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

Abstract

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.