Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
Department of Physics and Medical Technology, VU University Medical Center, Amsterdam, The Netherlands.
Brain Struct Funct. 2017 Nov;222(8):3453-3475. doi: 10.1007/s00429-017-1412-4. Epub 2017 Apr 9.
Maladaptive changes in the involvement of striatal and frontal cortical regions in drug use are thought to underlie the progression to habitual drug use and loss of cognitive control over drug intake that occur with accumulating drug experience. The present experiments focus on changes in neuronal activity in these regions associated with short-term (10 days) and long-term (60 days) self-administration of cocaine. Quantitative in situ hybridization for the immediate early gene Mkp1 was combined with statistical parametric mapping to assess the distribution of neuronal activity. We hypothesized that neuronal activity in striatum would increase in its dorsal part and that activity in frontal cortex would decrease with prolonged cocaine self-administration experience. Expression of Mkp1 was profoundly increased after cocaine self-administration, and the magnitude of this effect was greater after short-term compared to long-term self-administration. Increased neuronal activity was seen in both dorsal and ventral sectors of the striatum after 10 days exposure to cocaine. However, enhanced activity was restricted to dorsomedial and dorsocentral striatum after 60 days cocaine self-administration. In virtually all medial prefrontal and most orbitofrontal areas, increased expression of Mkp1 was observed after 10 days of cocaine taking, whereas after 60 days, enhanced expression was restricted to caudal parts of medial prefrontal and caudomedial parts of orbitofrontal cortex. Our data reveal functional changes in cellular activity in striatum and frontal cortex with increasing cocaine self-administration experience. These changes might reflect the neural processes that underlie the descent from recreational drug taking to compulsive cocaine use.
纹状体和额皮质区域参与的适应性变化被认为是导致习惯性药物使用和认知控制丧失的基础，而这种丧失是随着药物使用经验的积累而发生的。本实验主要关注与短期（10 天）和长期（60 天）可卡因自我给药相关的这些区域神经元活动的变化。即时早期基因 Mkp1 的定量原位杂交与统计参数映射相结合，以评估神经元活动的分布。我们假设，随着可卡因自我给药经验的延长，纹状体的神经元活动会在其背侧部分增加，而前额皮质的活动会减少。Mkp1 的表达在可卡因自我给药后显著增加，且短期给药后的增加幅度大于长期给药。在接触可卡因 10 天后，纹状体的背侧和腹侧区域均可见神经元活动增强。然而，在 60 天可卡因自我给药后，增强的活动仅限于背侧纹状体的背侧和背中部。在几乎所有的内侧前额叶皮质和大多数眶额皮质区域，在可卡因摄入 10 天后观察到 Mkp1 的表达增加，而在 60 天后，增强的表达仅限于内侧前额叶皮质的尾部和眶额皮质的尾部。我们的数据揭示了随着可卡因自我给药经验的增加，纹状体和前额皮质中细胞活动的功能变化。这些变化可能反映了从娱乐性药物使用到强迫性可卡因使用的神经过程。
