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

J Neurosci. 2015 Oct 14;35(41):14057-69. doi: 10.1523/JNEUROSCI.1312-15.2015.

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.

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.

Keywords: Parkinsonism; TAAR1; dyskinesia; l-DOPA; trace amine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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 Plasma Membrane Transport Proteins / metabolism
  • Dopamine and cAMP-Regulated Phosphoprotein 32 / metabolism
  • Glutamic Acid / metabolism*
  • Levodopa / pharmacology
  • Levodopa / therapeutic use*
  • Male
  • 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

Substances

  • Adrenergic Agents
  • Antiparkinson Agents
  • Dopamine Plasma Membrane Transport Proteins
  • Dopamine and cAMP-Regulated Phosphoprotein 32
  • Oligodeoxyribonucleotides, Antisense
  • Radiopharmaceuticals
  • Receptors, G-Protein-Coupled
  • Glutamic Acid
  • Levodopa
  • 2beta-carbomethoxy-3beta-(4-iodophenyl)tropane
  • Oxidopamine
  • Tyrosine 3-Monooxygenase
  • Cocaine
  • Dopamine
  • Trace amine-associated receptor 1