Effects of the novel endocannabinoid uptake inhibitor, LY2183240, on fear-potentiated startle and alcohol-seeking behaviors in mice selectively bred for high alcohol preference.
Effects of the novel endocannabinoid uptake inhibitor, LY2183240, on fear-potentiated startle and alcohol-seeking behaviors in mice selectively bred for high alcohol preference.
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DOI：
10.1007/s00213-010-1997-2
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发表时间：
2010-12
影响因子：
3.4
通讯作者：
Chester, Julia A.
中科院分区：
文献类型：
--
作者：
Powers, Matthew S.;Barrenha, Gustavo D.;Mlinac, Nate S.;Barker, Eric L.;Chester, Julia A.
在人类中，酒精使用障碍经常与焦虑症一起发生，这可能部分是由于共同的遗传遗传因素。有证据表明，内源性大麻素系统（ECS）是治疗焦虑和/或酒精使用障碍个体的有希望的治疗靶点。本研究在一种独特的动物模型中评估了一种新型内源性大麻素摄取抑制剂LY2183240对焦虑和酒精寻求行为的影响，这种动物模型可能代表人类并发焦虑和酒精使用障碍的遗传风险增加。选择高酒精偏好（HAP）的小鼠比选择低酒精偏好（LAP）的小鼠表现出更大的恐惧增强惊吓（FPS）。我们检测了LY2183240对HAP和LAP小鼠FPS表达的影响，以及对HAP小鼠酒精诱导的条件位置偏好（CPP）和限制饮酒行为的影响。LY2183240 （30 mg/kg）在恐惧条件反射后48 h进行第二次FPS测试之前重复给药，可降低HAP小鼠的FPS表达，但LAP小鼠的FPS表达不降低。10和30 mg/kg剂量的LY2183240均增强了酒精诱导的CPP的表达，并且这种作用在没有药物的情况下持续存在。LY2183240没有改变有限饮酒行为、非条件惊吓反应或运动活动。这些发现表明，ECS调节同时影响条件性恐惧和条件性酒精奖励行为。LY2183240可能是一种有效的药物治疗焦虑症的个体，如创伤后应激障碍，但可能不适合患有焦虑和酒精使用障碍的个体。
Alcohol-use disorders often occur together with anxiety disorders in humans which may be partly due to common inherited genetic factors. Evidence suggests that the endocannabinoid system (ECS) is a promising therapeutic target for the treatment of individuals with anxiety and/or alcohol-use disorders. The present study assessed the effects of a novel endocannabinoid uptake inhibitor, LY2183240, on anxiety- and alcohol-seeking behaviors in a unique animal model that may represent increased genetic risk to develop comorbid anxiety and alcohol-use disorders in humans. Mice selectively bred for high alcohol preference (HAP) show greater fear-potentiated startle (FPS) than mice selectively bred for low alcohol preference (LAP). We examined the effects of LY2183240 on the expression of FPS in HAP and LAP mice and on alcohol-induced conditioned place preference (CPP) and limited-access alcohol drinking behavior in HAP mice. Repeated administration of LY2183240 (30 mg/kg) reduced the expression of FPS in HAP but not LAP mice when given prior to a second FPS test 48 h after fear conditioning. Both the 10 and 30 mg/kg doses of LY2183240 enhanced the expression of alcohol-induced CPP and this effect persisted in the absence of the drug. LY2183240 did not alter limited-access alcohol drinking behavior, unconditioned startle responding, or locomotor activity. These findings suggest that ECS modulation influences both conditioned fear and conditioned alcohol reward behavior. LY2183240 may be an effective pharmacotherapy for individuals with anxiety disorders, such as post-traumatic stress disorder, but may not be appropriate for individuals with co-morbid anxiety and alcohol-use disorders.
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影响因子：
7.6
作者：
Blednov, Yuri A.;Cravatt, Benjamin F.;Harris, R. Adron
通讯作者：
Harris, R. Adron
影响因子：
3.4
作者：
Colombo, G;Serra, S;Gessa, GL
通讯作者：
Gessa, GL
DOI：
10.1097/00000374-199804000-00025
发表时间：
1998-04-01
影响因子：
3.2
作者：
Chester, JA;Risinger, FO;Cunningham, CL
通讯作者：
Cunningham, CL
影响因子：
3.6
作者：
Chester, Julia A.;Coon, Laran E.
通讯作者：
Coon, Laran E.
影响因子：
2.7
作者：
Adams, RE;Boscarino, JA;Galea, S
通讯作者：
Galea, S