title: Modulation by Trace Amine-Associated Receptor 1 of Experimental Parkinsonism, L-DOPA Responsivity, and Glutamatergic Neurotransmission.
abstract: Parkinson's disease (PD) is a movement disorder characterized by a progressive loss of nigrostriatal dopaminergic neurons. Restoration of dopamine transmission by l-DOPA relieves symptoms of PD but causes dyskinesia. Trace Amine-Associated Receptor 1 (TAAR1) modulates dopaminergic transmission, but its role in experimental Parkinsonism and l-DOPA responses has been neglected. Here, we report that TAAR1 knock-out (KO) mice show a reduced loss of dopaminergic markers in response to intrastriatal 6-OHDA administration compared with wild-type (WT) littermates. In contrast, the TAAR1 agonist RO5166017 aggravated degeneration induced by intrastriatal 6-OHDA in WT mice. Subchronic l-DOPA treatment of TAAR1 KO mice unilaterally lesioned with 6-OHDA in the medial forebrain bundle resulted in more pronounced rotational behavior and dyskinesia than in their WT counterparts. The enhanced behavioral sensitization to l-DOPA in TAAR1 KO mice was paralleled by increased phosphorylation of striatal GluA1 subunits of AMPA receptors. Conversely, RO5166017 counteracted both l-DOPA-induced rotation and dyskinesia as well as AMPA receptor phosphorylation. Underpinning a role for TAAR1 receptors in modulating glutamate neurotransmission, intrastriatal application of RO5166017 prevented the increase of evoked corticostriatal glutamate release provoked by dopamine deficiency after 6-OHDA-lesions or conditional KO of Nurr1. Finally, inhibition of corticostriatal glutamate release by TAAR1 showed mechanistic similarities to that effected by activation of dopamine D2 receptors. These data unveil a role for TAAR1 in modulating the degeneration of dopaminergic neurons, the behavioral response to l-DOPA, and presynaptic and postsynaptic glutamate neurotransmission in the striatum, supporting their relevance to the pathophysiology and, potentially, management of PD.
  
  
  CONCLUSIONS
  Parkinson's disease (PD) is characterized by a progressive loss of nigrostriatal dopaminergic neurons. Restoration of dopamine transmission by l-DOPA relieves symptoms of PD but causes severe side effects. Trace Amine-Associated Receptor 1 (TAAR1) modulates dopaminergic transmission, but its role in PD and l-DOPA responses has been neglected. Here, we report that TAAR1 potentiates the degeneration of dopaminergic neurons and attenuates the behavioral response to l-DOPA and presynaptic and postsynaptic glutamate neurotransmission in the striatum, supporting the relevance of TAAR1 to the pathophysiology and, potentially, management of PD.
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, SE-17176 Stockholm, Sweden, alexandra.alvarsson@ki.se per.svenningsson@ki.se.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Alvarsson
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, SE-17176 Stockholm, Sweden.
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, SE-17176 Stockholm, Sweden.
authors.forename: Tiberiu L
authors.initials: TL
authors.lastname: Stan
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, SE-17176 Stockholm, Sweden.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Schintu
authors.affiliation: Ludwig Institute for Cancer Research, SE-17177 Stockholm, Sweden.
authors.forename: Banafsheh
authors.initials: B
authors.lastname: Kadkhodaei
authors.affiliation: Pole of Innovation in Neuropsychiatry, Institut de Recherches Servier, Centre de Recherches de Croissy, Paris 87290, France, and.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Millan
authors.affiliation: Ludwig Institute for Cancer Research, SE-17177 Stockholm, Sweden, Department of Cell and Molecular Biology, Karolinska Institutet, SE-17177 Stockholm, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Perlmann
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, SE-17176 Stockholm, Sweden, alexandra.alvarsson@ki.se per.svenningsson@ki.se.
authors.forename: Per
authors.initials: P
authors.lastname: Svenningsson
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D017109:Akathisia, Drug-Induced / Q000209:etiology; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D003042:Cocaine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D007980:Levodopa / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency* / Q000235:genetics; D013239:Stereotyped Behavior / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics*; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D000095383:Trace Amine-Associated Receptors
chemical_list: D018663:Adrenergic Agents; D000978:Antiparkinson Agents; D003042:Cocaine; D004298:Dopamine; D050483:Dopamine Plasma Membrane Transport Proteins; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D018698:Glutamic Acid; D007980:Levodopa; D020319:Oligodeoxyribonucleotides, Antisense; D016627:Oxidopamine; D019275:Radiopharmaceuticals; D043562:Receptors, G-Protein-Coupled; D014446:Tyrosine 3-Monooxygenase; D000095383:Trace Amine-Associated Receptors; C069723:2beta-carbomethoxy-3beta-(4-iodophenyl)tropane
keywords: Parkinsonism; TAAR1; dyskinesia; l-DOPA; trace amine