Effects of active anti-methamphetamine vaccination on intravenous self-administration in rats

Abstract

Background: d-Methamphetamine (METH) addiction is a serious public health concern for which successful treatment remains elusive. Immunopharmacotherapy has been shown to attenuate locomotor and thermoregulatory effects of METH. The current study investigated whether active vaccination against METH could alter intravenous METH self-administration in rats.

Methods: Male Sprague-Dawley rats (Experiment 1: N=24; Experiment 2: N=18) were vaccinated with either a control keyhole-limpet hemocyanin conjugate vaccine (KLH) or a candidate anti-METH vaccine (MH6-KLH) or. Effects of vaccination on the acquisition of METH self-administration under two dose conditions (0.05, 0.1mg/kg/inf) and post-acquisition dose-substitution (0, 0.01, 0.05, 0.20mg/kg/inf, Experiment 1; 0.01, 0.05, 0.10, 0.15mg/kg/inf, Experiment 2) during steady-state responding were investigated. Plasma METH concentrations were determined 30min after an acute challenge dose of 3.2mg/kg METH.

Results: Active vaccination inhibited the acquisition of METH self-administration under the 0.1mg/kg/inf dose condition, with 66% of the MH6-KLH-vaccinated rats compared to 100% of the controls reaching criteria, and produced transient and dose-dependent effects on self-administration during the maintenance phase. Under the 0.05mg/kg/inf dose condition, MH6-KLH-vaccinated rats initially self-administered more METH than controls, but then self-administration decreased across the acquisition phase relative to controls; a subsequent dose-response assessment confirmed that MH6-KLH-vaccinated rats failed to acquire METH self-administration. Finally, plasma METH concentrations were higher in MH6-KLH-vaccinated rats compared to controls after an acute METH challenge, and these were positively correlated with antibody titers.

Conclusions: These data demonstrate that active immunopharmacotherapy for METH attenuates the acquisition of METH self-administration.

Keywords: Active vaccination; Drug addiction; Immunopharmacotherapy; Methamphetamine; Self-administration.

Figure 1

A. Cumulative percent of MH6-KLH-vaccinated and KLH-control rats (N=12 per group) that acquired intravenous METH self-administration. B. Mean number of days to acquire self-administration for each group. C. Mean number of infusions for each group across the 13-day acquisition period. D. Cumulative METH dose (mg/kg) during the acquisition period for both groups. Significant difference between groups are depicted with * and differences relative to the first session within group by #. Error bars are ±SEM.

Figure 2

Mean (N=12 per group) number of infusions after a dose substitution of 0.05 mg/kg/inf and a return to the training dose (0.10 mg/kg/inf) for MH6-KLH-vaccinated and KLH-control rats. Significant difference between and within groups are shown by * and #, respectively. Error bars are ±SEM.

Figure 3

Mean (N=12 per group) number of infusions across a range of METH doses (saline, 0.01, 0.05, 0.20 mg/kg/inf) shown for each 4-session block of the dose-response assessment (i.e., 1^st, 2^nd, and 3^rd cycle) for KLH-control and MH6-KLH-vaccinated rats. Significant differences between groups within a cycle are depicted with *; see text for additional differences. Error bars are ±SEM.

Figure 4

A. Mean number of infusions during acquisition of METH self-administration for MH6-KLH-vaccinated (N=9) and KLH-control (N=8) rats summated across 7-session bins. B. Mean number of infusions in the individual 21-session acquisition period is depicted for both groups. C. Mean number of infusions across a range of doses of METH (0.01, 0.05, 0.10, 0.15 mg/kg/inf) for both groups. Significant differences between groups are depicted with * and within groups (relative to the first 7 sessions) are depicted with #. Error bars are ±SEM.

Figure 5

A. Mean (N=8 per group) plasma METH concentrations (ng/ul) for KLH-control and MH6-KLH-vaccinated rats. B. Individual plasma METH concentrations (ng/ul) as a function of individual antibody titer (dilution). All samples were obtained 30 min after a 3.2 mg/kg (s.c.) METH challenge given during week 22 of the study. Significant differences between groups are shown by * and error bars are ±SEM.