title: 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.
authors.affiliation: Department of Neurological Surgery, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Ming-Hua
authors.initials: MH
authors.lastname: Li
authors.affiliation: National Institute of Mental Health, National Institutes of Health, Laboratory of Molecular and Cellular Neurobiology, Bethesda, MD, USA.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Underhill
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Reed
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA.|VA Portland Health Care System, Portland, OR, USA.
authors.forename: Tamara J
authors.initials: TJ
authors.lastname: Phillips
authors.affiliation: National Institute of Mental Health, National Institutes of Health, Laboratory of Molecular and Cellular Neurobiology, Bethesda, MD, USA.
authors.forename: Susan G
authors.initials: SG
authors.lastname: Amara
authors.affiliation: Department of Neurological Surgery, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Ingram
mesh_terms: D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005260:Female; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism*; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055366:Synaptic Potentials / Q000187:drug effects* / Q000502:physiology
chemical_list: D000697:Central Nervous System Stimulants; D018691:Excitatory Amino Acid Antagonists; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D008694:Methamphetamine; D000661:Amphetamine