Glutamate receptors on dopamine neurons control the persistence of cocaine seeking

David Engblom; Ainhoa Bilbao; Carles Sanchis-Segura; Lionel Dahan; Stéphanie Perreau-Lenz; Bénédicte Balland; Jan Rodriguez Parkitna; Rafael Luján; Briac Halbout; Manuel Mameli; Rosanna Parlato; Rolf Sprengel; Christian Lüscher; Günther Schütz; Rainer Spanagel

doi:10.1016/j.neuron.2008.07.010

Glutamate receptors on dopamine neurons control the persistence of cocaine seeking

Neuron. 2008 Aug 14;59(3):497-508. doi: 10.1016/j.neuron.2008.07.010.

Authors

David Engblom¹, Ainhoa Bilbao, Carles Sanchis-Segura, Lionel Dahan, Stéphanie Perreau-Lenz, Bénédicte Balland, Jan Rodriguez Parkitna, Rafael Luján, Briac Halbout, Manuel Mameli, Rosanna Parlato, Rolf Sprengel, Christian Lüscher, Günther Schütz, Rainer Spanagel

Affiliation

¹ Division of Molecular Biology of the Cell I, German Cancer Research Center, 69120 Heidelberg, Germany.

PMID: 18701074
DOI: 10.1016/j.neuron.2008.07.010

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Behavior, Animal
Cocaine-Related Disorders / metabolism
Cocaine-Related Disorders / physiopathology*
Conditioning, Operant / drug effects
Conditioning, Operant / physiology
Dopamine / metabolism*
Excitatory Amino Acid Antagonists / pharmacology
In Vitro Techniques
Membrane Potentials / drug effects
Membrane Potentials / genetics
Mice
Mice, Knockout
Motor Activity / physiology
Neuronal Plasticity / drug effects
Neuronal Plasticity / genetics
Neurons / drug effects
Neurons / physiology*
Patch-Clamp Techniques
Receptors, AMPA / deficiency
Receptors, Glutamate / physiology*
Receptors, N-Methyl-D-Aspartate / deficiency
Time Factors
Valine / analogs & derivatives
Valine / pharmacology
Ventral Tegmental Area / cytology
gamma-Aminobutyric Acid / pharmacology

Substances

Excitatory Amino Acid Antagonists
NR1 NMDA receptor
Receptors, AMPA
Receptors, Glutamate
Receptors, N-Methyl-D-Aspartate
gamma-Aminobutyric Acid
2-amino-5-phosphopentanoic acid
Valine
glutamate receptor ionotropic, AMPA 2
glutamate receptor ionotropic, AMPA 1
Dopamine