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.

Figure 1. Effect of vaccination on acquisition of HSA.

Mean (± SEM) infusions (0.06 mg/kg/inf heroin; left panel) and mean (± SEM) lever presses (right panel) on the active and inactive lever per session during the acquisition phase. Different from KLH, **p<0.01.

Figure 2. Effects of vaccination on HSA during dose reduction and reinstatement.

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 (Χ²) 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.

Figure 3. Consumption of heroin in vaccinated and control rats as a function of unit price (FR/unit dose).

Panel A represents absolute log consumption for each group and panels B and C represent individual subject data. Vaccinated rats had a higher Q₀ (*p<0.01) compared to controls, but there was no difference in α.

Figure 4. Distribution of heroin and its metabolites in plasma and brain after i.v. infusion of 0.125 or 0.0625 mg/kg heroin.

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 S1 Table for exact values.

Figure 5. Relationship between morphine-specific antibody concentrations and opioid concentrations in brain.

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).