Abstract |
The mesostriatal dopamine (DA) system contributes to several aspects of responses to rewarding substances and is implicated in conditions such as drug addiction and eating disorders. A subset of DA neurons has been shown to express the type 2 Vesicular glutamate transporter (Vglut2) and may therefore corelease glutamate. In the present study, we analyzed mice with a conditional deletion of Vglut2 in DA neurons (Vglut2(f/f;DAT-Cre)) to address the functional significance of the glutamate-DA cophenotype for responses to cocaine and food reinforcement. Biochemical parameters of striatal DA function were also examined by using DA receptor autoradiography, immediate-early gene quantitative in situ hybridization after cocaine challenge, and DA-selective in vivo chronoamperometry. Mice in which Vglut2 expression had been abrogated in DA neurons displayed enhanced operant self-administration of both high- sucrose food and intravenous cocaine. Furthermore, cocaine seeking maintained by drug-paired cues was increased by 76%, showing that reward-dependent plasticity is perturbed in these mice. In addition, several lines of evidence suggest that adaptive changes occurred in both the ventral and dorsal striatum in the absence of VGLUT2: DA receptor binding was increased, and basal mRNA levels of the DA-induced early genes Nur77 and c-fos were elevated as after cocaine induction. Furthermore, in vivo challenge of the DA system by potassium-evoked depolarization revealed less DA release in both striatal areas. This study demonstrates that absence of VGLUT2 in DA neurons leads to perturbations of reward consumption as well as reward-associated memory, features of particular relevance for addictive-like behavior.
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Authors | Johan Alsiö, Karin Nordenankar, Emma Arvidsson, Carolina Birgner, Souha Mahmoudi, Briac Halbout, Casey Smith, Guillaume M Fortin, Lars Olson, Laurent Descarries, Louis-Éric Trudeau, Klas Kullander, Daniel Lévesque, Asa Wallén-Mackenzie |
Journal | The Journal of neuroscience : the official journal of the Society for Neuroscience
(J Neurosci)
Vol. 31
Issue 35
Pg. 12593-603
(Aug 31 2011)
ISSN: 1529-2401 [Electronic] United States |
PMID | 21880920
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Dopamine Plasma Membrane Transport Proteins
- Dopamine Uptake Inhibitors
- Nr4a1 protein, mouse
- Nuclear Receptor Subfamily 4, Group A, Member 1
- Proto-Oncogene Proteins c-fos
- RNA, Messenger
- Receptors, Dopamine
- Slc17a6 protein, mouse
- Vesicular Glutamate Transport Protein 2
- Sucrose
- Potassium Chloride
- Cocaine
- Dopamine
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Topics |
- Analysis of Variance
- Animals
- Autoradiography
- Behavior, Addictive
(genetics, physiopathology)
- Behavior, Animal
- Cell Death
(drug effects, genetics, immunology)
- Cocaine
(administration & dosage)
- Conditioning, Operant
(drug effects, physiology)
- Cues
- Dopamine
(metabolism)
- Dopamine Plasma Membrane Transport Proteins
(genetics)
- Dopamine Uptake Inhibitors
(administration & dosage)
- Electrochemical Techniques
(methods)
- Food Preferences
(drug effects, physiology)
- Gene Expression Regulation
(drug effects, genetics)
- Male
- Mesencephalon
(cytology, drug effects, metabolism)
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Neurons
(metabolism)
- Nuclear Receptor Subfamily 4, Group A, Member 1
(genetics, metabolism)
- Potassium Chloride
(pharmacology)
- Protein Binding
(genetics)
- Proto-Oncogene Proteins c-fos
(genetics, metabolism)
- RNA, Messenger
(metabolism)
- Receptors, Dopamine
(metabolism)
- Reinforcement Schedule
- Reward
- Self Administration
(methods)
- Sucrose
(administration & dosage)
- Vesicular Glutamate Transport Protein 2
(deficiency)
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