The next step in preclinical research on vaccines for addiction is to test if there are functional effects. That is, it is important to see that vaccinated animals show different, often seen as attenuated, behavioral or physiological responses to the administration of the target drug. While this may seem straightforward, it is often not. Drugs of abuse have multiple effects and most of these can differ by the dose administered. In addition, many of these responses will change with repeated drug administration. When an increase in a response to a drug is seen with repeated administration, this is considered sensitization. Sensitization is also seen by demonstrating that lower doses produce a response that would be seen in a drug-naive animal given a higher dose under acute conditions. Conversely, some drug responses decrease with repeated administration, a phenomenon called tolerance. Tolerance is also seen by demonstrating that higher doses are needed to produce a response that would be seen in a drug-naive animal given a lower dose under acute conditions. Further complicating the picture is that the dose-response function of a specific drug rarely appears to be linear with increasing response levels induced by increasing doses. In some cases, an increase in dose produces an effect that masks or interferes with the expression of the response under study. The net effect will look like a response to a lower dose. Thus, it is very important to test the function of a vaccine with multiple doses of the drug and include the appropriate control groups or conditions.

Various functional assays have been used in the preclinical assessments of MA vaccines. Since MA affects locomotor activity and this is easily measured in a standard, commercially available apparatus, it is usually the first behavior to examine. Other tests can be used to evaluate the addictive properties of MA. These include conditioned place preference (CPP) and operant self-administration. And both of these procedures can be used to assess acquisition and reinstatement of the behavior. The latter effect is particularly significant because it is thought to be a model of relapse to drug use after abstinence in humans (Shaham et al. 2003). Other functional assessments of the efficacy of MA vaccines that have been used include measuring body temperature and the discriminative stimulus effects of MA.

Overall, several animal studies suggest that immunotherapy for MA abuse is a viable treatment approach. Further research is needed to determine the most effective anti-MA vaccine construct by using multiple behavioral and physiological assays. In particular, tests using MA self-administration would provide important information on whether the vaccine can attenuate the reinforcing effects of MA that maintain addictive behavior or block drug-induced reinstatement of extinguished self-administration behavior, an important model of relapse.