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.
Highlights
Heroin is the most widely abused illicit opioid worldwide [1] and its use has doubled over the last 10 years in the United States [2]
The current study evaluated the effects of vaccination with the previously characterized M-keyhole limpet hemocyanin (KLH) immunogen on the acquisition of heroin self-administration (HSA), maintenance of HSA during a dose-reduction protocol, and heroin-primed reinstatement of HSA
The goal of this study was to investigate the effects of vaccination with M-KLH on HSA and to understand how these effects might be explained by associated changes in heroin and metabolite distribution
Summary
Heroin is the most widely abused illicit opioid worldwide [1] and its use has doubled over the last 10 years in the United States [2]. Pharmacotherapies available for the treatment of heroin addiction act at opioid receptors in the brain as either agonists to reduce cravings and prevent withdrawal (e.g. methadone), as antagonists to block heroin-reinforcing effects (e.g. naltrexone), or mixed agonist/ antagonist (e.g. buprenorphine). These medications are effective but have side effects or constraints on their use that limit their appeal. Vaccination against heroin has been studied in animals as a mechanistically distinct treatment option for heroin addiction. Vaccines targeting heroin have shown preclinical efficacy for blocking a variety of heroin-induced behavioral effects, including heroin self-administration (HSA), anti-nociception, and locomotor activity in animals [3, 4, 6, 8, 11, 12]
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