TY - JOUR T1 - Modulation by Trace Amine-Associated Receptor 1 of Experimental Parkinsonism, <span class="sc">l</span>-DOPA Responsivity, and Glutamatergic Neurotransmission JF - The Journal of Neuroscience JO - J. Neurosci. SP - 14057 LP - 14069 DO - 10.1523/JNEUROSCI.1312-15.2015 VL - 35 IS - 41 AU - Alexandra Alvarsson AU - Xiaoqun Zhang AU - Tiberiu L Stan AU - Nicoletta Schintu AU - Banafsheh Kadkhodaei AU - Mark J. Millan AU - Thomas Perlmann AU - Per Svenningsson Y1 - 2015/10/14 UR - http://www.jneurosci.org/content/35/41/14057.abstract N2 - 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.SIGNIFICANCE STATEMENT 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. ER -