Development of novel therapeutic drugs for Alzheimer disease

1.研究了阿片受体拮抗剂纳洛唑嗪（mu(1)-阿片受体拮抗剂）和胆碱酯酶抑制剂毒豆碱（physostming）对内啡肽诱导的小鼠被动回避学习障碍的影响。内啡肽-1（10微米）和内啡肽-2（10微米）显著损害被动回避学习，而纳洛唑嗪（35 mg/kg, s.c），一个μ(1)-阿片受体拮抗剂，单独不能影响被动回避学习显著抑制内啡肽-1（10微米）-但没有内啡肽-2（10微米）诱导的这种学习障碍。非选择性高剂量（50 mg/kg, s.c）纳洛唑嗪几乎完全拮抗内啡肽-1（10 μ g）和内啡肽-2（10 μ g）引起的被动回避学习障碍。相反，毒豆碱（0.025和0.05 mg/kg, i.p.）显著逆转内啡肽-1（10微克）和内啡肽-2（10微克）引起的被动回避学习障碍，而毒豆碱（0.025和0.05 mg/kg, i.p.）单独对这种学习没有影响。这些结果表明，内啡肽-1而非内啡肽-2损害学习和记忆是由胆碱能功能障碍和mu(1)-阿片受体的激活引起的。我们研究了阿片受体激动剂U-50,488H对抑郁症小鼠习得性无助模型的影响。预先暴露于不可避免的足电刺激的小鼠用u -50,488处理。u -50,488 （10 mg/kg/d, i.p）刺激kappa-阿片受体可减弱预暴露休克引起的逃逸失败。阿片受体拮抗剂MR2266 （10mg /kg/day, s.c）阻断了U-50,488H的这种衰减。这些结果表明，kappa-阿片系统在小鼠习得性无助抑郁中起重要作用。

1.The effects of naloxonazine, a mu(1)-opioid receptor antagonist, and physostigmine, a cholinesterase inhibitor, on the endomorphins-induced impairment of passive avoidance learning were investigated in mice. Endomorphin-1(10 microg) and endomorphin-2(10 microg) significantly impaired passive avoidance learning, while naloxonazine (35 mg/kg, s.c.), a mu(1)-opioid receptor antagonist, which alone failed to influence passive avoidance learning significantly inhibited the endomorphin-1(10 microg)- but not endomorphin-2(10 microg)-induced disturbance of such learning. A rather nonselective higher dose (50 mg/kg, s.c.) of naloxonazine almost completely antagonized the endomorphin-1(10 microg)- and endomorphin-2(10 microg)-induced impairment of passive avoidance learning. In contrast, physostigmine (0.025 and 0.05 mg/kg, i.p.) significantly reversed the endomorphin-1(10 microg)- and endomorphin-2(10 microg)-induced disturbance of passive avoidance learning, whereas physostigmine (0.025 and 0.05 mg/kg, i.p.) alone did not influence such learning. These results suggest that endomorphin-1 but not endomorphin-2 impairs learning and memory resulting from cholinergic dysfunction, and from activation of mu(1)-opioid receptors.2.We investigated the effects of U-50,488H, a kappa-opioid receptor agonist, on the learned helplessness model of depression in mice. Mice pre-exposed to inescapable electric footshock were treated with U-50,488H. Stimulation of the kappa-opioid receptor by U-50,488H (10 mg/kg/day, i.p.) attenuated the escape failure induced by pre-exposure to shock. This attenuation by U-50,488H was blocked by MR2266 (10 mg/kg/day, s.c.), an opioid receptor antagonist. These results suggest that the kappa-opioid system plays an important role in the learned helplessness depression in mice.