mGluR5 antagonism attenuates methamphetamine reinforcement and prevents reinstatement of methamphetamine-seeking behavior in rats

Methamphetamine addiction is a chronic, relapsing condition with no currently FDA-approved pharmacological treatments. Given the involvement of the glutamatergic system in psychostimulant addiction, the researchers investigated whether the type 5 metabotropic glutamate receptor (mGluR5) serves as a viable target for therapeutic intervention. Specifically, this study examined if systemic administration of the selective mGluR5 antagonist MTEP could reduce methamphetamine reinforcement and prevent the reinstatement of drug-seeking behavior.

Using male Sprague-Dawley rats, the authors employed intravenous self-administration models under two schedules of reinforcement: Fixed-Ratio 1 (FR1) and Progressive Ratio (PR). In the PR schedule, the effort required to earn each successive drug infusion increased, allowing researchers to evaluate the reinforcing efficacy of methamphetamine. Following stabilization, rats received MTEP (0.3, 1, or 3 mg/kg) to assess its impact on drug-taking. Furthermore, the study utilized an extinction/reinstatement model to see if MTEP could inhibit cue-induced and drug-primed reinstatement, a standard proxy for relapse-like behavior. Food-maintained behavior was used as a control to ensure the observed effects were specific to the addictive properties of methamphetamine rather than general motor suppression or appetite disruption.

MTEP dose-dependently reduced methamphetamine self-administration under both FR1 and PR schedules. Notably, under the PR schedule, while MTEP decreased the overall number of drug infusions earned, it did not alter the time taken to reach the breakpoint, suggesting a decrease in the reinforcing efficacy of the drug. In the relapse model, MTEP effectively prevented both cue- and drug-induced reinstatement of methamphetamine-seeking behavior at doses that did not interfere with food-seeking behavior. These data support the hypothesis that mGluR5 receptors play a critical role in the neural substrates of methamphetamine reinforcement and relapse.