Characterization of the striatal dopaminergic neurotransmission in MEN2B mice with elevated cerebral tissue dopamine

Jelena Mijatovic, Outi Patrikainen, Leonid Yavich, Mikko Airavaara, Liisa Ahtee, Mart Saarma, Petteri Piepponen

    Research output: Contribution to journalArticleScientificpeer-review

    Abstract

    The Ret receptor tyrosine kinase is the common signaling receptor for the glial cell line-derived neurotrophic factor (GDNF) family ligands. The Met918Thr mutation leads to constitutive activation of Ret and is responsible for dominantly inherited cancer syndrome MEN2B. Previously, we found that the mice carrying the mutation (MEN2B mice) have profoundly increased tissue dopamine (DA) concentrations in the striatum as well as increased striatal levels of tyrosine hydroxylase (TH) and dopamine transporter. The aim of this study was to characterize the striatal dopaminergic neurotransmission in MEN2B mice and to clarify the mechanisms by which they compensate their over-production of DA. We found that tyrosine hydroxylase activity and DA synthesis are increased in MEN2B mice. Augmented effects of alpha-methyl-para-tyrosine (alpha MT, an inhibitor of TH) and tetrabenazine (VMAT2 blocker) on DA levels suggest that also storage of DA is increased in MEN2B mice. There was no difference in the basal extracellular DA concentrations or potassium-evoked DA release between the genotypes. The effects of cocaine and haloperidol were also similar between the genotypes as assessed by in vivo microdialysis. However, with in vivo voltammetry we found increase in stimulated DA release in MEN2B mice and detailed analysis of DA overflow showed that uptake of DA was also enhanced in MEN2B mice. Thus, our data show that enhanced synthesis of DA leading to increased storage and releasable pools in pre-synaptic terminals in MEN2B mice apparently also leads to increased DA release, which in turn is compensated by higher dopamine transporter activity.
    Original languageEnglish
    JournalJournal of Neurochemistry
    Volume105
    Issue number5
    Pages (from-to)1716-1725
    Number of pages10
    ISSN0022-3042
    DOIs
    Publication statusPublished - 2008
    MoE publication typeA1 Journal article-refereed

    Cite this

    @article{b2d80286b9a0497392b66b0df1e38065,
    title = "Characterization of the striatal dopaminergic neurotransmission in MEN2B mice with elevated cerebral tissue dopamine",
    abstract = "The Ret receptor tyrosine kinase is the common signaling receptor for the glial cell line-derived neurotrophic factor (GDNF) family ligands. The Met918Thr mutation leads to constitutive activation of Ret and is responsible for dominantly inherited cancer syndrome MEN2B. Previously, we found that the mice carrying the mutation (MEN2B mice) have profoundly increased tissue dopamine (DA) concentrations in the striatum as well as increased striatal levels of tyrosine hydroxylase (TH) and dopamine transporter. The aim of this study was to characterize the striatal dopaminergic neurotransmission in MEN2B mice and to clarify the mechanisms by which they compensate their over-production of DA. We found that tyrosine hydroxylase activity and DA synthesis are increased in MEN2B mice. Augmented effects of alpha-methyl-para-tyrosine (alpha MT, an inhibitor of TH) and tetrabenazine (VMAT2 blocker) on DA levels suggest that also storage of DA is increased in MEN2B mice. There was no difference in the basal extracellular DA concentrations or potassium-evoked DA release between the genotypes. The effects of cocaine and haloperidol were also similar between the genotypes as assessed by in vivo microdialysis. However, with in vivo voltammetry we found increase in stimulated DA release in MEN2B mice and detailed analysis of DA overflow showed that uptake of DA was also enhanced in MEN2B mice. Thus, our data show that enhanced synthesis of DA leading to increased storage and releasable pools in pre-synaptic terminals in MEN2B mice apparently also leads to increased DA release, which in turn is compensated by higher dopamine transporter activity.",
    author = "Jelena Mijatovic and Outi Patrikainen and Leonid Yavich and Mikko Airavaara and Liisa Ahtee and Mart Saarma and Petteri Piepponen",
    year = "2008",
    doi = "10.1111/j.1471-4159.2008.05265.x",
    language = "English",
    volume = "105",
    pages = "1716--1725",
    journal = "Journal of Neurochemistry",
    issn = "0022-3042",
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    number = "5",

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    Characterization of the striatal dopaminergic neurotransmission in MEN2B mice with elevated cerebral tissue dopamine. / Mijatovic, Jelena; Patrikainen, Outi; Yavich, Leonid; Airavaara, Mikko; Ahtee, Liisa; Saarma, Mart; Piepponen, Petteri.

