Identification of TAAR5 Agonist Activity of Alpha-NETA and Its Effect on Mismatch Negativity Amplitude in Awake Rats

Neurotox Res. 2018 Oct;34(3):442-451. doi: 10.1007/s12640-018-9902-6. Epub 2018 May 1.

Abstract

Mismatch negativity (MMN) is a well-defined component of human event-related potentials that reflects the pre-attentive, stimulus-discrimination process and is associated with involuntary switching of attention. MMN-like responses detected in animal models provide an opportunity to investigate the neural mechanisms of this process that involves several neurotransmitter and neuromodulator systems. Trace amines are believed to play a significant role in neuromodulation of synaptic transmission. The present study aimed to determine the role of trace amine-associated receptor 5 (TAAR5) in the MMN-like response in rats. First, using a bioluminescence resonance energy transfer (BRET) cAMP biosensor, we performed unbiased screening of TAAR5 ligands from a commercially available compound library (661 compounds) and identified 2-(alpha-naphthoyl)ethyltrimethylammonium iodide (alpha-NETA) as a potent (EC50 150 nM) TAAR5 agonist. Then, we recorded auditory event-related potentials during an oddball paradigm in awake freely moving rats that were intraperitoneally injected with a vehicle or two doses of the putative TAAR5 agonist alpha-NETA. The MMN-like response was increased by alpha-NETA 3 mg/kg dose, but not by 1 mg/kg dose or 0.9% saline solution. These results suggest that the MMN-like response in rats may be modulated, at least in part, through TAAR5-dependent processes.

Keywords: 2-(Alpha-naphthoyl)ethyltrimethylammonium iodide (alpha-NETA); Awake rats; Mismatch negativity (MMN); Oddball paradigm; TAAR5; Trace amine-associated receptors.

MeSH terms

  • Acoustic Stimulation
  • Animals
  • Contingent Negative Variation / drug effects*
  • Dose-Response Relationship, Drug
  • Evoked Potentials, Auditory / drug effects*
  • Evoked Potentials, Auditory / physiology
  • Functional Laterality / drug effects
  • Male
  • Naphthalenes / pharmacology*
  • Quaternary Ammonium Compounds / pharmacology*
  • Rats
  • Rats, Wistar
  • Reaction Time / drug effects
  • Receptors, AMPA / agonists*
  • Receptors, AMPA / metabolism
  • Resonance Frequency Analysis
  • Statistics, Nonparametric
  • Wakefulness / drug effects*
  • Wakefulness / physiology

Substances

  • Cacng5 protein, rat
  • Naphthalenes
  • Quaternary Ammonium Compounds
  • Receptors, AMPA
  • 2-naphthoylethyltrimethylammonium