Reid M S, Ho L B, Tolliver B K, Wolkowitz O M, Berger S P
Langley Porter Psychiatric Institute, University of California at San Francisco, San Francisco Veteran's Affairs Medical Center, 116W 4150 Clement St., San Francisco, CA 94121, USA.
Brain Res. 1998 Feb 2;783(1):133-42. doi: 10.1016/s0006-8993(97)01319-x.
Several studies indicate that blockade of stress-induced corticosterone secretion prevents the development of stress-induced sensitization to the behavioral effects of stimulants. The present study examined whether chronic blockade of corticosterone synthesis with metyrapone could reverse stress-induced amphetamine sensitization in rats. Restraint stress in cylindrical chambers, 2 times 30 min/day for 5 days over an 8-day schedule, was used as the stressor. Following completion of the stress protocol, animals were cannulated with microdialysis guide cannulae over the nucleus accumbens, and then treated with either metyrapone (50 mg/kg, i.p.) or vehicle (1 ml/kg) for 7 days. On the seventh day, animals were implanted with microdialysis probes in the nucleus accumbens, and on the following day, all animals were tested for their locomotor, stereotypy, and nucleus accumbens dopamine and DOPAC release responses to an injection of saline followed 60 min later by d-amphetamine (1.5 mg/kg, i.p.). Neither stress or metyrapone treatment had an effect on the behavioral or dopamine release response to saline. However, amphetamine-stimulated locomotion and stereotypy were strongly enhanced, while amphetamine-stimulated dopamine release response was slightly enhanced (significant only by drug x time interaction), in stressed animals. Metyrapone treatment reduced the stress-induced increase in the locomotor, but not stereotypy, response to amphetamine. In contrast, the dopamine release response to amphetamine was enhanced in metyrapone-treated animals, in both stressed and non-stressed groups, while DOPAC levels were unaffected by treatment group. This augmentation was particularly evident in the stressed-metyrapone-treated animals. Furthermore, non-stressed animals showed an increased locomotor and stereotypy response to amphetamine after treatment with metyrapone. These findings indicate that metyrapone treatment can reverse, or inhibit the expression of, stress-induced sensitization to the behavioral effects of amphetamine. However, the ability of metyrapone treatment to enhance the behavioral (in non-stressed animals) and dopamine release (in non-stressed and stressed animals) responses to amphetamine indicate that chronic metyrapone treatment will produce stimulant sensitization when given alone.
多项研究表明，阻断应激诱导的皮质酮分泌可预防应激诱导的对兴奋剂行为效应的敏化作用的发展。本研究检测了用甲吡酮长期阻断皮质酮合成是否能逆转大鼠应激诱导的苯丙胺敏化作用。将大鼠置于圆柱形笼中进行束缚应激，在8天的时间里，每天2次，每次30分钟，持续5天，以此作为应激源。应激方案完成后，给动物在伏隔核上方植入微透析引导套管，然后用甲吡酮（50毫克/千克，腹腔注射）或溶剂（1毫升/千克）处理7天。在第7天，给动物在伏隔核植入微透析探针，在接下来的一天，对所有动物进行测试，检测它们对注射生理盐水后的运动、刻板行为以及伏隔核多巴胺和3,4-二羟基苯乙酸（DOPAC）释放反应，60分钟后再注射d-苯丙胺（1.5毫克/千克，腹腔注射）。应激或甲吡酮处理对生理盐水的行为或多巴胺释放反应均无影响。然而，在应激动物中，苯丙胺刺激的运动和刻板行为显著增强，而苯丙胺刺激的多巴胺释放反应略有增强（仅通过药物×时间交互作用有显著性差异）。甲吡酮处理减少了应激诱导的对苯丙胺运动反应的增加，但对刻板行为无影响。相反，在应激和非应激组中，甲吡酮处理的动物对苯丙胺的多巴胺释放反应均增强，而DOPAC水平不受处理组影响。这种增强在应激-甲吡酮处理的动物中尤为明显。此外，非应激动物在用甲吡酮处理后对苯丙胺的运动和刻板行为反应增加。这些结果表明，甲吡酮处理可逆转或抑制应激诱导的对苯丙胺行为效应的敏化作用。然而，甲吡酮处理增强对苯丙胺的行为反应（在非应激动物中）和多巴胺释放反应（在非应激和应激动物中）的能力表明，单独给予长期甲吡酮处理会产生兴奋剂敏化作用。
