Graduate School of Literature and Human Sciences, Osaka City University, Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan.
Graduate School of Literature and Human Sciences, Osaka City University, Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan.
Behav Brain Res. 2019 Sep 16;370:111926. doi: 10.1016/j.bbr.2019.111926. Epub 2019 Apr 25.
It has been proposed that animals administered early postnatal NMDA (N-methyl-d-aspartate) glutamate receptor antagonists represent a model of schizophrenia; however, drug treatment schedules remain quite different among these animal studies. In this study, we compared the behavioral effects of long-term (14-day) and short-term (5-day) early postnatal treatment of the NMDA receptor antagonist MK-801 (dizocilpine; 5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine). In addition, different drug treatment periods were applied to the short-term treatment study in order to determine the critical developmental period of drug effects. For experiment 1, rats were treated with MK-801 (0.2 or 0.4 mg/kg, twice daily) during postnatal days (PNDs) 7-20. For experiment 2, MK-801 (0.2 mg/kg, twice daily) was administered during the periods of PNDs 7-11, 12-16, and 17-21. In adulthood, several behavioral tests, including prepulse inhibition, open-field, and spontaneous alternation tests, were performed in experiments 1 and 2. The delayed nonmatching-to-position task was also conducted in experiment 2 on separate rats treated for 5 days in the same manner. Our results indicated that the 14-day MK-801 treatment inhibited the prepulse inhibition and decreased immobility in the forced-swim test, whereas the 5-day MK-801 treatment induced only slight behavioral effects. Collectively, our findings suggest that long-term early postnatal treatment with an NMDA receptor antagonist may be detrimental to some behavioral functions, such as sensorimotor gating and stress coping; however, treatment for longer periods is needed to elicit detrimental effects.
有人提出，给予新生后早期 NMDA（N-甲基-D-天冬氨酸）谷氨酸受体拮抗剂的动物代表精神分裂症模型；然而，这些动物研究中的药物治疗方案仍有很大不同。在这项研究中，我们比较了长期（14 天）和短期（5 天）早期新生后 NMDA 受体拮抗剂 MK-801（地卓西平；5-甲基-10,11-二氢-5H-二苯并[a,d]环庚烯-5,10-亚胺）治疗的行为效应。此外，为了确定药物效应的关键发育时期，在短期治疗研究中应用了不同的药物治疗期。对于实验 1，大鼠在出生后第 7-20 天接受 MK-801（0.2 或 0.4mg/kg，每日两次）治疗。对于实验 2，MK-801（0.2mg/kg，每日两次）在出生后第 7-11 天、12-16 天和 17-21 天期间给予。在成年期，在实验 1 和 2 中进行了几项行为测试，包括预脉冲抑制、旷场和自发交替测试。在实验 2 中，还对以相同方式治疗 5 天的单独大鼠进行了延迟非匹配到位置任务。我们的结果表明，14 天的 MK-801 治疗抑制了预脉冲抑制并减少了强迫游泳试验中的不动性，而 5 天的 MK-801 治疗仅引起轻微的行为效应。总的来说，我们的研究结果表明，长期早期新生后 NMDA 受体拮抗剂治疗可能对某些行为功能有害，例如感觉运动门控和应激应对；然而，需要更长的治疗时间才能产生有害影响。
