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Enhanced Sucrose and Cocaine Self-Administration and Cue-Induced Drug Seeking after Loss of VGLUT2 in Midbrain Dopamine Neurons in Mice
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
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2011 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 31, no 35, 12593-12603 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2011. Vol. 31, no 35, 12593-12603 p.
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-158895DOI: 10.1523/JNEUROSCI.2397-11.2011ISI: 000294451900022OAI: oai:DiVA.org:uu-158895DiVA: diva2:441830
Available from: 2011-09-19 Created: 2011-09-19 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Functional Analysis of the Vesicular Glutamate Transporter 2 in Specific Neuronal Circuits of the Brain
Open this publication in new window or tab >>Functional Analysis of the Vesicular Glutamate Transporter 2 in Specific Neuronal Circuits of the Brain
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A key issue in neuroscience is to determine the connection between neuronal circuits and behaviour. In the adult brain, all neuronal circuits include a glutamatergic component. Three proteins designated Vesicular glutamate transporter 1-3 (VGLUT1-3) possess the capability of packaging glutamate into presynaptic vesicles for release of glutamate at the nerve terminal.

The present study aimed at determining the role of VGLUT2 in neuronal circuits of higher brain function, emotion, and reward-pocessing. A conditional knockout (cKO) strategy was utilised, and three different mouse lines were produced to delete VGLUT2 in specific neuronal circuits in a temporally and spatially controlled manner. First, we produced a cKO mouse in which Vglut2 was deleted in specific subpopulations of the cortex, amygdala and hippocampus from preadolescence. This resulted in blunted aspects in cognitive, emotional and social behaviour in a schizophrenia-related phenotype. Furthermore, we showed a downstream effect of the targeted deletion on the dopaminergic system. In a subsequent analysis of the same cKO mice, we showed that female cKO mice were more affected their male counterparts, and we also found that female schizophrenia patients, but not male patients, had increased Vglut2 levels in the cortex.  Second, we produced and analysed cKO mice in which Vglut2 was deleted in the cortex, amygdala and hippocampus already from midgestation, and could show that this deletion affected emotional, but not cognitive, function. Third, we addressed the role of VGLUT2 in midbrain dopamine neurons by targeting Vglut2 specifically in these neurons. These cKO mice showed a blunted activational response to the psychostimulant amphetamine and increased operant self-administration of both sugar and cocaine reinforcers. Further, the cKO mice displayed strongly enhanced cocaine-seeking in response to cocaine-associated cues, a behaviour of relevance for addiction in humans.

In summary, this thesis work has addressed the role of the presynaptic glutamatergic neuron in different neuronal circuits and shown that the temporal and spatial distribution of VGLUT2 is of great significance for normal brain function.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 53 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 748
Keyword
Addiction, amphetamine, affective behaviour, cocaine, cognitive behaviour, conditional knockout mouse, dopamine, operant self-administration, reward system, schizophrenia
National Category
Neurosciences
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-170046 (URN)978-91-554-8297-8 (ISBN)
Public defence
2012-04-20, B22, BMC, Husargatan 3, 751 24 Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-03-30 Created: 2012-03-07 Last updated: 2012-04-19Bibliographically approved
2. Motion and Emotion: Functional In Vivo Analyses of the Mouse Basal Ganglia
Open this publication in new window or tab >>Motion and Emotion: Functional In Vivo Analyses of the Mouse Basal Ganglia
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A major challenge in the field of neuroscience is to link behavior with specific neuronal circuitries and cellular events. One way of facing this challenge is to identify unique cellular markers and thus have the ability to, through various mouse genetics tools, mimic, manipulate and control various aspects of neuronal activity to decipher their correlation to behavior. The Vesicular Glutamate Transporter 2 (VGLUT2) packages glutamate into presynaptic vesicles for axonal terminal release. In this thesis, VGLUT2 was used to specifically target cell populations within the basal ganglia of mice with the purpose of investigating its connectivity, function and involvement in behavior. The motor and limbic loops of the basal ganglia are important for processing of voluntary movement and emotions. During such physiological events, dopamine plays a central role in modulating the activity of these systems.

The brain reward system is mainly formed by dopamine projections from the ventral tegmental area (VTA) to the ventral striatum. Certain dopamine neurons within the VTA exhibit the ability to co-release dopamine and glutamate. In paper I, glutamate and dopamine co-release was targeted and our results demonstrate that the absence of VGLUT2 in dopamine neurons leads to perturbations of reward consumption and reward-associated memory, probably due to reduced DA release observed in the striatum as detected by in vivo chronoamperometry.

In papers II and IV, VGLUT2 in a specific subpopulation within the subthalamic nucleus (STN) was identified and targeted. Based on the described role of the STN in movement control, we hypothesized that the mice would be hyperlocomotive. As shown in paper II, this was indeed the case. In paper IV, a putative reward-related phenotype was approached and we could show reduced operant-self administration of sugar and altered dopamine release levels suggesting a role for the STN in reward processes.

In paper III, we investigated and identified age- and sex-dimorphisms in dopamine kinetics in the dorsal striatum of one of the most commonly used mouse lines worldwide, the C57/Bl6J. Our results point to the importance of taking these dimorphisms into account when utilizing the C57/Bl6J strain as model for neurological and neuropsychiatric disorders.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 78 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1019
Keyword
Dopamine, Basal Ganglia, Reward System, In Vivo Chronoamperometry, Optogenetics, Deep Brain Stimulation, Parkinson’s Disease, Addiction, Glutamate, Vesicular Glutamate Transporter, VGLUT2, Sex, Age, Subthalamic Nucleus, Striatum, Nucleus Accumbens, Ventral Tegmental Area
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-229910 (URN)978-91-554-9006-5 (ISBN)
Public defence
2014-10-03, B42, BMC, Husargatan, 3, 751 24 Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2014-09-10 Created: 2014-08-16 Last updated: 2015-01-22

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Alsiö, JohanNordenankar, KarinArvidsson, EmmaKullander, KlasWallén-Mackenzie, Åsa

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