Putative TAAR5 agonist alpha-NETA affects event-related potentials in oddball paradigm in awake mice.

Trace amines have been reported to be neuromodulators of monoaminergic systems. Trace amines receptor 5 (TAAR5) is expressed in several regions of mice central nervous system, such as amygdala, arcuate nucleus and ventromedial hypothalamus, but very limited information is available on its functional role. The purpose of this study is to examine the effect of TAAR5 agonist alpha-NETA on the generation of mismatch negativity (MMN) analogue in C57BL/6 mice. Event-related potentials have been recorded from awake mice in oddball paradigms before and after the alpha-NETA administration. Alpha-NETA has been found to decrease N40 MMN-like difference, which resulted from the increased response to standard stimuli. An opposite effect has been found for the P80 component: the amplitude increased in response both to standard and deviant stimuli. A significant increase in N40 peak latency after the alpha-NETA administration has been found. This may suggest a reduced speed of information processing similar to the increase in P50 and N100 components latencies in schizophrenia patients. These results provide new evidence for a role of TAAR5 in cognitive processes.

Referent's Lexical Frequency Predicts Mismatch Negativity Responses to New Words Following Semantic Training.

Lexical ERPs (event-related potentials) obtained in an oddball paradigm were suggested to be an index of the formation of new word representations in the brain in the learning process: with increased exposure to new lexemes, the ERP amplitude grows, which is interpreted as a signature of a new memory-trace build-up and activation. Previous learning studies using this approach have, however, mostly used meaningless novel word forms; it therefore remains uncertain whether the increased amplitude simply reflects increased familiarity with the new stimulus or is indeed a reflection of a complete word representation. Here, we used the oddball paradigm to measure the mismatch negativity (MMN) responses to novel word forms before and after semantic training, during which they were associated with previously familiar words of either high or low frequency of occurrence. Following training, the amplitude of the MMN to novel words was enhanced. Furthermore, these changes were dependent on the frequency of the reference which novel items became associated with: namely, the MMN amplitude became greater and the latency shorter for the item which was assigned the high-frequency meaning. Even though the amount of training was the same for both types of items, the low-frequency stimulus did not achieve similar significant changes. Our results suggest that the new surface form becomes linked to the existing representation, which then automatically activates in full when the respective stimulus is present at the input. This finding indicates that the learning-related MMN dynamics, manifest as a response increase after learning, likely reflects the formation and activation of a complete lexicosemantic memory circuits for words.

Neurophysiological Correlates of Fast Mapping of Novel Words in the Adult Brain.

Word acquisition could be mediated by the neurocognitive mechanism known as fast mapping (FM). It refers to a process of incidental exclusion-based learning and is believed to be a critical mechanism for the rapid build-up of lexicon, although its neural mechanisms are still poorly understood. To investigate the neural bases of this key learning skill, we used event-related potentials (ERPs) and employed an audio-visual paradigm that included a counterbalanced set of familiar and novel spoken word forms presented, in a single exposure, in conjunction with novel and familiar images. To define learning-related brain dynamics, passive auditory ERPs, known to index long-term memory trace activation, were recorded before and after the FM task. Following the single FM learning exposure, we found a significant enhancement in neural activation elicited by the newly trained word form, which was expressed at ~200-400 ms after the word onset. No similar amplitude increase was found either for the native familiar word used as a control stimulus in the same learning paradigm or for similar control stimuli which were not subject to training. Topographic analysis suggested a left-lateral shift of the ERP scalp distribution for the novel FM word form, underpinned by fronto-temporal cortical sources, which may indicate the involvement of pre-existing neurolinguistic networks for mastering new word forms with native phonology. Overall, the near-instant changes in neural activity after a single-shot novel word training indicate that FM could promote rapid integration of newly learned items into the brain's neural lexicon, even in adulthood.

Effect of alpha-NETA on auditory event related potentials in sensory gating study paradigm in mice.

The potential contribution of trace amines (TA) to the pathophysiology of neuropsychiatric disorders makes it interesting to examine the effect of TA receptor ligands on schizophrenia biomarkers. We studied the effect of systemic administration of a putative Trace Amine-Associated Receptor 5 (TAAR5) agonist, alpha-NETA (2-(alpha-naphthoyl) ethyltrimethylammonium iodide), on the amplitude of the N40 event related potentials component and on the sensory gating (SG) index in C57BL/6 mice. It was found that low doses of alpha-NETA (2.5 mg/kg and 5 mg/kg) do not elicit a significant effect on the parameters of the N40 component and the SG index. However, the higher dose of alpha-NETA (10 mg/kg) induces a significant effect on the N40 component, but since a decrease in amplitude is observed on both the first and second stimuli in the pair, the SG index does not change. Thus, alpha-NETA administration causes a steady decrease in the N40 amplitude in response to both the first and second stimuli in the paired-click paradigm, and an increase in the N40 peak latency.

