A methamphetamine vaccine attenuates methamphetamine-induced disruptions in thermoregulation and activity in rats

Abstract

Background: There are no approved pharmacotherapies for d-methamphetamine (METH) addiction and existing therapies have limited efficacy. Advances in using immunotherapeutic approaches for cocaine and nicotine addiction have stimulated interest in creating a similar approach for METH addiction. This study investigated whether active vaccination against METH could potentially attenuate responses to METH in vivo.

Methods: Male Sprague Dawley rats (n = 32) received a four-boost series with one of three candidate anti-METH vaccines (MH2[R], MH6, and MH7) or a control keyhole limpet hemocyanin conjugate vaccine. Effects of METH on rectal temperature and wheel activity at 27°C ambient temperature were determined. The most efficacious vaccine, MH6, was then contrasted with keyhole limpet hemocyanin conjugate vaccine in a subsequent experiment (n = 16), wherein radiotelemetry determined home cage locomotor activity and body temperature at 23°C ambient temperature.

Results: The MH6 vaccine produced high antibody titers with nanomolar affinity for METH and sequestered METH in the periphery of rats. In experiment 1, the thermoregulatory and psychomotor responses produced by METH at 27°C were blocked in the MH6 group. In experiment 2, METH-induced decreases in body temperature and locomotor activity at 23°C were also attenuated in the MH6 group. A pharmacokinetic study in experiment 2 showed that MH6-vaccinated rats had higher METH serum concentrations, yet lower brain METH concentrations, than control rats, and METH concentrations correlated with individual antibody titer.

Conclusions: These data demonstrate that active immunopharmacotherapy provides functional protection against physiological and behavioral disruptions induced by METH.

Figure 1

Top panel: Normalized mean antibody titer concentrations (µg/ml) for MH2(R), MH6, and MH7 across 12 weeks. Arrows depict vaccinations (weeks 0, 2, 5, and 9). Acute METH challenges are shown by the box labeled ‘METH.’ Bottom panel: Mean antibody titer (dilution) across 12 (Experiment 1) and 20 weeks (Experiment 2) for MH6-vaccinated rats (N=8 per group). Acute METH challenges for Experiments 1 and 2 are shown by the boxes labeled ‘METH’ or ‘M’ in the top and bottom row, respectively; surgery is depicted by “s” for rats in Experiment 2. Error bars are ±SEM.

Figure 2

Mean rectal temperature values (°C) across successive 30-min intervals (top panel) and number of quarter wheel rotations across successive 5-min intervals (bottom panel) following a challenge dose of 5.6 mg/kg METH in MH6-vaccinated and KLH-control groups at T_A = 27°C (Experiment 1). Significant differences between and within groups are shown by * and #, respectively. Error bars are ±SEM.

Figure 3

Mean body temperature values (°C; top panel) and locomotor activity (bottom panel) across successive 30-min intervals following challenge doses of METH (0.0, 0.5, 1.0, 3.2, 5.6 mg/kg) in MH6-vaccinated and KLH-control rats at T_A = 23°C (Experiment 2). Significant differences between and within groups are shown by * and #, respectively. Note that the y-axis values differ for locomotor activity at the 5.6 mg/kg dose. Error bars are ±SEM.

Figure 4

Top & middle panels: Serum and brain METH concentrations (ng/ul) for KLH-control and MH6-vaccinated rats. Bottom panel: 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 METH challenge. Significant differences between groups are shown by * and error bars are ±SEM.