Trace Amine-Associated Receptor 1 Agonist Modulates Mismatch Negativity-Like Responses in Mice

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.

Trace Amine-Associated Receptor 5 Provides Olfactory Input Into Limbic Brain Areas and Modulates Emotional Behaviors and Serotonin Transmission

“…Indeed, in our study, we observed significant alterations in various measures of anxiety and affectivity of TAAR5-KO mice in a number of behavioral tests used to test putative anxiolytic and antidepressant drugs. Importantly, the lack of TAAR5 results in the anxiolytic/antidepressant-like phenotype, while recently identified putative nonselective TAAR5 receptor agonist 2-(alpha-naphthoyl) ethyltrimethylammonium iodide (alpha-NETA) increases cortical gamma-rhythm in rats (Belov et al, 2019), causes deficits in sensorimotor gating in rats (Aleksandrov et al, 2018a), and increases mismatch negativity (MMN)-like responses in rats and mice (Aleksandrov et al, 2018b(Aleksandrov et al, , 2019 in a manner consistent with psychosis-related cognitive deficits described in humans and experimental animals (Light and Swerdlow, 2015).…”

Therapeutic Potential of TAAR1 Agonists in Schizophrenia: Evidence from Preclinical Models and Clinical Studies

“…Particularly deficits in MMN are believed to reflect cognitive decline and have been associated with glutamatergic NMDA receptor alterations [139,142]. In naïve mice, ulotaront and RO5263397 increase PPI and MMN, respectively [120]. Whether TAAR1 agonists can reverse impairments in PPI and MMN (e.g., in rodent models of schizophrenia) remains to be investigated.…”

Discovery of Novel Trace Amine-Associated Receptor 5 (TAAR5) Antagonists Using a Deep Convolutional Neural Network

“…α-NETA, an inhibitor of acetyl-cholinesterase, potently activates TAAR5, and displays interesting in vivo properties in mice and rats, inducing psychotic-like states and influencing cortical parameters related to cognitive functions [25,26,[34][35][36].…”

“…Although with lower potencies, two other tertiary amines activate TAAR5, namely N-N-dimethylethylamine and N-methylpiperidine [ 5 ]. α-NETA, an inhibitor of acetyl-cholinesterase, potently activates TAAR5, and displays interesting in vivo properties in mice and rats, inducing psychotic-like states and influencing cortical parameters related to cognitive functions [ 25 , 26 , 34 , 35 , 36 ].…”