title: Enhanced sucrose and cocaine self-administration and cue-induced drug seeking after loss of VGLUT2 in midbrain dopamine neurons in mice.
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.
authors: Department of Neuroscience, Unit of Developmental Genetics, Uppsala University, S-751 24 Uppsala, Sweden.
authors: Johan
authors: J
authors: Alsiö
authors: Karin
authors: K
authors: Nordenankar
authors: Emma
authors: E
authors: Arvidsson
authors: Carolina
authors: C
authors: Birgner
authors: Souha
authors: S
authors: Mahmoudi
authors: Briac
authors: B
authors: Halbout
authors: Casey
authors: C
authors: Smith
authors: Guillaume M
authors: GM
authors: Fortin
authors: Lars
authors: L
authors: Olson
authors: Laurent
authors: L
authors: Descarries
authors: Louis-Éric
authors: LÉ
authors: Trudeau
authors: Klas
authors: K
authors: Kullander
authors: Daniel
authors: D
authors: Lévesque
authors: Asa
authors: A
authors: Wallén-Mackenzie
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001345:Autoradiography; D016739:Behavior, Addictive / Q000235:genetics / Q000503:physiopathology*; D001522:Behavior, Animal; D016923:Cell Death / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D003042:Cocaine / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D003463:Cues; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D055664:Electrochemical Techniques / Q000379:methods; D005518:Food Preferences / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D008297:Male; D008636:Mesencephalon / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D011485:Protein Binding / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D012055:Reinforcement Schedule; D012201:Reward; D012646:Self Administration / Q000379:methods; D013395:Sucrose / Q000008:administration & dosage*; D050599:Vesicular Glutamate Transport Protein 2 / Q000172:deficiency*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D011954:Receptors, Dopamine; C493477:Slc17a6 protein, mouse; D050599:Vesicular Glutamate Transport Protein 2; D013395:Sucrose; D011189:Potassium Chloride; D003042:Cocaine; D004298:Dopamine