Effects of an Oxycodone Conjugate Vaccine on Oxycodone Self-Administration and Oxycodone-Induced Brain Gene Expression in Rats

Prescription opioid abuse is an increasing public health concern in the USA. A vaccine comprising a hapten (OXY) conjugated to the carrier protein keyhole limpet hemocyanin (OXY-KLH) has been shown to attenuate the antinociceptive effects of oxycodone. Here, the vaccine's ability to prevent acquisition of intravenous (i.v.) oxycodone self-administration was studied in rats. Effects of vaccination on oxycodone-induced changes in the expression of several genes within the mesolimbic system, which are regulated by chronic opiate use, were also examined. Vaccination with OXY-KLH reduced the proportion of rats acquiring i.v. self-administration of oxycodone under a fixed ratio (FR) 3 schedule of reinforcement compared to control rats immunized with the unconjugated KLH carrier protein. Vaccination significantly reduced the mean number of infusions at FR3, total number of infusions, and total oxycodone intake during the entire protocol. Compared to oxycodone self-administering control rats immunized with the carrier alone, rats vaccinated with the OXY-KLH immunogen showed increased levels of adenylate cyclase 5 (Adcy5) and decreased levels of early growth response protein 2 (Egr2) and the early immediate gene c-Fos in the striatum. These data suggest that vaccination with OXY-KLH can attenuate the reinforcing effects of oxycodone at a clinically-relevant exposure level. Analysis of mRNA expression identified some addiction-relevant markers that may be of interest in understanding oxycodone effects or the protection provided by vaccination

Effects of portion size on chronic energy intake

© 2007 Jeffery et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Pharmacokinetic Correlates of the Effects of a Heroin Vaccine on Heroin Self-Administration in Rats

<div><p>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.</p></div

Distribution of heroin and its metabolites in plasma and brain after i.v. infusion of 0.125 or 0.0625 mg/kg heroin.

<p>Plasma (A) opioid concentrations (mean ± SD) after the 1^st infusion of heroin. Plasma (B) and brain (C) opioid concentrations (mean ± SD) after the 8^th infusion of 0.125 or 0.0625 mg/kg heroin (cumulative doses of 1.0 and 0.5 mg/kg heroin, respectively). Vaccination increased retention of heroin and its metabolites in plasma after the 1^st as well as after all 8 heroin infusions, at both doses. Vaccination also reduced opioid concentrations in brain after all 8 heroin infusions, though effects were greatest at the lower heroin unit dose. Numbers in parentheses are the percent decrease compared to controls. *p<0.05, **p<0.01, and ***p<0.001 compared to KLH controls. Some drug levels were quite low. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115696#pone.0115696.s001" target="_blank">S1 Table</a> for exact values.</p

Effects of vaccination on HSA during dose reduction and reinstatement.

<p>Median total heroin infusions in rats that acquired HSA and completed the dose-reduction protocol (left panel). Rats were trained at a heroin unit dose of 0.06 mg/kg/inf. The heroin dose was sequentially decreased every 5 days to 0.03, 0.01, 0.003 and 0 mg/kg to obtain a dose-response curve. Median infusions compared to KLH *p<0.05, ***p<0.001. Proportion (<i>Χ²</i>) below 0.06 mg/kg compared to M-KLH #p<0.05. Blockade of reinstatement of heroin responding in vaccinated rats (right panel). Mean (± SEM) active lever presses during extinction in vaccinated and control rats after a s.c. priming injection of saline or 0.6 mg/kg heroin. *p<0.05 compared to saline control and #p<0.05 compared to KLH control.</p

Relationship between morphine-specific antibody concentrations and opioid concentrations in brain.

<p>Heroin (A), 6-AM (B), and morphine (C) concentrations in brain after the final (8^th) i.v. infusion of 0.125 or 0.0625 mg/kg heroin in vaccinated rats. KLH data shown as mean ± SD. Deviation not shown for ‘KLH, 0.125 mg/kg/inf heroin’ in the top panel because it was large (32±58 ng/g, mean ± SD).</p

Molar ratios of calculated opioid-specific IgG binding sites to the administered heroin dose.

<p>IgG binding site concentrations are the means for all vaccinated rats in that experiment. Doses listed for the HSA studies are the mean total heroin intake over the 2-hr self-administration session. Doses listed for the drug distribution studies are the total amount of heroin administered over the 1-hr experiment.</p>1<p>Last three HSA sessions at 0.06 mg/kg/inf heroin during FR3.</p>2<p>s.c. administration, all other heroin doses administered i.v.</p><p>Molar ratios of calculated opioid-specific IgG binding sites to the administered heroin dose.</p

Adaptation of the Müller method to allow quantitative characterization of the affinity and cross-reactivity of antibodies by competitive radioimmunoassay

A quantitative expression is derived for the evaluation of antigen-antibody affinity constants from radioimmunoassays for the completely general situation in which antigen and antibody are both multivalent. The theoretical analysis is then extended to encompass quantitative characterization of the competitive inhibition observed in screening tests for cross-reactivity of antibody with structural analogs of the eliciting antigen. These procedures are illustrated with a radioimmunological study of the cross-reactivity of a desipramine-elicited monoclonal antibody with other tricyclic antidepressants. An unexpected finding to emerge from this immunochemical study is the demonstration that a single affinity constant suffices to describe the interaction of desipramine with a polyclonal antibody elicited by this univalent antigen