Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, UP 226031, India.
Division of molecular and structural biology, CSIR-Central Drug Research Institute, Lucknow, UP 226031, India.
Sci Rep. 2016 Sep 16;6:33401. doi: 10.1038/srep33401.
Psychotomimetic and prodepressive effect by kappa opioid receptor (KOR) activation in rodents and human is widely known. Significantly, recent clinical investigations demonstrated the salutary effects of KOR antagonists in patients with treatment resistant depression, indicating essential role of KOR signaling in refractory depression. This study was undertaken to reveal the molecular determinant of KOR mediated depression and antidepressant response of KOR antagonist. We observed that chronic KOR activation by U50488, a selective KOR agonist, significantly increased depression like symptoms (behavioral despair, anhedonia and sociability) in C57BL/6J mice, which were blocked by KOR antagonist norBNI and antidepressant imipramine, but not by fluoxetine or citalopram. Further, chronic KOR activation increased phosphorylation of NR2B subunit of NMDA at tyrosine 1472 (pNR2B NMDA) in the hippocampus, but not in the cortex. Similar to behavioral effects norBNI and imipramine, but not SSRIs, blocked NR2B phosphorylation. Moreover, KOR induced depression like behaviors were reversed by NR2B selective inhibitor Ro 25-6981. Mechanistic studies in primary cultured neurons and brain tissues using genetic and pharmacological approaches revealed that stimulation of KOR modulates several molecular correlates of depression. Thus, these findings elucidate molecular mechanism of KOR signaling in treatment resistant depression like behaviors in mice.
在啮齿动物和人类中，κ 阿片受体（KOR）的致幻和促抑郁作用是广为人知的。值得注意的是，最近的临床研究表明 KOR 拮抗剂在治疗抵抗性抑郁症患者中的有益作用，这表明 KOR 信号在难治性抑郁症中起着重要作用。本研究旨在揭示 KOR 介导的抑郁症的分子决定因素以及 KOR 拮抗剂的抗抑郁反应。我们观察到，选择性 KOR 激动剂 U50488 慢性激活 KOR 会显著增加 C57BL/6J 小鼠的抑郁样症状（行为绝望、快感缺失和社交性），而 KOR 拮抗剂 norBNI 和抗抑郁药丙咪嗪可以阻断这些症状，但选择性 5-羟色胺再摄取抑制剂（SSRIs）氟西汀或西酞普兰则不能。此外，慢性 KOR 激活会增加海马体中 NMDA 受体 NR2B 亚基酪氨酸 1472 位的磷酸化（pNR2B NMDA），但不会增加皮质中的磷酸化。norBNI 和丙咪嗪与行为效应相似，可阻断 NR2B 磷酸化，但 SSRIs 则不能。此外，NR2B 选择性抑制剂 Ro 25-6981 可逆转 KOR 诱导的抑郁样行为。使用遗传和药理学方法在原代培养神经元和脑组织中进行的机制研究表明，KOR 的刺激可调节几种与抑郁相关的分子相关性。因此，这些发现阐明了 KOR 信号在小鼠治疗抵抗性抑郁样行为中的分子机制。
