Postsynaptic D2 dopamine receptor supersensitivity in the striatum of mice lacking TAAR1

Neuropharmacology. 2015 Jun;93:308-13. doi: 10.1016/j.neuropharm.2015.02.010. Epub 2015 Feb 24.

Abstract

Trace Amine-Associated Receptor 1 (TAAR1) is a G protein-coupled receptor (GPCR) known to modulate dopaminergic system through several mechanisms. Mice lacking this receptor show a higher sensitivity to dopaminergic stimuli, such as amphetamine; however, it is not clear whether D1 or D2 dopamine receptors and which associated intracellular signaling events are involved in this modulation. In the striatum of TAAR1 knock out (TAAR1-KO mice) we found that D2, but not D1, dopamine receptors were over-expressed, both in terms of mRNA and protein levels. Moreover, the D2 dopamine receptor-related G protein-independent AKT/GSK3 signaling pathway was selectively activated, as indicated by the decrease of phosphorylation of AKT and GSK3β. The decrease in phospho-AKT levels, suggesting an increase in D2 dopamine receptor activity in basal conditions, was associated with an increase of AKT/PP2A complex, as revealed by co-immunoprecipitation experiments. Finally, we found that the locomotor activation induced by the D2 dopamine receptor agonist quinpirole, but not by the full D1 dopamine receptor agonist SKF-82958, was increased in TAAR1-KO mice. These data demonstrate pronounced supersensitivity of postsynaptic D2 dopamine receptors in the striatum of TAAR1-KO mice and indicate that a close interaction of TAAR1 and D2 dopamine receptors at the level of postsynaptic structures has important functional consequences.

Keywords: D2 receptor; Dopamine; Striatum; TAAR1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzazepines / pharmacology
  • Corpus Striatum / cytology*
  • Dopamine Agonists / pharmacology
  • Dopamine Plasma Membrane Transport Proteins / genetics
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Gene Expression Regulation / genetics*
  • Immunoprecipitation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity / genetics
  • Protein Binding / drug effects
  • Protein Binding / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Quinpirole / pharmacology
  • RNA, Messenger / metabolism
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, G-Protein-Coupled / deficiency*
  • Receptors, G-Protein-Coupled / genetics
  • Signal Transduction / genetics
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology*

Substances

  • Benzazepines
  • Dopamine Agonists
  • Dopamine Plasma Membrane Transport Proteins
  • RNA, Messenger
  • Receptors, Dopamine D2
  • Receptors, G-Protein-Coupled
  • Quinpirole
  • SK&F 82958
  • Proto-Oncogene Proteins c-akt
  • Trace amine-associated receptor 1