Neuroprotective action of MPEP, a selective mGluR5 antagonist, in methamphetamine-induced dopaminergic neurotoxicity is associated with a decrease in dopamine outflow and inhibition of hyperthermia in rats

Methamphetamine is a powerful neurotoxin that damages dopaminergic neurons in the striatum, causing long-term deficits in dopamine and its metabolites. This damage is often linked to excessive dopamine release, oxidative stress, and hyperthermia. This study investigated whether blocking the metabotropic glutamate receptor 5 (mGluR5) with the selective antagonist MPEP could protect these neurons from methamphetamine-induced damage and explored the physiological mechanisms behind this potential protection.

The researchers used male Wistar rats to examine the effects of MPEP. They administered methamphetamine systemically to induce neurotoxicity and tested whether pre-treating the rats with MPEP could prevent the resulting depletion of striatal dopamine. To understand the underlying mechanisms, the team used in vivo microdialysis to monitor extracellular dopamine levels in the striatum. They also measured changes in the rats' body temperature to see how MPEP influenced methamphetamine-induced hyperthermia.

• Neuroprotection: Repeated systemic administration of MPEP successfully prevented the methamphetamine-induced depletion of dopamine, DOPAC, and HVA in the striatum, indicating a robust neuroprotective effect.
• Reduced Dopamine Outflow: Systemic MPEP significantly reduced basal extracellular dopamine levels and blunted the surge in dopamine release typically caused by methamphetamine.
• Hyperthermia Inhibition: MPEP transiently reduced the hyperthermia (increased body temperature) caused by methamphetamine, which is known to exacerbate neurotoxicity.
• Extrastriatal Action: Interestingly, when MPEP was administered directly into the striatum via a microdialysis probe, it failed to decrease dopamine release and actually increased it at high concentrations, suggesting that MPEP's protective effects result from blocking mGluR5 receptors located outside the striatum.