors.initials: GF
authors.lastname: Koob
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000378:metabolism; D000697:Central Nervous System Stimulants; D003042:Cocaine / Q000008:administration & dosage / Q000276:immunology* / Q000493:pharmacokinetics; D019970:Cocaine-Related Disorders / Q000517:prevention & control* / Q000523:psychology; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000276:immunology* / Q000493:pharmacokinetics; D005108:Extinction, Psychological / Q000187:drug effects; D005822:Genetic Vectors / Q000008:administration & dosage; D006241:Haptens; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011863:Radioimmunoassay / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D012054:Reinforcement, Psychology; D012646:Self Administration; D013997:Time Factors; D014163:Transfer, Psychology / Q000187:drug effects; D014316:Tritium / Q000493:pharmacokinetics; D014611:Vaccination / Q000379:methods*
chemical_list: D000697:Central Nervous System Stimulants; D018765:Dopamine Uptake Inhibitors; D006241:Haptens; D007074:Immunoglobulin G; D014316:Tritium; D008694:Methamphetamine; D003042:Cocaine