ONE EXPERIENCE WITH LOWER OR HIGHER INTENSITY STRESSORS, RESPECTIVELY ENHANCES OR DIMINISHES RESPONSIVENESS TO HALOPERIDOL WEEKS LATER - IMPLICATIONS FOR UNDERSTANDING DRUG VARIABILITY
ONE EXPERIENCE WITH LOWER OR HIGHER INTENSITY STRESSORS, RESPECTIVELY ENHANCES OR DIMINISHES RESPONSIVENESS TO HALOPERIDOL WEEKS LATER - IMPLICATIONS FOR UNDERSTANDING DRUG VARIABILITY
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DOI：
10.1016/0006-8993(91)91709-a
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发表时间：
1991-12-06
期刊：
影响因子：
2.9
通讯作者：
BARRY, H
中科院分区：
文献类型：
--
作者：
ANTELMAN, SM;CAGGIULA, AR;BARRY, H
该实验室先前已经表明，急性暴露于各种短暂的应激事件可以对随后对药理学和非药理学应激源的反应产生非常持久的影响。在某些情况下，对这些因素的反应会增强，而在另一些情况下，反应会减弱：共同点是，在每种情况下，随着时间的推移，初始压力源的影响会越来越强。在这里，我们确定了一个因素，决定了时间依赖性的影响是明显的。在3项单独的实验中，雄性大鼠单次暴露于较低或较高强度的应激源，并在1-2小时或2周后测量其对氟哌啶醇诱导的僵住症以及中脑核和内侧额叶皮质中多巴胺和二羟基苯乙酸水平的影响。应激源是环境（针刺或1小时的固定），代谢（200或750毫克/公斤，腹膜内的2-脱氧-D-葡萄糖），或药理学（0.5克/公斤或2.0克/公斤，乙醇）。压力的程度通过测量血浆皮质酮水平来衡量。当应激源先于此类行为测试1-2 h时，对氟哌啶醇诱导的僵住症无影响。相比之下，当间隔为2周时，低强度的应激源都增加了氟哌啶醇僵硬症，而高强度的应激源则减少了相同的反应。换句话说，无论氟哌啶醇的作用是否发生致敏或减弱，都观察到随着时间推移而进行的过程。与观察到的统一的双极行为效应相反，根据预应激的强度，神经化学研究结果未能显示任何双极的证据。相反，环境和药物应激源诱导长期的，通常是时间依赖性的变化，表明多巴胺利用率持续下降，而我们的代谢应激源没有影响。我们的研究结果表明，压力诱导的，时间依赖性的过程，增加或减少对药物的反应，这取决于早期的压力的强度。它们可能与实验和临床文献中经常遇到的药物反应的变异性有关。
This laboratory has previously shown that acute exposure to a variety of brief stressful events can have a very long-lasting influence on subsequent responsiveness to pharmacological and non-pharmacological stressors. In some cases the response to these agents is enhanced, while in others it is diminished: the common denominator being that in each instance the influence of the initial stressor grows stronger with the passage of time. Here, we identify one factor that determines which time-dependent effect is manifest. In 3 separate experiments, male rats were subjected to a single exposure to stressors of either lower or higher intensity and their effects on haloperidol-induced catalepsy and dopamine and dihydroxyphenylacetic acid levels in the nucleus accumbens and medial frontal cortex, measured either 1-2 h or 2 weeks later. The stressors were either environmental (needle jab or 1 h of immobilization), metabolic (200 or 750 mg/kg, i.p. of 2-deoxy-D-glucose), or pharmacological (0.5 g/kg or 2.0 g/kg, ethanol). Degree of stressfulness was indexed by measuring plasma corticosterone levels. There was no effect on haloperidol-induced catalepsy when stressors preceded such behavioral testing by 1-2 h. By contrast, when the interval was 2 weeks, the lower-intensity stressors all increased haloperidol catalepsy, whereas the higher-intensity stressors decreased the same response. In other words, a process that progressed with the passage of time was observed regardless of whether sensitization or diminution of haloperidol's action occurred. In contrast to the uniform bipolar behavioral effects observed, depending on the intensity of the prestressor, the neurochemical findings failed to show any evidence of bipolarity whatever. Instead, both environmental and pharmacological stressors induced long-term, generally time-dependent changes, suggestive of a persistent decrease in dopamine utilization, while our metabolic stressor had no effect. Our results demonstrate a stressor-induced, time-dependent process that either increases or decreases responsiveness to drugs, depending on the intensity of the earlier stressor. They may be relevant to the variability in response to drugs frequently encountered in both the experimental and clinical literatures.