Liu Xiu, Weiss Friedbert
Department of Neuropharmacology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, USA.
Psychopharmacology (Berl). 2003 Jul;168(1-2):184-191. doi: 10.1007/s00213-002-1267-z. Epub 2002 Nov 22.
Stress and conditioned responses to drug cues have been implicated as critical factors in relapse to drug use. In the animal literature, both the conditioned effects of drug-related stimuli and the unconditioned effects of foot-shock stress have been well documented to reinstate extinguished drug-seeking behavior. What has remained largely unexplored, however, is the significance of stimuli conditioned to foot-shock stress for the resumption of drug seeking. Additionally, although relapse is often the result of several risk factors acting in combination, the possibility that interactions among risk factors such as conditioned stress and drug cues may intensify drug-seeking behavior has received little experimental attention.
The purpose of this study was to examine the individual and interactive effects of a stimulus conditioned to foot-shock stress (STRESS CS) and a stimulus conditioned to ethanol reward (EtOH CS) on the reinstatement of ethanol-seeking behavior following extinction.
Male Wistar rats were trained to orally self-administer 10% ethanol on a fixed-ratio 3 schedule of reinforcement. The EtOH CS was established by response-contingently pairing 0.5 s illumination of a white cue light with each reinforced response. The STRESS CS was established by pairing a continuous white noise (70 dB) with intermittent foot shock (10 min; 0.5 mA; 0.5 s on; mean off period of 40 s). Ethanol dependence was induced by an ethanol vapor-inhalation procedure. After ethanol-maintained instrumental responding was extinguished by withholding ethanol and the EtOH CS, reinstatement tests were conducted.
Both exposure to the STRESS CS and response-contingent presentation of the EtOH CS reinstated extinguished responding at the previously active, ethanol-paired lever without further ethanol availability. When response-contingent availability of the EtOH CS was preceded by exposure to the STRESS CS, interactive effects of these stimuli on responding were observed. However, both the individual and interactive effects of the STRESS CS and the EtOH CS reached statistical significance only in rats with a history of ethanol dependence but not in ethanol-nondependent rats.
The results confirm that both conditioned stress and ethanol cues elicit ethanol-seeking behavior and, more importantly, that these stimuli produce interactive effects resulting in an increased ethanol-seeking response. The findings also indicate that susceptibility to ethanol seeking induced by conditioned stress and alcohol cues depends significantly on the history of prior alcohol exposure.
压力以及对药物线索的条件反应被认为是药物使用复发的关键因素。在动物文献中，与药物相关刺激的条件作用以及足部电击应激的非条件作用都已被充分证明可恢复已消退的觅药行为。然而，很大程度上仍未被探索的是与足部电击应激相关的条件刺激对觅药行为恢复的意义。此外，尽管复发通常是多种风险因素共同作用的结果，但诸如条件应激和药物线索等风险因素之间的相互作用可能会加剧觅药行为这一可能性几乎未受到实验关注。
本研究的目的是检验与足部电击应激相关的条件刺激（应激条件刺激）和与乙醇奖赏相关的条件刺激（乙醇条件刺激）对消退后乙醇觅药行为恢复的个体及交互作用。
雄性Wistar大鼠在固定比率为3的强化程序下接受训练，通过口服方式自我给药10%的乙醇。乙醇条件刺激是通过将白色提示灯0.5秒的照明与每次强化反应进行反应偶联配对来建立的。应激条件刺激是通过将连续的白噪声（70分贝）与间歇性足部电击（10分钟；0.5毫安；0.5秒开启；平均关闭时间为40秒）配对来建立的。通过乙醇蒸汽吸入程序诱导乙醇依赖。在通过停止给予乙醇和乙醇条件刺激使乙醇维持的工具性反应消退后，进行恢复测试。
暴露于应激条件刺激以及乙醇条件刺激的反应偶联呈现均恢复了在先前活跃的、与乙醇配对的杠杆处已消退的反应，且无需进一步提供乙醇。当在乙醇条件刺激的反应偶联可得性之前先暴露于应激条件刺激时，观察到了这些刺激对反应的交互作用。然而，应激条件刺激和乙醇条件刺激的个体及交互作用仅在有乙醇依赖史的大鼠中达到统计学显著水平，而在无乙醇依赖的大鼠中未达到。
结果证实，条件应激和乙醇线索均能引发乙醇觅药行为，更重要的是，这些刺激会产生交互作用，导致乙醇觅药反应增加。研究结果还表明，条件应激和酒精线索诱导的乙醇觅药易感性显著取决于先前酒精暴露的历史。
