Glutamate receptors on dopamine neurons control the persistence of cocaine seeking.
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.
Engblom
David
D
Division of Molecular Biology of the Cell I, German Cancer Research Center, 69120 Heidelberg, Germany.
Bilbao
Ainhoa
A
Sanchis-Segura
Carles
C
Dahan
Lionel
L
Perreau-Lenz
Stéphanie
S
Balland
Bénédicte
B
Parkitna
Jan Rodriguez
JR
Luján
Rafael
R
Halbout
Briac
B
Mameli
Manuel
M
Parlato
Rosanna
R
Sprengel
Rolf
R
Lüscher
Christian
C
Schütz
Günther
G
Spanagel
Rainer
R
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
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