Modulation by Trace Amine-Associated Receptor 1 of Experimental Parkinsonism, L-DOPA Responsivity, and Glutamatergic Neurotransmission

• Published in: The Journal of neuroscience 2015-10, Vol.35 (41), p.14057-14069
• Main Authors: Alvarsson, Alexandra, Zhang, Xiaoqun, Stan, Tiberiu L, Schintu, Nicoletta, Kadkhodaei, Banafsheh, Millan, Mark J, Perlmann, Thomas, Svenningsson, Per
• Format: Article
• Language: English
• Subjects: Adrenergic Agents - toxicity; Akathisia, Drug-Induced - etiology; Animals; Antiparkinson Agents - therapeutic use; Cocaine - analogs & derivatives; Cocaine - pharmacokinetics; Corpus Striatum - drug effects; Corpus Striatum - pathology; Disease Models, Animal; Dopamine - metabolism; Dopamine and cAMP-Regulated Phosphoprotein 32 - metabolism; Dopamine Plasma Membrane Transport Proteins - metabolism; Glutamic Acid - metabolism; Levodopa - pharmacology; Levodopa - therapeutic use; Male; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Mice, Knockout; Oligodeoxyribonucleotides, Antisense - pharmacology; Oxidopamine - toxicity; Parkinsonian Disorders - chemically induced; Parkinsonian Disorders - drug therapy; Parkinsonian Disorders - pathology; Radiopharmaceuticals - pharmacokinetics; Receptors, G-Protein-Coupled - deficiency; Receptors, G-Protein-Coupled - genetics; Stereotyped Behavior - drug effects; Synaptic Transmission - drug effects; Synaptic Transmission - genetics; Time Factors; Tyrosine 3-Monooxygenase - metabolism
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/jneurosci.1312-15.2015

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. 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, manage