    In: Journal of Neurochemistry, Vol. 105, No. 5, 2008, p. 1716-1725.

    Research output: Contribution to journalArticleScientificpeer-review

    TY - JOUR

    T1 - Characterization of the striatal dopaminergic neurotransmission in MEN2B mice with elevated cerebral tissue dopamine

    AU - Mijatovic, Jelena

    AU - Patrikainen, Outi

    AU - Yavich, Leonid

    AU - Airavaara, Mikko

    AU - Ahtee, Liisa

    AU - Saarma, Mart

    AU - Piepponen, Petteri

    PY - 2008

    Y1 - 2008

    N2 - The Ret receptor tyrosine kinase is the common signaling receptor for the glial cell line-derived neurotrophic factor (GDNF) family ligands. The Met918Thr mutation leads to constitutive activation of Ret and is responsible for dominantly inherited cancer syndrome MEN2B. Previously, we found that the mice carrying the mutation (MEN2B mice) have profoundly increased tissue dopamine (DA) concentrations in the striatum as well as increased striatal levels of tyrosine hydroxylase (TH) and dopamine transporter. The aim of this study was to characterize the striatal dopaminergic neurotransmission in MEN2B mice and to clarify the mechanisms by which they compensate their over-production of DA. We found that tyrosine hydroxylase activity and DA synthesis are increased in MEN2B mice. Augmented effects of alpha-methyl-para-tyrosine (alpha MT, an inhibitor of TH) and tetrabenazine (VMAT2 blocker) on DA levels suggest that also storage of DA is increased in MEN2B mice. There was no difference in the basal extracellular DA concentrations or potassium-evoked DA release between the genotypes. The effects of cocaine and haloperidol were also similar between the genotypes as assessed by in vivo microdialysis. However, with in vivo voltammetry we found increase in stimulated DA release in MEN2B mice and detailed analysis of DA overflow showed that uptake of DA was also enhanced in MEN2B mice. Thus, our data show that enhanced synthesis of DA leading to increased storage and releasable pools in pre-synaptic terminals in MEN2B mice apparently also leads to increased DA release, which in turn is compensated by higher dopamine transporter activity.

    AB - The Ret receptor tyrosine kinase is the common signaling receptor for the glial cell line-derived neurotrophic factor (GDNF) family ligands. The Met918Thr mutation leads to constitutive activation of Ret and is responsible for dominantly inherited cancer syndrome MEN2B. Previously, we found that the mice carrying the mutation (MEN2B mice) have profoundly increased tissue dopamine (DA) concentrations in the striatum as well as increased striatal levels of tyrosine hydroxylase (TH) and dopamine transporter. The aim of this study was to characterize the striatal dopaminergic neurotransmission in MEN2B mice and to clarify the mechanisms by which they compensate their over-production of DA. We found that tyrosine hydroxylase activity and DA synthesis are increased in MEN2B mice. Augmented effects of alpha-methyl-para-tyrosine (alpha MT, an inhibitor of TH) and tetrabenazine (VMAT2 blocker) on DA levels suggest that also storage of DA is increased in MEN2B mice. There was no difference in the basal extracellular DA concentrations or potassium-evoked DA release between the genotypes. The effects of cocaine and haloperidol were also similar between the genotypes as assessed by in vivo microdialysis. However, with in vivo voltammetry we found increase in stimulated DA release in MEN2B mice and detailed analysis of DA overflow showed that uptake of DA was also enhanced in MEN2B mice. Thus, our data show that enhanced synthesis of DA leading to increased storage and releasable pools in pre-synaptic terminals in MEN2B mice apparently also leads to increased DA release, which in turn is compensated by higher dopamine transporter activity.

    U2 - 10.1111/j.1471-4159.2008.05265.x

    DO - 10.1111/j.1471-4159.2008.05265.x

    M3 - Article

    VL - 105

    SP - 1716

    EP - 1725

    JO - Journal of Neurochemistry

    JF - Journal of Neurochemistry

    SN - 0022-3042

    IS - 5

    ER -