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

• Published in: Journal of neurochemistry Vol. 105; no. 5; pp. 1716 - 1725
• Main Authors: Mijatovic, Jelena, Patrikainen, Outi, Yavich, Leonid, Airavaara, Mikko, Ahtee, Liisa, Saarma, Mart, Petteri Piepponen, T
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.06.2008; Blackwell Publishing Ltd; Blackwell
• Subjects: Animals; Biochemistry; Biological and medical sciences; Brain; brain dopamine; Central nervous system; Central neurotransmission. Neuromudulation. Pathways and receptors; Corpus Striatum - metabolism; Corpus Striatum - physiology; Dopamine - biosynthesis; Dopamine - genetics; Dopamine - metabolism; dopamine transporter; Fundamental and applied biological sciences. Psychology; glial cell line-derived neurotrophic factor; in vivo voltammetry; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; microdialysis; Multiple Endocrine Neoplasia Type 2b - genetics; Multiple Endocrine Neoplasia Type 2b - metabolism; Multiple Endocrine Neoplasia Type 2b - physiopathology; Mutation; Neurology; Neurotransmitters; Ret receptor; Rodents; Signal transduction; Synaptic Transmission - physiology; tyrosine hydroxylase; Up-Regulation - genetics; Vascular diseases and vascular malformations of the nervous system; Vertebrates: nervous system and sense organs; Central nervous system; Activation; Encephalon; glial cell line-derived neurotrophic factor; Signal transduction; brain dopamine; Glial cell line derived neurotrophic factor; Biological receptor; Tyrosine; in vivo voltammetry; Dopamine; Rodentia; Basal ganglion; Corpus striatum; Malignant tumor; Catecholamine; Extracellular; tyrosine hydroxylase; Vertebrata; Mammalia; Storage; dopamine transporter; Mouse; microdialysis; Neurotransmitter; Mutation; Potassium; Neurotransmission; Ret receptor; Cancer
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2008.05265.x

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 α-methyl-para-tyrosine (αMT, 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.