Miczek K A, Nikulina E, Kream R M, Carter G, Espejo E F
Department of Psychology, Tufts University, Medford, Massachusetts 02155, USA.
Psychopharmacology (Berl). 1999 Jan;141(3):225-34. doi: 10.1007/s002130050829.
The experiments explored the nature and time course of changes in behavior and Fos expression in the periaqueductal grey area (PAG) in response to an injection of cocaine that was given following a single episode of social defeat stress. Social defeat stress was defined as an intruder mouse's response to an aggressive resident mouse. First, the intruder was briefly attacked, and secondly, it was threatened while protected by a perforated cage for 20 min. Plasma corticosterone levels rose after the beginning of the confrontation and remained elevated during the protected phase. In a first experiment, separate groups of intruder and control mice were challenged once with cocaine (20, 30, or 40 mg/kg) or saline. During tests for motor activity, behavioral measurements were obtained via (1) photobeam interruptions, (2) tracking of movements via image analysis, and (3) quantitative ethological analysis of postures and acts via videorecords. Several indices of ambulatory or horizontal forward locomotion confirmed the stimulant effects of cocaine. In a further experiment, separate groups of mice were challenged with 40 mg/kg cocaine at one time point, either during the social stress or 3, 5, 7 or 9 days thereafter. A cocaine challenge significantly increased locomotion 5 and 7 days after a brief social defeat stress, in excess of the level that is seen in non-stressed animals. Further experiments used immunohistochemical assays of sections through the caudal ventrolateral PAG and showed a significant increase in Fos-like immunoreactivity (Fos-LI) 1 h after the social stress experience or after cocaine. Importantly, concurrent administration of cocaine with social defeat stress produced inhibition of Fos expression throughout the PAG. A partial to complete recovery of cocaine-induced Fos expression was observed 5-7 days after social defeat stress. The results suggest that a single social stress episode is sufficient to engender a delayed sensitization of stimulant hyperactivity. The initial inhibition of Fos expression by concurrent social stress and cocaine may point to a relevant initiating event in the process of sensitization to stimulants.
这些实验探究了在单次社会挫败应激后注射可卡因时，中脑导水管周围灰质区（PAG）行为变化和Fos表达的性质及时间进程。社会挫败应激定义为一只入侵小鼠对具有攻击性的领地小鼠的反应。首先，入侵小鼠会受到短暂攻击，其次，在被带孔笼子保护20分钟的同时会受到威胁。对抗开始后血浆皮质酮水平升高，并在受保护阶段持续升高。在第一个实验中，将单独分组的入侵小鼠和对照小鼠分别用可卡因（20、30或40毫克/千克）或生理盐水进行一次挑战。在运动活动测试期间，通过以下方式获得行为测量数据：（1）光束中断，（2）通过图像分析跟踪运动，以及（3）通过视频记录对姿势和行为进行定量行为学分析。几种动态或水平向前运动指标证实了可卡因的兴奋作用。在进一步的实验中，将单独分组的小鼠在一个时间点用40毫克/千克可卡因进行挑战，要么在社会应激期间，要么在其后3、5、7或9天。短暂的社会挫败应激后5天和7天，可卡因挑战显著增加了运动，超过了非应激动物的水平。进一步的实验使用了对尾侧腹外侧PAG切片的免疫组织化学分析，结果显示在社会应激经历后或可卡因注射后1小时，Fos样免疫反应性（Fos-LI）显著增加。重要的是，可卡因与社会挫败应激同时给药会抑制整个PAG中的Fos表达。在社会挫败应激后5 - 7天观察到可卡因诱导的Fos表达部分至完全恢复。结果表明，单次社会应激事件足以引发对兴奋剂多动的延迟敏化。社会应激和可卡因同时给药对Fos表达的初始抑制可能表明在对兴奋剂敏化过程中有一个相关的起始事件。
