title: Drug-driven AMPA receptor redistribution mimicked by selective dopamine neuron stimulation.
abstract: BACKGROUND
  Addictive drugs have in common that they cause surges in dopamine (DA) concentration in the mesolimbic reward system and elicit synaptic plasticity in DA neurons of the ventral tegmental area (VTA). Cocaine for example drives insertion of GluA2-lacking AMPA receptors (AMPARs) at glutamatergic synapes in DA neurons. However it remains elusive which molecular target of cocaine drives such AMPAR redistribution and whether other addictive drugs (morphine and nicotine) cause similar changes through their effects on the mesolimbic DA system.
  
  
  RESULTS
  We used in vitro electrophysiological techniques in wild-type and transgenic mice to observe the modulation of excitatory inputs onto DA neurons by addictive drugs. To observe AMPAR redistribution, post-embedding immunohistochemistry for GluA2 AMPAR subunit was combined with electron microscopy. We also used a double-floxed AAV virus expressing channelrhodopsin together with a DAT Cre mouse line to selectively express ChR2 in VTA DA neurons. We find that in mice where the effect of cocaine on the dopamine transporter (DAT) is specifically blocked, AMPAR redistribution was absent following administration of the drug. Furthermore, addictive drugs known to increase dopamine levels cause a similar AMPAR redistribution. Finally, activating DA VTA neurons optogenetically is sufficient to drive insertion of GluA2-lacking AMPARs, mimicking the changes observed after a single injection of morphine, nicotine or cocaine.
  
  
  CONCLUSIONS
  We propose the mesolimbic dopamine system as a point of convergence at which addictive drugs can alter neural circuits. We also show that direct activation of DA neurons is sufficient to drive AMPAR redistribution, which may be a mechanism associated with early steps of non-substance related addictions.
authors.affiliation: Department of Basic Neurosciences, Medical Faculty, University of Geneva, Geneva, Switzerland.
authors.forename: Matthew T C
authors.initials: MT
authors.lastname: Brown
authors.forename: Camilla
authors.initials: C
authors.lastname: Bellone
authors.forename: Manuel
authors.initials: M
authors.lastname: Mameli
authors.forename: Gwenael
authors.initials: G
authors.lastname: Labouèbe
authors.forename: Christina
authors.initials: C
authors.lastname: Bocklisch
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Balland
authors.forename: Lionel
authors.initials: L
authors.lastname: Dahan
authors.forename: Rafael
authors.initials: R
authors.lastname: Luján
authors.forename: Karl
authors.initials: K
authors.lastname: Deisseroth
authors.forename: Christian
authors.initials: C
authors.lastname: Lüscher
mesh_terms: D000818:Animals; D003042:Cocaine / Q000494:pharmacology; D000229:Dependovirus / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004594:Electrophysiology / Q000379:methods; D005973:Glutamine / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology; D018091:Receptors, AMPA / Q000378:metabolism*; D013569:Synapses; D017557:Ventral Tegmental Area / Q000378:metabolism
chemical_list: D018091:Receptors, AMPA; D005973:Glutamine; D009538:Nicotine; D009020:Morphine; D003042:Cocaine; D004298:Dopamine