Journal
JOURNAL OF NEUROSCIENCE
Volume 30, Issue 36, Pages 11973-11982Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2550-10.2010
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Funding
- Deutsche Forschungsgemeinschaft through Collaborative Research Centers [SFB 488, SFB 636]
- Fonds der Chemischen Industrie
- European Union [LSHM-CT-2005-018652]
- Bundesministerium fur Bildung und Forschung [FZK 01GS08153, 01GS08142]
- Helmholtz Gemeinschaft Deutscher Forschungszentren through Initiative CoReNe and Alliance HelMA
- Deutsche Krebshilfe [108567]
- Swedish Research Council
- Thuring foundation
- Wiberg foundation
- Jeansson foundation
- Swedish Society of Medicine
- Biotechnology and Biological Sciences Research Council
- Pfizer Inc.
- United Kingdom Medical Research Council
- Marie Curie reintegration award
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Understanding the psychobiological basis of relapse remains a challenge in developing therapies for drug addiction. Relapse in cocaine addiction often occurs following exposure to environmental stimuli previously associated with drug taking. The metabotropic glutamate receptor, mGluR5, is potentially important in this respect; it plays a central role in several forms of striatal synaptic plasticity proposed to underpin associative learning and memory processes that enable drug-paired stimuli to acquire incentive motivational properties and trigger relapse. Using cell type-specific RNA interference, we have generated a novel mouse line with a selective knock-down of mGluR5 in dopamine D1 receptor-expressing neurons. Although mutant mice self-administer cocaine, we show that reinstatement of cocaine-seeking induced by a cocaine-paired stimulus is impaired. By examining different aspects of associative learning in the mutant mice, we identify deficits in specific incentive learning processes that enable a reward-paired stimulus to directly reinforce behavior and to become attractive, thus eliciting approach toward it. Our findings show that glutamate signaling through mGluR5 located on dopamine D1 receptor-expressing neurons is necessary for incentive learning processes that contribute to cue-induced reinstatement of cocaine-seeking and which may underpin relapse in drug addiction.
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