title: Pharmacokinetic correlates of the effects of a heroin vaccine on heroin self-administration in rats.
abstract: The purpose of this study was to evaluate the effects of a morphine-conjugate vaccine (M-KLH) on the acquisition, maintenance, and reinstatement of heroin self-administration (HSA) in rats, and on heroin and metabolite distribution during heroin administration that approximated the self-administered dosing rate. Vaccination with M-KLH blocked heroin-primed reinstatement of heroin responding. Vaccination also decreased HSA at low heroin unit doses but produced a compensatory increase in heroin self-administration at high unit doses. Vaccination shifted the heroin dose-response curve to the right, indicating reduced heroin potency, and behavioral economic demand curve analysis further confirmed this effect. In a separate experiment heroin was administered at rates simulating heroin exposure during HSA. Heroin and its active metabolites, 6-acetylmorphine (6-AM) and morphine, were retained in plasma and metabolite concentrations were reduced in brain in vaccinated rats compared to controls. Reductions in 6-AM concentrations in brain after vaccination were consistent with the changes in HSA rates accompanying vaccination. These data provide evidence that 6-AM is the principal mediator of heroin reinforcement, and the principal target of the M-KLH vaccine, in this model. While heroin vaccines may have potential as therapies for heroin addiction, high antibody to drug ratios appear to be important for obtaining maximal efficacy.
authors.affiliation: Minneapolis Medical Research Foundation, Minneapolis, Minnesota, United States of America; Hennepin Healthcare System, Minneapolis, Minnesota, United States of America.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Raleigh
authors.affiliation: Minneapolis Medical Research Foundation, Minneapolis, Minnesota, United States of America; Hennepin Healthcare System, Minneapolis, Minnesota, United States of America; Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America; Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Pentel
authors.affiliation: Minneapolis Medical Research Foundation, Minneapolis, Minnesota, United States of America; Hennepin Healthcare System, Minneapolis, Minnesota, United States of America; Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America; Department of Psychology, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Mark G
authors.initials: MG
authors.lastname: LeSage
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D003932:Heroin / Q000097:blood / Q000378:metabolism; D006556:Heroin Dependence / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D009020:Morphine / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009022:Morphine Derivatives / Q000097:blood / Q000378:metabolism; D051381:Rats; D012646:Self Administration; D018074:Vaccines, Conjugate / Q000032:analysis / Q000097:blood / Q000627:therapeutic use*
chemical_list: D009022:Morphine Derivatives; D018074:Vaccines, Conjugate; D003932:Heroin; D009020:Morphine; C026979:6-O-monoacetylmorphine