The kappa opioid receptor antagonist aticaprant reverses behavioral effects from unpredictable chronic mild stress in male mice.
The kappa opioid receptor antagonist aticaprant reverses behavioral effects from unpredictable chronic mild stress in male mice.
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DOI：
10.1007/s00213-020-05649-y
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发表时间：
2020-12
影响因子：
3.4
通讯作者：
Lucki I
中科院分区：
文献类型：
--
作者：
Jacobson ML;Wulf HA;Browne CA;Lucki I
重度抑郁症是世界范围内残疾的主要原因，可能是由慢性压力引起的。虽然目前有许多抗抑郁药，但这些药物需要每天服用数周至数月才能减轻症状，许多患者尽管接受了几个疗程的治疗，但仍对治疗产生耐药性。目前迫切需要新的治疗方法来治疗与压力有关的疾病。卡帕阿片受体（KOR）是治疗抑郁症和快感缺失的一个有前途的新治疗靶点，因为急性KOR阻断可以防止啮齿动物应激的许多影响。以下研究评估了选择性KOR拮抗剂aticaprant（也称为JNJ-67953964，之前称为LY-2456302和CERC-501）重复给药是否可有效逆转啮齿动物暴露于不可预测的慢性轻度应激（UCMS）后的行为。将成年雄性C57 BL/6 J小鼠暴露于四周的UCMS。在三周的应激后，每天给予阿替卡普兰（10 mg/kg），共11次治疗。行为评估包括蔗糖偏好测试、筑巢、强迫游泳测试、热板测试、光暗测试和社会互动测试。Aticaprant显着逆转压力诱导的赤字所产生的UCMS的SPT，嵌套，FST，和热板测试。在应激和治疗恢复期，抗卡泮的作用持续存在。Aticaprant在光暗和社会互动测试中不能有效逆转压力引起的行为效应。这些结果支持进一步研究KOR在调节与奖励，自我照顾和认知相关的回路中的作用，当它们被慢性压力破坏时。它们也与抗惊厥药作为针对快感缺失的应激相关疾病（例如抑郁症和创伤后应激障碍）治疗药物的临床开发一致。
Major depressive disorder is a leading cause of disability worldwide and is likely precipitated by chronic stress. Although many antidepressants are currently available, these drugs require weeks to months of daily administration before reduction of symptoms occur and many patients remain treatment resistant despite several courses of treatment. There is a pressing need for new treatments for stress-related disorders. Kappa opioid receptors (KORs) are a promising new therapeutic target for MDD and anhedonia because acute KOR blockade prevents many effects of stress in rodents. The following study assessed whether repeated treatment with the selective KOR antagonist aticaprant (also known as JNJ-67953964, and previously LY-2456302 and CERC-501) was effective in reversing behaviors in rodents following exposure to unpredictable chronic mild stress (UCMS). Adult male C57BL/6J mice were exposed to four weeks of UCMS. After three weeks of stress, aticaprant (10 mg/kg) was administered daily for 11 treatments. Behavioral assessments included the sucrose preference test, nesting, forced swim test, hot plate test, light-dark test, and social interaction test. Aticaprant significantly reversed stress-induced deficits produced by UCMS on the SPT, nesting, FST, and hot plate test. The effects of aticaprant persisted through a stress and treatment recovery period. Aticaprant was not effective at reversing behavioral effects caused by stress in the light-dark and social interaction tests. The results support further study of the role of KORs in regulating circuits related to reward, self-care, and cognition when they are disrupted by chronic stress. They are also consistent with the clinical development of aticaprant as a therapeutic for stress-related disorders targeted at anhedonia, such as depression and post-traumatic stress disorder.
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DOI：
10.1176/appi.focus.16407
发表时间：
2018-10-01
期刊：
Focus (American Psychiatric Publishing)
影响因子：
--
作者：
Cipriani, Andrea;Furukawa, Toshi A;Geddes, John R
通讯作者：
Geddes, John R
影响因子：
7.6
作者：
Domi, E.;Barbier, E.;Heilig, M.
通讯作者：
Heilig, M.
影响因子：
7.6
作者：
Falcon, Edgardo;Browne, Caroline A.;Lucki, Irwin
通讯作者：
Lucki, Irwin
影响因子：
10.6
作者：
ADLER, G;GATTAZ, WF
通讯作者：
GATTAZ, WF
影响因子：
3.4
作者：
Bruchas, Michael R.;Chavkin, Charles
通讯作者：
Chavkin, Charles