title: Cocaine Exposure Enhances the Activity of Ventral Tegmental Area Dopamine Neurons via Calcium-Impermeable NMDARs.
abstract: Potentiation of excitatory inputs onto dopamine neurons of the ventral tegmental area (VTA) induced by cocaine exposure allows remodeling of the mesocorticolimbic circuitry, which ultimately drives drug-adaptive behavior. This potentiation is mediated by changes in NMDAR and AMPAR subunit composition. It remains unknown how this synaptic plasticity affects the activity of dopamine neurons. Here, using rodents, we demonstrate that a single cocaine injection increases the firing rate and bursting activity of VTA dopamine neurons, and that these increases persist for 7 d. This enhanced activity depends on the insertion of low-conductance, Ca2+-impermeable NMDARs that contain GluN3A. Since such receptors are not capable of activating small-conductance potassium channels, the intrinsic excitability of VTA dopamine neurons increases. Activation of group I mGluRs rescues synaptic plasticity and restores small-conductance calcium-dependent potassium channel function, normalizing the firing activity of dopamine neurons. Our study characterizes a mechanism linking drug-evoked synaptic plasticity to neural activity, revealing novel targets for therapeutic interventions.
  
  
  
  We show that cocaine-evoked synaptic changes onto ventral tegmental area (VTA) dopamine (DA) neurons leads to long-lasting increases in their burst firing. This increase is due to impaired function of Ca2+-activated small-conductance calcium-dependent potassium (SK) channels; SK channels regulate firing of VTA DA neurons, but this regulation was absent after cocaine. Cocaine exposure drives the insertion of GluN3A-containing NMDARs onto VTA DA neurons. These receptors are Ca2+-impermeable, and thus SK channels are not efficiently activated by synaptic activity. In GluN3A knock-out mice, cocaine did not alter SK channel function or VTA DA neuron firing. This study directly links synaptic changes to increased intrinsic excitability of VTA DA neurons after cocaine, and explains how acute cocaine induces long-lasting remodeling of the mesolimbic DA system.
authors: Department of Basic Neuroscience, University of Geneva, 1205 Geneva, Switzerland.
authors: Meaghan
authors: 0000-0002-9658-2601
authors: M
authors: Creed
authors: Centre National de la Recherche Scientifique, Interdisciplinary Institute for Neuroscience, UMR 5297, F-33076 Bordeaux, France.
authors: Jennifer
authors: 0000-0001-8115-6039
authors: J
authors: Kaufling
authors: Université de Bordeaux and.|Centre National de la Recherche Scientifique, Neurodegeneratives Diseases Institute, UMR 5293, F-33076 Bordeaux, France.
authors: Giulia R
authors: 0000-0002-1366-3394
authors: GR
authors: Fois
authors: Université de la Méditerranée, UMR S901, F-13009 Marseille, France.|Institut national de la santé et de la recherche médicale, Institut de Neurobiologie de la Méditerranée, UMR 901, F-13009 Marseille, France, and.
authors: Marion
authors: M
authors: Jalabert
authors: Department of Basic Neuroscience, University of Geneva, 1205 Geneva, Switzerland.
authors: Tifei
authors: T
authors: Yuan
authors: Department of Basic Neuroscience, University of Geneva, 1205 Geneva, Switzerland.|Department of Neurology, University of Geneva Hospital, 1205 Geneva, Switzerland.
authors: Christian
authors: 0000-0001-7917-4596
authors: C
authors: Lüscher
authors: Université de Bordeaux and camilla.bellone@unige.ch francois.georges@u-bordeaux2.fr.|Centre National de la Recherche Scientifique, Neurodegeneratives Diseases Institute, UMR 5293, F-33076 Bordeaux, France.|Centre National de la Recherche Scientifique, Interdisciplinary Institute for Neuroscience, UMR 5297, F-33076 Bordeaux, France.
authors: Francois
authors: F
authors: Georges
authors: Department of Basic Neuroscience, University of Geneva, 1205 Geneva, Switzerland, camilla.bellone@unige.ch francois.georges@u-bordeaux2.fr.
authors: Camilla
authors: 0000-0002-6774-6275
authors: C
authors: Bellone
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003042:Cocaine / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D059290:Dopaminergic Neurons / Q000187:drug effects*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D018345:Mice, Knockout; D009473:Neuronal Plasticity; D018408:Patch-Clamp Techniques; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects*
chemical_list: D018765:Dopamine Uptake Inhibitors; C096392:Grin3a protein, rat; D008562:Membrane Glycoproteins; D024681:Potassium Channels, Calcium-Activated; D016194:Receptors, N-Methyl-D-Aspartate; D003042:Cocaine; D002118:Calcium
keywords: GluN3A; NMDA; dopamine; firing rate