NR2B Antagonist CP-101,606 Abolishes Pitch-Mediated Deviance Detection in Awake Rats.

Digavalli V Sivarao,Rick Pieschl,Yu-Wen Li,Michael K Ahlijanian,Ping Chen,Yili Yang

doi:10.3389/fpsyt.2014.00096

Digavalli V Sivarao, Rick Pieschl + Show 4 more

Open Access

https://doi.org/10.3389/fpsyt.2014.00096

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Abstract

Schizophrenia patients exhibit a decreased ability to detect change in their auditory environment as measured by auditory event-related potentials (ERP) such as mismatch negativity. This deficit has been linked to abnormal NMDA neurotransmission since, among other observations, non-selective channel blockers of NMDA reliably diminish automatic deviance detection in human subjects as well as in animal models. Recent molecular and functional evidence links NR2B receptor subtype to aberrant NMDA transmission in schizophrenia. However, it is unknown if NR2B receptors participate in pre-attentive deviance detection. We recorded ERP from the vertex of freely behaving rats in response to frequency mismatch protocols. We saw a robust increase in N1 response to deviants compared to standard as well as control stimuli indicating true deviance detection. Moreover, the increased negativity was highly sensitive to deviant probability. Next, we tested the effect of a non-selective NMDA channel blocker (ketamine, 30 mg/kg) and a highly selective NR2B antagonist, CP-101,606 (10 or 30 mg/kg) on deviance detection. Ketamine attenuated deviance mainly by increasing the amplitude of the standard ERP. Amplitude and/or latency of several ERP components were also markedly affected. In contrast, CP-101,606 robustly and dose-dependently inhibited the deviant’s N1 amplitude, and as a consequence, completely abolished deviance detection. No other ERPs or components were affected. Thus, we report first evidence that NR2B receptors robustly participate in processes of automatic deviance detection in a rodent model. Lastly, our model demonstrates a path forward to test specific pharmacological hypotheses using translational endpoints relevant to aberrant sensory processing in schizophrenia.

Highlights

While recording event-related potentials (ERPs), when a stream of identical stimuli are interrupted occasionally by an atypical stimulus, the so-called odd ball, an enhanced negativity to the odd ball or deviant is observed from fronto-central regions of the scalprecorded clinical electroencephalogram
To further characterize the effect of NMDA antagonists on ERPs, we looked at mean N1 amplitude of standards and deviants under all treatment conditions as outlined above
ERP TO AUDITORY TONES An overlay of grand averaged ERPs from 16 subjects in response to a 1.5 kHz tone delivered as a standard, control, or deviant are shown in Figure 1

Summary

Introduction

While recording event-related potentials (ERPs), when a stream of identical stimuli are interrupted occasionally by an atypical stimulus, the so-called odd ball, an enhanced negativity to the odd ball or deviant is observed from fronto-central regions of the scalprecorded clinical electroencephalogram. This response is called the mismatch negativity (MMN) and has been recognized as a preattentive neurocognitive mechanism for change detection in the environment [1,2,3]. It is known that there is neural activity in anatomical structures along the sensory processing hierarchy involved in change detection, some apparent as early as 30 ms after stimulus presentation [15]

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