mGluR2/3 blockade produces rapid and long-lasting reversal of anhedonia caused by chronic stress exposure.
mGluR2/3 blockade produces rapid and long-lasting reversal of anhedonia caused by chronic stress exposure.
复制标题
DOI：
10.1186/2049-9256-1-15
复制
发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Duman RS
中科院分区：
文献类型：
--
作者：
Dwyer JM;Lepack AE;Duman RS
抑郁症是一种流行的神经精神疾病，影响着全世界约3.5亿人。目前可用的抑郁症治疗方法在发病速度和疗效方面都有所欠缺。最近的药理学工作已经使用N-甲基-D-天冬氨酸（NMDA）受体拮抗剂氯胺酮靶向多巴胺能神经递质系统，以产生快速和强大的抗抑郁作用，然而，由于副作用和滥用倾向，氯胺酮的广泛临床使用受到限制。最近，评价代谢型mGluR 2/3受体拮抗剂的工作已证明与氯胺酮有许多相似之处。雄性Sprague-Dawley大鼠暴露于慢性不可预测的应激模式，其产生降低的蔗糖偏好，这是快感缺乏的量度。然后用媒介物或单次注射mGluR 2/3拮抗剂LY 341495（3 mg/kg，i. p.）并在单次处理后24小时、48小时或10天进行测试。我们证明，LY 341495单次治疗可快速（1-2天内）和持久（10天）逆转大鼠慢性不可预测的应激引起的快感缺乏。该模型提供了对速效药物的严格测试，因为典型的抗抑郁药需要几周的治疗才能产生反应。这些数据表明，LY 341495能够产生与氯胺酮相似的快速和稳健的抗抑郁作用。总之，这些结果突出了类似化合物在治疗抑郁症方面产生快速和持久疗效的潜力。
Depression is a prevalent neuropsychiatric disorder that affects an estimated 350 million people worldwide. Currently available treatments for depression are lacking in both speed of onset and efficacy. Recent pharmacological efforts have targeted the glutamatergic neurotransmitter system using the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine to produce rapid and robust antidepressant effects, however the widespread clinical use of ketamine is limited due to side effects and abuse liability. More recently, work evaluating metabotropic mGluR2/3 receptor antagonists has demonstrated many similarities with ketamine. Male, Sprague–Dawley rats were exposed to a chronic unpredictable stress paradigm, which produces decreased sucrose preference, a measure of anhedonia. Rats were then treated with vehicle or a single injection of the mGluR2/3 antagonist LY341495 (3 mg/kg, i.p.) and tested at 24 hrs, 48 hrs or 10 days after a single treatment. We demonstrate that a single treatment with LY341495 produces a rapid (within 1–2 days) and long-lasting (10 days) reversal of anhedonia caused by chronic unpredictable stress in rats. This model provides a rigorous test of rapid-acting agents as typical antidepressants require several weeks of treatment to produce a response. These data suggest that LY341495 has the ability to produce rapid and robust antidepressant effects similar to ketamine. Together, the results highlight the potential for similar compounds to produce rapid and lasting efficacy for the treatment of depression.