Graduate School of Literature and Human Sciences, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan.
Pharmacol Biochem Behav. 2017 Aug;159:48-54. doi: 10.1016/j.pbb.2017.06.009. Epub 2017 Jun 21.
The two-hit hypothesis has been used to explain the onset mechanism of schizophrenia. It assumes that predisposition to schizophrenia is originally attributed to vulnerability in the brain which stems from genetic or early developmental factors, and that onset is triggered by exposure to later detrimental factors such as stress in adolescence or adulthood. Based on this hypothesis, the present study examined whether rats that had received neonatal repeated treatment with an N-methyl-d-aspartate (NMDA) receptor antagonist (MK-801), an animal model of schizophrenia, were vulnerable to chronic stress. Rats were treated with MK-801 (0.2mg/kg) or saline twice daily on postnatal days 7-20, and animals in the stress subgroups were subjected to 20days (5days/week×4weeks) of forced-swim stress in adulthood. Following this, behavioral tests (prepulse inhibition, spontaneous alternation, open-field, and forced-swim tests) were carried out. The results indicate that neonatal repeated MK-801 treatment in rats inhibits an increase in immobility in the forced-swim test after they have experienced chronic forced-swim stress. This suggests that rats that have undergone chronic neonatal repeated NMDA receptor blockade could have a reduced ability to habituate or adapt to a stressful situation, and supports the hypothesis that these rats are sensitive or vulnerable to stress.
双打击假说被用来解释精神分裂症的发病机制。它假设精神分裂症的易感性最初归因于大脑的脆弱性，这种脆弱性源于遗传或早期发育因素，而发病是由青春期或成年期暴露于后来的有害因素（如压力）引发的。基于这一假说，本研究探讨了是否接受过新生大鼠反复使用 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂（MK-801）治疗的大鼠易患慢性应激。大鼠在出生后第 7-20 天每天接受两次 MK-801（0.2mg/kg）或生理盐水治疗，应激亚组的动物在成年期接受 20 天（每周 5 天×4 周）的强迫游泳应激。之后，进行行为测试（前脉冲抑制、自发交替、旷场和强迫游泳测试）。结果表明，新生大鼠反复接受 MK-801 治疗可抑制其在经历慢性强迫游泳应激后强迫游泳试验中不动时间的增加。这表明，经历慢性新生期重复 NMDA 受体阻断的大鼠可能对适应应激环境的能力降低，这支持了这些大鼠对压力敏感或易感性的假说。
