title: Glutamate receptors on dopamine neurons control the persistence of cocaine seeking.
abstract: Cocaine strengthens excitatory synapses onto midbrain dopamine neurons through the synaptic delivery of GluR1-containing AMPA receptors. This cocaine-evoked plasticity depends on NMDA receptor activation, but its behavioral significance in the context of addiction remains elusive. Here, we generated mice lacking the GluR1, GluR2, or NR1 receptor subunits selectively in dopamine neurons. We report that in midbrain slices of cocaine-treated mice, synaptic transmission was no longer strengthened when GluR1 or NR1 was abolished, while in the respective mice the drug still induced normal conditioned place preference and locomotor sensitization. In contrast, extinction of drug-seeking behavior was absent in mice lacking GluR1, while in the NR1 mutant mice reinstatement was abolished. In conclusion, cocaine-evoked synaptic plasticity does not mediate concurrent short-term behavioral effects of the drug but may initiate adaptive changes eventually leading to the persistence of drug-seeking behavior.
authors.affiliation: Division of Molecular Biology of the Cell I, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Engblom
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Bilbao
authors.forename: Carles
authors.initials: C
authors.lastname: Sanchis-Segura
authors.forename: Lionel
authors.initials: L
authors.lastname: Dahan
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Perreau-Lenz
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Balland
authors.forename: Jan Rodriguez
authors.initials: JR
authors.lastname: Parkitna
authors.forename: Rafael
authors.initials: R
authors.lastname: Luján
authors.forename: Briac
authors.initials: B
authors.lastname: Halbout
authors.forename: Manuel
authors.initials: M
authors.lastname: Mameli
authors.forename: Rosanna
authors.initials: R
authors.lastname: Parlato
authors.forename: Rolf
authors.initials: R
authors.lastname: Sprengel
authors.forename: Christian
authors.initials: C
authors.lastname: Lüscher
authors.forename: Günther
authors.initials: G
authors.lastname: Schütz
authors.forename: Rainer
authors.initials: R
authors.lastname: Spanagel
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D019970:Cocaine-Related Disorders / Q000378:metabolism / Q000503:physiopathology*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D018091:Receptors, AMPA / Q000172:deficiency; D017470:Receptors, Glutamate / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000172:deficiency; D013997:Time Factors; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000166:cytology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D004298:Dopamine; D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D014633:Valine; D005680:gamma-Aminobutyric Acid; C409466:NR1 NMDA receptor; C056639:2-amino-5-phosphopentanoic acid; C104722:glutamate receptor ionotropic, AMPA 2