Departamento de Psicologia, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo (USP), 14040-901, Ribeirão Preto, SP, Brazil; Instituto de Neurociências e Comportamento-INeC, Campus USP, 14040-901, Ribeirão Preto, SP, Brazil.
Departamento de Psicologia, Uni-FACEF, 14401-135, Franca, SP, Brazil; Departamento de Psicologia, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo (USP), 14040-901, Ribeirão Preto, SP, Brazil; Instituto de Neurociências e Comportamento-INeC, Campus USP, 14040-901, Ribeirão Preto, SP, Brazil.
Neurotoxicology. 2018 Dec;69:1-10. doi: 10.1016/j.neuro.2018.08.013. Epub 2018 Aug 28.
Ketamine (KET) is a non-competitive N-Methyl-d-aspartate (NMDA) receptors antagonist that intensifies sensory experiences, prompts hallucinations and delusions, exacerbates previously installed psychosis and disrupts physiological evoked potentials (AEPs). Pharmacologically, KET stimulates glutamate efflux in the medial prefrontal cortex, mainly in the prelimbic (PrL) sub-region. Efferences from this region exert a top-down regulatory control of bottom-up sensory processes either directly or indirectly. In the midbrain, the central nucleus of the inferior colliculus (CIC) plays a fundamental role in the processing of auditory ascending information related to sound localization, sensorimotor gating, and preattentive event-related potentials. Auditory hallucinations elicited during a psychotic outbreak are accompanied by CIC neural activation. Thus, it is possible that NMDA-mediated glutamate neurotransmission in the PrL indirectly modulates CIC neuronal firing. The aim of the present study was to assess the effects of KET on the latency and amplitude of AEPs elicited in the CIC of rats tested during KET effects and following withdrawal from the chronic administration. Changes on emotionally induced by KET treatment were evaluated with the use of the elevated zero maze (EZM). Unlike typical neuroleptics, the atypical antipsychotic clozapine (CLZ) potently blocks the disruption of the sensorimotor gating induced by NMDA antagonists. Therefore, the effects of KET withdrawal on AEPs were challenged with a systemic injection of CLZ. In addition, we further investigated the role of NMDA receptors of the PrL on the AEPs expression recorded in the CIC through intra-PrL infusions of NMDA itself. Our results showed that the processing of sensory information in the CIC is under indirect control of PrL. These data suggest that the long-term KET treatment disrupts the collicular auditory field potentials, possibly through influencing PrL glutamate activity on intrinsic 5-HT mechanisms in the dorsal raphe and CIC.
氯胺酮（KET）是一种非竞争性 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，可增强感官体验，引发幻觉和妄想，加重先前存在的精神病，并破坏生理诱发电位（AEPs）。药理学上，KET 刺激内侧前额叶皮层中的谷氨酸外排，主要在前扣带皮层（PrL）亚区。该区域的传出神经对来自下至上的感觉过程施加自上而下的调节控制，无论是直接还是间接的。在中脑，下丘脑中脑核心（CIC）在处理与声音定位、感觉门控和前注意事件相关电位相关的听觉上行信息方面发挥着基本作用。精神病发作期间引发的听觉幻觉伴随着 CIC 神经激活。因此，NMDA 介导的 PrL 中的谷氨酸能神经传递可能间接调节 CIC 神经元的放电。本研究旨在评估 KET 对 KET 作用期间和慢性给药后戒断时大鼠 CIC 中诱发的 AEPs 的潜伏期和振幅的影响。使用高架零迷宫（EZM）评估 KET 处理引起的情绪变化。与典型的神经安定剂不同，非典型抗精神病药氯氮平（CLZ）强力阻断 NMDA 拮抗剂引起的感觉门控破坏。因此，通过系统注射 CLZ 来挑战 KET 戒断对 AEPs 的影响。此外，我们通过在 PrL 内注射 NMDA 本身，进一步研究了 PrL 中的 NMDA 受体对 CIC 中记录的 AEPs 表达的作用。我们的结果表明，CIC 中的感觉信息处理受到 PrL 的间接控制。这些数据表明，长期 KET 治疗会破坏丘脑血管电位，可能是通过影响 PrL 谷氨酸活性对背侧中缝核和 CIC 中的固有 5-HT 机制的影响。
