Acute ketamine administration results in psychotic symptoms similar to those observed in schizophrenia and is regarded as a pharmacological model of schizophrenia. Accumulating evidence suggests that patients with schizophrenia show increased IL-6 levels in the blood and cerebrospinal fluid and that IL-6 levels are associated with the severity of psychotic symptoms. In the present study, we found that a single ketamine exposure led to increased expression of IL-6 and IL-6Rα, decreased dendritic spine density, increased expression and currents of T-type calcium channels, and increased neuron excitability in the hippocampal CA1 area 12 h after exposure. Acute ketamine administration also led to impaired prepulse inhibition (PPI) 12 h after administration. Additionally, we found that the expression of signaling molecules IKKα/β, NF-κB, JAK2, and STAT3 was upregulated 12 h after a single ketamine injection. The decreases in dendritic spine density, the increases in calcium currents and neuron excitability, and the impairments in PPI were ameliorated by blocking IL-6 or IL-6Rα. Our findings show that blocking IL-6 or its receptor may protect hippocampal neurons from hyperexcitability, thereby ameliorating ketamine-induced psychotic effects. Our study provides additional evidence that targeting IL-6 and its receptor is a potential strategy for treating psychotic symptoms in acute ketamine-induced psychosis and schizophrenia.

急性服用氯胺酮会导致与精神分裂症相似的精神病症状精神分裂症，被视为精神分裂症的药理学模型。越来越多的证据表明，精神分裂症患者的血液和脑脊液中 IL-6 水平升高，并且 IL-6 水平与精神病症状的严重程度相关。在本研究中，我们发现单次氯胺酮暴露导致海马CA1区IL-6和IL-6Rα表达增加、树突棘密度降低、T型钙通道表达和电流增加以及神经元兴奋性增加暴露后 12 小时。急性氯胺酮给药也会导致给药 12 小时后前脉冲抑制 (PPI) 受损。此外，我们发现单次注射氯胺酮 12 小时后信号分子 IKKα/β、NF-κB、JAK2 和 STAT3 的表达上调。通过阻断 IL-6 或 IL-6Rα 可以改善树突棘密度的降低、钙电流和神经元兴奋性的增加以及 PPI 的损伤。我们的研究结果表明，阻断 IL-6 或其受体可以保护海马神经元免于过度兴奋，从而改善氯胺酮诱导的精神病作用。我们的研究提供了额外的证据，表明靶向 IL-6 及其受体是治疗急性氯胺酮诱发的精神病和精神分裂症中精神病症状的潜在策略。