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VGLUT2 in dopamine neurons is required for psychostimulant-induced behavioural activation
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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2010 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, no 1, 389-394 p.Article in journal (Refereed) Published
Abstract [en]

The “One neuron-one neurotransmitter” concept has been challenged frequently during the last three decades, and the coexistence of neurotransmitters in individual neurons is now regarded as a common phenomenon. The functional significance of neurotransmitter coexistence is, however, less well understood. Several studies have shown that a subpopulation of dopamine (DA) neurons in the ventral tegmental area (VTA) expresses the vesicular glutamate transporter 2 (VGLUT2) and has been suggested to use glutamate as a cotransmitter. The VTA dopamine neurons project to limbic structures including the nucleus accumbens, and are involved in mediating the motivational and locomotor activating effects of psychostimulants. To determine the functional role of glutamate cotransmission by these neurons, we deleted VGLUT2 in DA neurons by using a conditional gene-targeting approach in mice. A DAT-Cre/Vglut2Lox mouse line (Vglut2f/f;DAT-Cre mice) was produced and analyzed by in vivo amperometry as well as by several behavioral paradigms. Although basal motor function was normal in the Vglut2f/f;DAT-Cre mice, their risk-taking behavior was altered. Interestingly, in both home-cage and novel environments, the gene targeted mice showed a greatly blunted locomotor response to the psychostimulant amphetamine, which acts via the midbrain DA system. Our results show that VGLUT2 expression in DA neurons is required for normal emotional reactivity as well as for psychostimulant-mediated behavioral activation.

Place, publisher, year, edition, pages
2010. Vol. 107, no 1, 389-394 p.
Keyword [en]
amphetamine, midbrain, neurotransmission, reward, striatum
National Category
Neurosciences
Research subject
Neuroscience
Identifiers
URN: urn:nbn:se:uu:diva-169996DOI: 10.1073/pnas.0910986107ISI: 000273559200068PubMedID: 20018672OAI: oai:DiVA.org:uu-169996DiVA: diva2:508214
Available from: 2012-03-07 Created: 2012-03-07 Last updated: 2017-12-07Bibliographically 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)
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Supervisors
Available from: 2012-03-30 Created: 2012-03-07 Last updated: 2012-04-19Bibliographically approved

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Nordenankar, KarinFredriksson, AndersKullander, KlasWallén-Mackenzie, Åsa

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