Department of Pharmaceutical and Administrative Sciences, Loma Linda University School of Pharmacy, Loma Linda, CA 92350, USA.
Division of Pharmacy, Zhejiang University College of Pharmaceutical Sciences, Hangzhou, Zhejiang 310058, PR China.
Neuroscience. 2018 Aug 1;384:178-187. doi: 10.1016/j.neuroscience.2018.05.037. Epub 2018 Jun 1.
Indirect evidence suggests that low doses of ketamine disinhibit (excite) pyramidal neurons in the prefrontal cortex (PFC). In this study, we directly examined the effect of ketamine on PFC pyramidal neurons using simultaneous single-cell and local-field-potential (LFP) recording in chloral hydrate-anesthetized rats. In all animals studied, PFC LFPs showed oscillations (0.3-1.5 Hz) between the active UP state and the relatively quiescent DOWN state, and pyramidal neurons fired preferentially during the UP state. Ketamine (1.25-20 mg/kg, i.v.) inhibited 80% of cells tested and consistently shifted PFC LFPs toward the DOWN state. The inhibitory effect of ketamine was mimicked by MK801, but not by the NR2B-selective NMDA receptor antagonist Ro25-6981. It was not blocked by the dopamine receptor antagonist fluphenazine, the GABA receptor antagonist picrotoxinin, or the GABA receptor antagonist CGP46381. These results are consistent with the high density of NMDA receptors expressed on PFC pyramidal neurons and our previous studies showing that blockade of NMDA receptors by ketamine inhibits dendritic NMDA receptor-mediated bursting in PFC pyramidal neurons. Thus, in addition to the previously proposed disinhibitory effect mediated through PFC interneurons, our data suggest that ketamine has an inhibitory effect on PFC pyramidal neurons. Our evidence further suggests that the effect is mediated through non-NR2B-containing NMDA receptors, independent of ketamine's effect on dopamine and GABA transmission. Further understanding of the two opposing effects of ketamine on PFC pyramidal neurons may provide important new insights into its mechanism of action.
间接证据表明，低剂量氯胺酮可抑制（兴奋）前额叶皮层（PFC）中的锥体神经元。在这项研究中，我们使用氯醛麻醉大鼠的单细胞和局部场电位（LFP）同步记录，直接检查氯胺酮对 PFC 锥体神经元的影响。在所有研究的动物中，PFC 的 LFP 在活跃的 UP 状态和相对安静的 DOWN 状态之间显示出（0.3-1.5 Hz）的振荡，并且锥体神经元在 UP 状态下优先发射。氯胺酮（1.25-20 mg/kg，iv）抑制了 80%测试的细胞，并一致地将 PFC 的 LFP 推向 DOWN 状态。MK801 模拟了氯胺酮的抑制作用，但 NR2B 选择性 NMDA 受体拮抗剂 Ro25-6981 则没有。氯胺酮的抑制作用不受多巴胺受体拮抗剂氟奋乃静、GABA 受体拮抗剂印防己毒素或 GABA 受体拮抗剂 CGP46381 的阻断。这些结果与 NMDA 受体在 PFC 锥体神经元上的高表达密度以及我们之前的研究一致，这些研究表明，氯胺酮通过阻断 NMDA 受体抑制 PFC 锥体神经元树突 NMDA 受体介导的爆发。因此，除了先前提出的通过 PFC 中间神经元介导的去抑制作用外，我们的数据表明氯胺酮对 PFC 锥体神经元具有抑制作用。我们的证据进一步表明，该作用是通过非 NR2B 包含的 NMDA 受体介导的，与氯胺酮对多巴胺和 GABA 传递的作用无关。进一步了解氯胺酮对 PFC 锥体神经元的两种相反作用可能为其作用机制提供重要的新见解。
