Department of Neurochemistry and Neuropharmacology, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, IDIBAPS, Barcelona, Spain.
Int J Neuropsychopharmacol. 2012 Aug;15(7):945-56. doi: 10.1017/S1461145711001064. Epub 2011 Jul 7.
Previous studies have shown that systemic, but not unilateral intra-prefrontal cortex administration of non-competitive NMDA antagonists, increased prefrontal activity, the cortical efflux of serotonin, and induced stereotypies. In this work we used in-vivo microdialysis and immunohistochemistry to test the hypothesis as to whether MK-801 and ketamine need to act on both prefrontal cortices to reproduce these neurochemical and behavioural changes. Dialysis probes were implanted in the medial prefrontal cortex, and extracellular serotonin as well as behavioural stereotypies was measured after systemic administration of MK-801 and ketamine (1 mg/kg and 25 mg/kg, respectively), and unilateral and bilateral perfusion of both drugs (300 μm and 3 mm, respectively). Additionally, the prefrontal (glutamatergic) level of activity was measured using c-Fos immunohistochemistry. Systemic and bilateral (but not unilateral) prefrontal administration of MK-801 and ketamine increased serotonin efflux whereas only systemic administration of both drugs produced hyperlocomotion and stereotypies. The unilateral perfusion of 1 μm tetrodotoxin in the medial prefrontal cortex reduced increases of serotonin in both hemispheres, the expression of c-Fos in the contralateral side, and stereotypy scores after systemic NMDA antagonists. Our results support the hypothesis that a bilateral impairment of cortical inhibition in the medial prefrontal cortex is needed for non-competitive NMDA antagonists to induce the state of pyramidal cell hyperactivity and concurrent efflux of serotonin. Furthermore, hyperlocomotion and stereotypies produced by MK-801 and ketamine do not appear to result from changes in the activity of prefrontal cortex although this structure exerts some control over these behaviours.
先前的研究表明，非竞争性 NMDA 拮抗剂全身而非单侧前额叶皮质内给药会增加前额叶皮质活动、皮质内 5-羟色胺流出，并引起刻板行为。在这项工作中，我们使用活体微透析和免疫组织化学来测试以下假设：即 MK-801 和氯胺酮是否需要作用于两个前额叶皮质才能重现这些神经化学和行为变化。在系统给予 MK-801 和氯胺酮（分别为 1mg/kg 和 25mg/kg）以及单侧和双侧灌注两种药物（分别为 300μm 和 3mm）后，将透析探针植入内侧前额叶皮质，并测量细胞外 5-羟色胺以及行为刻板行为。此外，使用 c-Fos 免疫组织化学测量前额叶（谷氨酸能）活动水平。全身和双侧（而非单侧）给予 MK-801 和氯胺酮会增加 5-羟色胺流出，而只有全身给予两种药物会产生过度活跃和刻板行为。在内侧前额叶皮质中单侧灌注 1μm 河豚毒素会减少两个半球中 5-羟色胺的增加、对侧 c-Fos 的表达以及全身给予 NMDA 拮抗剂后的刻板行为评分。我们的结果支持以下假设：即内侧前额叶皮质中皮质抑制的双侧损伤是必需的，非竞争性 NMDA 拮抗剂才能诱导锥体神经元过度活跃和同时释放 5-羟色胺的状态。此外，MK-801 和氯胺酮产生的过度活跃和刻板行为似乎不是由于前额叶皮质活动的变化引起的，尽管该结构对这些行为有一定的控制作用。
