Cocaine Exposure Enhances the Activity of Ventral Tegmental Area Dopamine Neurons via Calcium-Impermeable NMDARs.
J. Neurosci.. 2016-10-19; 36(42): 10759-10768
DOI: 10.1523/jneurosci.1703-16.2016
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1. J Neurosci. 2016 Oct 19;36(42):10759-10768.
Cocaine Exposure Enhances the Activity of Ventral Tegmental Area Dopamine Neurons
via Calcium-Impermeable NMDARs.
Creed M(1), Kaufling J(2), Fois GR(3)(4), Jalabert M(5)(6), Yuan T(1), Lüscher
C(1)(7), Georges F(8)(4)(2), Bellone C(9).
Author information:
(1)Department of Basic Neuroscience, University of Geneva, 1205 Geneva,
Switzerland.
(2)Centre National de la Recherche Scientifique, Interdisciplinary Institute for
Neuroscience, UMR 5297, F-33076 Bordeaux, France.
(3)Université de Bordeaux and.
(4)Centre National de la Recherche Scientifique, Neurodegeneratives Diseases
Institute, UMR 5293, F-33076 Bordeaux, France.
(5)Université de la Méditerranée, UMR S901, F-13009 Marseille, France.
(6)Institut national de la santé et de la recherche médicale, Institut de
Neurobiologie de la Méditerranée, UMR 901, F-13009 Marseille, France, and.
(7)Department of Neurology, University of Geneva Hospital, 1205 Geneva,
Switzerland.
(8)Université de Bordeaux and
.
(9)Department of Basic Neuroscience, University of Geneva, 1205 Geneva,
Switzerland, .
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.SIGNIFICANCE STATEMENT: 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.
Copyright © 2016 the authors 0270-6474/16/3610759-10$15.00/0.
DOI: 10.1523/JNEUROSCI.1703-16.2016
PMID: 27798131 [Indexed for MEDLINE]