Effect of trace amine-associated receptor 1 agonist RO5263397 on sensory gating in mice.

The trace amine-associated receptor 1 (TAAR1) agonist RO5263397 effect on sensory gating in C57BL/6 mice was studied. Sensory gating is a mechanism for dosing and filtering the incoming information, by which the brain regulates the responses to sensory stimuli coming from the environment. Sensory gating deficit is considered to be one of the schizophrenia endophenotypes. TAAR1 agonist at a 1 mg/kg dosage contributed to the sensory gating index (S1-S2) increase. Sensory gating index rose due to the N40 amplitude increase in response to the first stimulus in a pair, whereas the amplitude of the second stimulus remained unchanged. These results suggest that the sensory gating in mice may be modulated through TAAR1-dependent processes, indicating potential contribution of TAAR1 and trace amines in general to the neuropharmacology of cognitive processes.

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

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.

The TAAR5 agonist α-NETA causes dyskinesia in mice.

It is known that trace amine-associated receptor 5 (TAAR5) is expressed in various regions of the central nervous system. However, very limited information is available on the behavioral effects of TAAR5 activation and the TAAR5 functional role, in general. We studied the effect of TAAR5 agonist (2-(alpha-naphthoyl) ethyltrimethylammonium iodide) systemic administration on animal behavior. The study was performed on male C57BL/6 mice. It was observed that α-NETA in 10 mg/kg dose caused specific impairment of motor behavior, similar to the manifestations of tardive dyskinesia in humans. It can be assumed that trace amines and TAAR5 may be involved in the human tardive dyskinesia pathogenesis.

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

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.

TAAR5 receptor agonist affects sensory gating in rats.

Trace amines are structurally close to classical monoamines and dysregulation in trace amines and/or their receptors might contribute to pathology of mental disorders. The study was aimed to investigate the effect of recently identified Trace Amine-Associated Receptor 5 (TAAR5) agonist 2-(alpha-naphthoyl)ethyltrimethylammonium iodide (alpha-NETA) on sensory gating (SG) in awake freely moving rats. SG was studied in paired-click paradigm and SG index was calculated as difference in event related potentials component N40 amplitudes to the first and second stimulus in the pair. The 1 mg/kg dose of alpha-NETA as well as the control injection of saline had no significant effects on the SG index. However, higher doses of alpha-NETA (3 and 5 mg/kg) significantly decreased the SG index. The change in the SG index was mainly due to a decrease in the N40 amplitude, and the 5 mg/kg dose caused the N40 decrease both in response to the first and second stimulus in the pair. Thus, TAAR5 activation can influence SG, indicating the potential role of trace amines and TAAR5 in sensory information dosing.

The Development of Muscle Fatigue Suppresses Auditory Sensory Gating (P50) during Sustained Contraction.

Our aim was to study the influence of fatigue development on sensory gating during a muscle load. The fatiguing task was sustained contraction of a handgrip dynamometer with 7 and 30% maximum voluntary contraction (MVC). The suppression of P50, an auditory event-related potential, was used as the sensory gating index in the paired-click paradigm with a 500 ms interstimulus interval; the difference between the P50 amplitudes of the first and the second stimuli of the pair was used as the sensory gating index. We found that the 30% MVC fatigue development strongly decreased sensory gating, sometimes totally suppressing it. We concluded that central fatigue impaired motor performance and strongly suppressed inhibitory processes, as shown by the decreased P50 amplitude to the second stimulus. Therefore, muscle central fatigue influences sensory gating, similar to schizophrenia spectrum disorders.

Mismatch Negativity Affects Muscle Fatigue during Repeated Contraction Trials of Different Durations.

We examined the effect of involuntary attention switching (related to mismatch negativity generation in the oddball paradigm) on fatigue development during trials of different durations. The experiment consisted of two trials, long (40 min) and short (15 min), and two experimental conditions in each trial: the simple reaction task (deviants-only paradigm) and the stimuli recognition task (oddball paradigm). In each condition, a participant responded to each target acoustic stimulus by squeezing a handgrip dynamometer. We found the significantly lower rates of fatigue development in the short-trial deviants-only paradigm compared to the long trial. The short- and the long-trial oddball paradigms differed significantly from both the short- and the long-trial deviants-only paradigms. The results demonstrated that the fatigue developed differently depending on the expected trial duration. The involuntary activation of attention broke this subconscious regulative mechanism leading to increase of the compression force during the long trial and its decrease during the short.