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

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.

Differential Effects of an NR2B NAM and Ketamine on Synaptic Potentiation and Gamma Synchrony: Relevance to Rapid-Onset Antidepressant Efficacy

“…Consistent with these previous findings, in the present study Neurophysiological effects of an NR2B NAM and ketamine D Nagy et al ketamine increased gamma power multiple times over baseline values compared with vehicle-treated rats in both cortical and hippocampal regions. However, in a sharp contrast to ketamine, CP-101,606 did not disrupt auditory gating, nor did the compound impact gammaband power, in agreement with recent publications on CP-101,606 and other NR2B NAMs (Kocsis, 2012b;Sivarao et al, 2014).…”

Criteria for determining whether mismatch responses exist in animal models: Focus on rodents

“…Several laboratories have utilised the many-standards control sequence to demonstrate that rats exhibit human-like MMRs that are independent from adaptation. Adaptation-independent MMRs have been observed in awake, freely moving rats (Harms et al, 2014;Jung et al, 2013;Nakamura et al, 2011;Sivarao et al, 2014) and anesthetised (Ahmed et al, 2011;Astikainen et al, 2011;Nakamura et al, 2011;Shiramatsu et al, 2013) rats, using a variety of different anaesthetic agents (urethane, fentanyl/medetomidine and isoflurane). In addition, deviance detection was identified for a range of stimulus types, including frequency Harms et al, 2014;Jung et al, 2013;Nakamura et al, 2011;Shiramatsu et al, 2013;Sivarao et al, 2014), duration (Nakamura et al, 2011) and speech sounds (Ahmed et al, 2011).…”

“…Adaptation-independent MMRs have been observed in awake, freely moving rats (Harms et al, 2014;Jung et al, 2013;Nakamura et al, 2011;Sivarao et al, 2014) and anesthetised (Ahmed et al, 2011;Astikainen et al, 2011;Nakamura et al, 2011;Shiramatsu et al, 2013) rats, using a variety of different anaesthetic agents (urethane, fentanyl/medetomidine and isoflurane). In addition, deviance detection was identified for a range of stimulus types, including frequency Harms et al, 2014;Jung et al, 2013;Nakamura et al, 2011;Shiramatsu et al, 2013;Sivarao et al, 2014), duration (Nakamura et al, 2011) and speech sounds (Ahmed et al, 2011). Additional studies in anesthetised rats, rather than using a many-standards sequence to control for adaptation, used complex deviations that involve combinations of stimulus features such that each individual feature occurs equally often and therefore subjected to equal amounts of adaptation, such as frequency x intensity conjunctions (Astikainen et al, 2006) or frequency-intensity relationship 'rules' (Astikainen et al, 2014).…”

“…Recordings made under anaesthesia, whether it be via urethane, isoflurane or pentobarbital sodium, tend to report ERPs with a large, single positive peak, that exhibits a positive shift in response to the deviant (Ahmed et al, 2011;Astikainen et al, 2014;Astikainen et al, 2006;Astikainen et al, 2011;Jung et al, 2013;Nakamura et al, 2011;Ruusuvirta et al, 2015;Tikhonravov et al, 2008Tikhonravov et al, , 2010, whereas studies using awake recordings report a more complex ERP morphology with a combination of negative and positive peaks. Of such studies using awake recordings, some report that the deviant induces negative shifts in the ERP (Cabungcal et al, 2013;Nakamura et al, 2011;Roger et al, 2009;Sivarao et al, 2014;Witten et al, 2014), but at least one other studyreports both negative and positive shifts, depending on the component (Harms et al, 2014). While positive shifts in ERPs to deviant stimuli are not necessarily consistent with human MMN, it is important to note that many of the studies that report such positive shifts have employed appropriate controls for adaptation (Ahmed et al, 2011;Astikainen et al, 2014;Astikainen et al, 2006;Astikainen et al, 2011;Jung et al, 2013;Nakamura et al, 2011;Tikhonravov et al, 2008Tikhonravov et al, , 2010, indicating that they have already met one of the more stringent criteria for determining whether a response is a human-like MMR.…”

Pharmaco-EEG Studies in Animals: An Overview of Contemporary Translational Applications

“…In rats, ketamine affected AEP latencies and attenuated deviance by increasing the amplitude to standard stimuli. CP-101,606, a highly selective antagonist at the NR2B subunit of the NMDA receptor, abolished the MMN response by inhibiting the N1 amplitude of the deviant stimulus [130]. Similarly, in rats the deviance detection associated with MMN-like responses (see fig.…”