Amphetamine and Methamphetamine Increase NMDAR-GluN2B Synaptic Currents in Midbrain Dopamine Neurons

The psychostimulants amphetamine (AMPH) and methamphetamine (MA) are widely abused illicit drugs. Here we show that both psychostimulants acutely increase NMDA Receptor (NMDAR)-mediated synaptic currents and decrease AMPA Receptor (AMPAR)/NMDAR ratios in midbrain dopamine neurons. The potentiation depends on the transport of AMPH into the cell by the Dopamine Transporter. NMDAR-GluN2B receptor inhibitors, ifenprodil, RO 25-6981, and RO 04-5595, inhibit the potentiation without affecting basal-evoked NMDA currents, indicating that NMDAR-GluN2B receptors are activated by AMPH. A selective peptide inhibitor of AMPH-dependent trafficking of the neuronal excitatory amino acid transporter 3 (EAAT3) blocks potentiation, suggesting that EAAT3 internalization increases extracellular glutamate concentrations and activates GluN2B-containing NMDARs. Experiments with the use-dependent NMDAR blocker, MK-801, indicate that potentiated NMDARs reside on the plasma membrane and are not inserted de novo. In behavioral studies, GluN2B inhibitors reduce MA-mediated locomotor activity, without affecting basal activity. These results reveal an important interaction between dopamine and glutamatergic signaling in midbrain dopamine neurons in response to acute administration of psychostimulants.