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Trace Amine-Associated Receptor 1 (TAAR1) modulates dopaminergic transmission, but its role in experimental Parkinsonism and<jats:sc>l<\/jats:sc>-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<jats:sc>l<\/jats:sc>-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<jats:sc>l<\/jats:sc>-DOPA in TAAR1 KO mice was paralleled by increased phosphorylation of striatal GluA1 subunits of AMPA receptors. Conversely, RO5166017 counteracted both<jats:sc>l<\/jats:sc>-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 D<jats:sub>2<\/jats:sub>receptors. These data unveil a role for TAAR1 in modulating the degeneration of dopaminergic neurons, the behavioral response to<jats:sc>l<\/jats:sc>-DOPA, and presynaptic and postsynaptic glutamate neurotransmission in the striatum, supporting their relevance to the pathophysiology and, potentially, management of PD.<\/jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT<\/jats:bold>Parkinson's disease (PD) is characterized by a progressive loss of nigrostriatal dopaminergic neurons. Restoration of dopamine transmission by<jats:sc>l<\/jats:sc>-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<jats:sc>l<\/jats:sc>-DOPA responses has been neglected. Here, we report that TAAR1 potentiates the degeneration of dopaminergic neurons and attenuates the behavioral response to<jats:sc>l<\/jats:sc>-DOPA and presynaptic and postsynaptic glutamate neurotransmission in the striatum, supporting the relevance of TAAR1 to the pathophysiology and, potentially, management of PD.<\/jats:p>","DOI":"10.1523\/jneurosci.1312-15.2015","type":"journal-article","created":{"date-parts":[[2015,10,14]],"date-time":"2015-10-14T16:38:11Z","timestamp":1444840691000},"page":"14057-14069","source":"Crossref","is-referenced-by-count":55,"title":["Modulation by Trace Amine-Associated Receptor 1 of Experimental Parkinsonism, l-DOPA Responsivity, and Glutamatergic 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