Pharmacokinetic correlates of the effects of a heroin vaccine on heroin self-administration in rats

• Published in: PloS one Vol. 9; no. 12; p. e115696
• Main Authors: Raleigh, Michael D, Pentel, Paul R, LeSage, Mark G
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23.12.2014; Public Library of Science (PLoS)
• Subjects: Addictions; Animals; Biology and Life Sciences; Brain; Brain - metabolism; Computer simulation; Demand analysis; Drug abuse; Drug addiction; Drug self-administration; Economic analysis; Heroin; Heroin - blood; Heroin - metabolism; Heroin Dependence - metabolism; Heroin Dependence - prevention & control; Immunization; Male; Medicine and Health Sciences; Metabolites; Morphine; Morphine - blood; Morphine - pharmacokinetics; Morphine - therapeutic use; Morphine Derivatives - blood; Morphine Derivatives - metabolism; Narcotics; Pharmacokinetics; Pharmacology; Rats; Reinstatement; Rodents; Self Administration; Social Sciences; Vaccination; Vaccines; Vaccines, Conjugate - analysis; Vaccines, Conjugate - blood; Vaccines, Conjugate - therapeutic use
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0115696

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.