Mattson Brandi J, Koya Eisuke, Simmons Danielle E, Mitchell Timothy B, Berkow Alexander, Crombag Hans S, Hope Bruce T
Behavioral Neuroscience Branch, Intramural Research Program, The National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.
Eur J Neurosci. 2008 Jan;27(1):202-12. doi: 10.1111/j.1460-9568.2007.05984.x. Epub 2007 Dec 17.
Repeated cocaine administration to rats outside their home cage induces behavioral sensitization that is strongly modulated by the drug administration environment. We hypothesized that stimuli in the drug administration environment activate specific sets of striatal neurons, called neuronal ensembles, for further cocaine-enhanced activation, and that repeated activation of these neuronal ensembles underlies context-specific sensitization. In the present study, we repeatedly administered cocaine or saline to rats on alternate days in two distinct environments outside the home cage, one paired with cocaine and the other with saline. On test day, cocaine challenge injections in the cocaine-paired environment produced strongly enhanced levels of locomotor activity, while cocaine challenge injections in the saline-paired environment did not. The corresponding record of past neuronal activation in nucleus accumbens and caudate-putamen during repeated drug administration was assessed using FosB immunohistochemistry, while acute neuronal activation on test day was assessed using c-fos in situ hybridization. Although only 2% of striatal neurons were FosB labeled, 87% of these FosB-labeled neurons were co-labeled with c-fos when cocaine was injected in the cocaine-paired environment. The degree of co-labeling was significantly less following cocaine or saline challenge injections in the saline-paired environment. Furthermore, the total number of c-fos-labeled neurons was greater with either cocaine or saline challenge injections in the cocaine-paired environment than in the saline-paired environment. These findings demonstrate that the drug administration environment partly determines which striatal neuronal ensembles are activated, and to what extent, following context-specific sensitization to cocaine.
在大鼠的笼外反复给予可卡因会诱导行为敏化，这种敏化受到药物给药环境的强烈调节。我们假设，药物给药环境中的刺激会激活特定的纹状体神经元组，即神经元集群，以进一步增强可卡因的激活作用，并且这些神经元集群的反复激活是情境特异性敏化的基础。在本研究中，我们在笼外的两个不同环境中，隔天给大鼠反复注射可卡因或生理盐水，一个环境与可卡因配对，另一个与生理盐水配对。在测试日，在与可卡因配对的环境中注射可卡因激发剂会使运动活动水平大幅增强，而在与生理盐水配对的环境中注射可卡因激发剂则不会。在反复给药期间，使用FosB免疫组织化学评估伏隔核和尾状核 - 壳核中过去神经元激活的相应记录，而在测试日使用c - fos原位杂交评估急性神经元激活。尽管只有2%的纹状体神经元被FosB标记，但当在与可卡因配对的环境中注射可卡因时，这些被FosB标记的神经元中有87%与c - fos共同标记。在与生理盐水配对的环境中注射可卡因或生理盐水激发剂后，共同标记的程度明显较低。此外，在与可卡因配对的环境中注射可卡因或生理盐水激发剂时，c - fos标记神经元的总数比在与生理盐水配对的环境中更多。这些发现表明，药物给药环境部分决定了在对可卡因进行情境特异性敏化后，哪些纹状体神经元集群会被激活以及激活的程度。
