Ahnaou Abdallah, Biermans Ria, Drinkenburg Wilhelmus H
Department of Neuroscience, Janssen Research & Development, A Division of Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340 Beerse, Belgium.
PLoS One. 2016 Jan 25;11(1):e0147365. doi: 10.1371/journal.pone.0147365. eCollection 2016.
Improvement of cognitive impairments represents a high medical need in the development of new antipsychotics. Aberrant EEG gamma oscillations and reductions in the P1/N1 complex peak amplitude of the auditory evoked potential (AEP) are neurophysiological biomarkers for schizophrenia that indicate disruption in sensory information processing. Inhibition of phosphodiesterase (i.e. PDE10A) and activation of metabotropic glutamate receptor (mGluR2) signaling are believed to provide antipsychotic efficacy in schizophrenia, but it is unclear whether this occurs with cognition-enhancing potential. The present study used the auditory paired click paradigm in passive awake Sprague Dawley rats to 1) model disruption of AEP waveforms and oscillations as observed in schizophrenia by peripheral administration of amphetamine and the N-methyl-D-aspartate (NMDA) antagonist phencyclidine (PCP); 2) confirm the potential of the antipsychotics risperidone and olanzapine to attenuate these disruptions; 3) evaluate the potential of mGluR2 agonist LY404039 and PDE10 inhibitor PQ-10 to improve AEP deficits in both the amphetamine and PCP models. PCP and amphetamine disrupted auditory information processing to the first click, associated with suppression of the P1/N1 complex peak amplitude, and increased cortical gamma oscillations. Risperidone and olanzapine normalized PCP and amphetamine-induced abnormalities in AEP waveforms and aberrant gamma/alpha oscillations, respectively. LY404039 increased P1/N1 complex peak amplitudes and potently attenuated the disruptive effects of both PCP and amphetamine on AEPs amplitudes and oscillations. However, PQ-10 failed to show such effect in either models. These outcomes indicate that modulation of the mGluR2 results in effective restoration of abnormalities in AEP components in two widely used animal models of psychosis, whereas PDE10A inhibition does not.
改善认知障碍是新型抗精神病药物研发中的一项迫切医疗需求。异常的脑电图γ振荡以及听觉诱发电位（AEP）中P1/N1复合波峰振幅的降低是精神分裂症的神经生理生物标志物，表明感觉信息处理存在障碍。抑制磷酸二酯酶（即PDE10A）和激活代谢型谷氨酸受体（mGluR2）信号传导被认为可在精神分裂症中提供抗精神病疗效，但尚不清楚这是否伴随着认知增强潜力。本研究在被动清醒的Sprague Dawley大鼠中使用听觉配对点击范式，以：1）通过外周给予苯丙胺和N-甲基-D-天冬氨酸（NMDA）拮抗剂苯环利定（PCP）来模拟精神分裂症中观察到的AEP波形和振荡的破坏；2）确认抗精神病药物利培酮和奥氮平减轻这些破坏的潜力；3）评估mGluR2激动剂LY404039和PDE10抑制剂PQ-10在苯丙胺和PCP模型中改善AEP缺陷的潜力。PCP和苯丙胺破坏了对第一次点击的听觉信息处理，这与P1/N1复合波峰振幅的抑制以及皮质γ振荡增加有关。利培酮和奥氮平分别使PCP和苯丙胺诱导的AEP波形异常和异常γ/α振荡恢复正常。LY404039增加了P1/N1复合波峰振幅，并有效减弱了PCP和苯丙胺对AEP振幅和振荡的破坏作用。然而，PQ-10在两种模型中均未显示出这种效果。这些结果表明，在两种广泛使用的精神病动物模型中，调节mGluR2可有效恢复AEP成分的异常，而抑制PDE10A则不能。
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