TY - JOUR

T1 - Identification of TAAR5 Agonist Activity of Alpha-NETA and Its Effect on Mismatch Negativity Amplitude in Awake Rats

AU - Aleksandrov, Aleksander A.

AU - Knyazeva, Veronika M.

AU - Volnova, Anna B.

AU - Dmitrieva, Elena S.

AU - Korenkova, Olga

AU - Espinoza, Stefano

AU - Gerasimov, Andrey

AU - Gainetdinov, Raul R.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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.

AB - 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.

KW - 2-(Alpha-naphthoyl)ethyltrimethylammonium iodide (alpha-NETA)

KW - Awake rats

KW - Mismatch negativity (MMN)

KW - Oddball paradigm

KW - TAAR5

KW - Trace amine-associated receptors

UR - http://www.scopus.com/inward/record.url?scp=85049160113&partnerID=8YFLogxK

U2 - 10.1007/s12640-018-9902-6

DO - 10.1007/s12640-018-9902-6

M3 - Article

C2 - 29713997

AN - SCOPUS:85049160113

VL - 34

SP - 442

EP - 451

JO - Neurotoxicity Research

JF - Neurotoxicity Research

SN - 1029-8428

IS - 3

ER -