Florey Neuroscience Institutes, University of Melbourne, Parkville, Vic, Australia, 3010.
J Physiol. 2012 May 15;590(10):2427-42. doi: 10.1113/jphysiol.2011.225219. Epub 2012 Mar 5.
Persistent vulnerability to relapse represents a major challenge in the treatment of drug addiction. The brain circuitry that underlies relapse-like behaviour can be investigated using animal models of drug seeking. As yet there have been no comprehensive brain mapping studies that have specifically examined the neuroanatomical substrates of cue-induced opiate seeking following abstinence in a mouse operant paradigm. The aim of this study was to compare the brain regions involved in sucrose vs. morphine seeking following protracted abstinence in mice. Male CD1 mice were trained to respond for either sucrose (10% w/v) or intravenous morphine (0.1 mg kg(-1) per infusion) in an operant paradigm in the presence of a discrete cue. Once stable responding was established, mice were subjected to abstinence in their home cages for 3 weeks and then perfused for tissue collection, or returned to the operant chambers to assess cue-induced reward seeking before being perfused for tissue collection. Brain tissue was processed for Fos immunohistochemistry and Fos expression was quantified in a range of brain nuclei. We identified unique patterns of neuronal activation for sucrose and morphine seeking mice as well as some overlap. Structures activated in both ‘relapse' groups included the anterior cingulate and orbitofrontal cortex, nucleus accumbens shell, bed nucleus of the stria terminalis, substantia nigra pars compacta, ventral tegmental area, hippocampus, periaqueductal grey, locus coeruleus and lateral habenula. Structures that were more activated in morphine seeking mice included the nucleus accumbens core, basolateral amygdala, substantia nigra pars reticulata, and the central nucleus of the amygdala. The dorsal raphe was the only structure examined that was specifically activated in sucrose seeking mice. Overall our findings support a cortico-striatal limbic circuit driving opiate seeking, and we have identified some additional circuitry potentially relevant to reward seeking following abstinence.
在治疗药物成瘾方面，持续存在的复发易感性是一个主要挑战。使用药物寻求的动物模型可以研究导致类似复发的行为的大脑回路。迄今为止，还没有全面的脑图谱研究专门检查在小鼠操作性范式中戒断后线索诱导阿片类药物寻求的神经解剖学基础。本研究的目的是比较在小鼠长期戒断后，与蔗糖相比，吗啡寻求涉及的大脑区域。雄性 CD1 小鼠在存在离散线索的情况下，通过操作性范式对蔗糖（10%w/v）或静脉内吗啡（0.1mg/kg 每输注）进行反应。一旦建立了稳定的反应，小鼠在其家庭笼中进行 3 周的禁欲，然后进行组织采集的灌注，或返回操作性室评估线索诱导的奖励寻求，然后进行组织采集的灌注。脑组织用于 Fos 免疫组织化学，定量分析了一系列脑核中的 Fos 表达。我们确定了蔗糖和吗啡寻求小鼠独特的神经元激活模式，以及一些重叠。在两个“复发”组中激活的结构包括前扣带皮层和眶额皮层、伏隔核壳、终纹床核、黑质致密部、腹侧被盖区、海马、导水管周围灰质、蓝斑和外侧缰核。在吗啡寻求小鼠中更活跃的结构包括伏隔核核心、基底外侧杏仁核、黑质网状部和杏仁核中央核。中缝背核是唯一在蔗糖寻求小鼠中特异性激活的结构。总体而言，我们的发现支持皮质-纹状体边缘回路驱动阿片类药物寻求，并且我们已经确定了一些额外的回路可能与戒断后奖励寻求有关。
