Abstract
The trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor widely expressed in the mammalian brain, particularly in limbic system and monoaminergic areas. It has proven to be an important modulator of dopaminergic, serotoninergic, and glutamatergic neurotransmission and is considered to be a potential useful target for the pharmacotherapy of neuropsychiatric disorders, including schizophrenia. One of the promising schizophrenia endophenotypes is a deficit in neurocognitive abilities manifested as mismatch negativity (MMN) deficit. This study examines the effect of TAAR1 partial agonist RO5263397 on the MMN-like response in freely moving C57BL/6 mice. Event-related potentials (ERPs) were recorded from awake mice in the oddball paradigm before and after RO5263397 administration. The RO5263397 (but not saline) administration increased the N40 amplitude in response to deviant stimuli. That provided the MMN-like difference at the 36–44 ms interval after the injection. The pitch deviance-elicited changes before the injection and in the control paradigm were established for the P68 component. After TAAR1 agonist administration the P68 amplitude in response both to standard and deviant stimuli was increased. These results suggest that the MMN-like response in mice may be modulated through TAAR1-dependent processes (possibly acting through the direct or indirect glutamate NMDA receptor modulation), indicating the TAAR1 agonists potential antipsychotic and pro-cognitive activity.
Highlights
Trace amines are related by structure to classical biogenic amines and have long been known to be present in low concentrations (0.1– 10 nM) in the mammalian nervous system
Fisher LSD post hoc test indicated significantly more negative response to the deviant stimuli after the trace amine-associated receptor 1 (TAAR1) agonist injection (p = 0.029) The difference between deviant and standard stimuli responses became significant after the RO5263397 administration (p < 0.001) (Figure 2)
The pitch deviance-elicited changes in the control paradigm and before the injection were established for the positive – with 68 ms latency (P68) component
Summary
Trace amines (tyramine, tryptamine, phenylethylamine, and octopamine) are related by structure to classical biogenic amines and have long been known to be present in low concentrations (0.1– 10 nM) in the mammalian nervous system. Trace amine associated receptor is the best studied member of the TA receptor family (Lindemann et al, 2008; Bradaia et al, 2009; Revel et al, 2011; Leo et al, 2014). It is found in the central nervous system of rodents, monkeys and humans and is activated by trace amines, such as phenylethylamine and tyramine (Miller, 2011). TAAR1 is mainly expressed in the limbic system and monoaminergic systems regions, including the hypothalamus, substantia nigra, dorsal raphe nucleus (DRN), and ventral tegmental area (VTA), amygdala, nucleus of the solitary tract, rhinal cortices and subiculum (Lindemann et al, 2008; Panas et al, 2010)
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