Elsevier

Biological Psychiatry

Volume 73, Issue 8, 15 April 2013, Pages 721-728
Biological Psychiatry

Archival Report
A Methamphetamine Vaccine Attenuates Methamphetamine-Induced Disruptions in Thermoregulation and Activity in Rats

https://doi.org/10.1016/j.biopsych.2012.09.010Get rights and content

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.

Section snippets

Experimental Design

There were two experiments in this investigation. Experiment 1 was an initial screen to determine which of three most promising candidate anti-METH vaccines from a previous study in mice (40) would confer effects consistent with the attenuation of METH’s impact in vivo in rats. Experiment 1 therefore assessed rectal temperature values under a high ambient temperature condition (TA = 27±1°C) to determine effects on METH-induced hyperthermia and locomotor activity as previously described 41, 42.

Experiment 1

Antibody Titers. An equilibrium dialysis assay was performed to normalize the results among MH2(R), MH6, and MH7 haptens. The MH6 and MH7 haptens produced similar binding constants (Kd = ∼25–30 nmol/L; Table 2) but the MH6 hapten produced two to three times more antibody (Figure 1). Although MH6 and MH2(R) produced similar levels of antibody, MH2(R) had much lower affinity than MH6 (Kd = ∼2.24 μmol/L). Specificity of MH6 antibodies for METH, AMPH, MDMA, and 4-MMC was assessed by equilibrium

Discussion

This study provides unequivocal evidence that active vaccination is capable of attenuating physiological and behavioral effects of METH, unlike prior attempts at active immunotherapy for METH 37, 38. It was shown that active vaccination attenuated METH-induced disruptions in thermoregulation (i.e., hyperthermia and hypothermia at 27°C and 23°C, respectively), wheel activity (experiment 1), and stereotypy (experiment 2) after the highest METH dose administered. The progression of psychomotor

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