Incentive learning underlying cocaine-seeking requires mGluR5 receptors located on dopamine D1 receptor-expressing neurons.
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.
Novak
Martin
M
Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany.
Halbout
Briac
B
O'Connor
Eoin C
EC
Rodriguez Parkitna
Jan
J
Su
Tian
T
Chai
Minqiang
M
Crombag
Hans S
HS
Bilbao
Ainhoa
A
Spanagel
Rainer
R
Stephens
David N
DN
Schütz
Günther
G
Engblom
David
D
D000704:Analysis of Variance; D000818:Animals; D001245:Association Learning / Q000187:drug effects*; D001522:Behavior, Animal; D001921:Brain / Q000166:cytology*; D003042:Cocaine / Q000008:administration & dosage; D019970:Cocaine-Related Disorders / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D003463:Cues; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D049452:Green Fluorescent Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009042:Motivation / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D034622:RNA Interference / Q000502:physiology; D064529:Receptor, Metabotropic Glutamate 5; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*; D012054:Reinforcement, Psychology; D012646:Self Administration / Q000379:methods
D018765:Dopamine Uptake Inhibitors; C578936:Grm5 protein, mouse; D064529:Receptor, Metabotropic Glutamate 5; D017447:Receptors, Dopamine D1; D018080:Receptors, GABA-B; D018094:Receptors, Metabotropic Glutamate; D049452:Green Fluorescent Proteins; D003042:Cocaine
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