Evidence for defective mesolimbic dopamine exocytosis in obesity-prone rats
Evidence for defective mesolimbic dopamine exocytosis in obesity-prone rats
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DOI：
10.1096/fj.08-110759
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发表时间：
2008-08-01
期刊：
影响因子：
4.8
通讯作者：
Pothos, Emmanuel N.
中科院分区：
文献类型：
--
作者：
Geiger, Brenda M.;Behr, Gerald G.;Pothos, Emmanuel N.
饮食性肥胖和调节进食的享乐方面的中脑边缘系统之间的关联目前尚未解决。在本研究中，我们研究了肥胖倾向（OP）和肥胖抵抗（OR）大鼠的基线和刺激中枢多巴胺水平的差异。OP大鼠是hyperphagic和显示了20%的体重增加超过OR大鼠在第15周的年龄，当喂食标准的食物饮食。这种表型与基础细胞外多巴胺减少50%相关，如通过微透析探针在中脑边缘核中测量的，中脑边缘多巴胺系统的投射部位与食物奖励有关。在较年轻的动物（4周龄）中也观察到类似的缺陷。在电生理学研究中，电诱发的多巴胺释放在切片制剂中显着衰减OP大鼠，不仅在延髓核，但也在其他终端网站的多巴胺神经元，如延髓壳，背侧纹状体，内侧前额叶皮层，这表明可能有一个广泛的功能障碍，在这种肥胖模型中的机制调节多巴胺释放。此外，在OP大鼠的多巴胺损伤是明显的，在出生时，并与几个因素的表达变化调节多巴胺的合成和释放：囊泡单胺转运蛋白-2，酪氨酸羟化酶，多巴胺转运蛋白，多巴胺受体-2短的形式。综上所述，这些结果表明，一个衰减的中枢多巴胺系统将减少与喂养相关的享乐反应，并诱导代偿性摄食过多，导致肥胖。
The association between dietary obesity and mesolimbic systems that regulate hedonic aspects of feeding is currently unresolved. In the present study, we examined differences in baseline and stimulated central dopamine levels in obesity-prone (OP) and obesity-resistant ( OR) rats. OP rats were hyperphagic and showed a 20% weight gain over OR rats at wk 15 of age, when fed a standard chow diet. This phenotype was associated with a 50% reduction in basal extracellular dopamine, as measured by a microdialysis probe in the nucleus accumbens, a projection site of the mesolimbic dopamine system that has been implicated in food reward. Similar defects were also observed in younger animals ( 4 wk old). In electrophysiology studies, electrically evoked dopamine release in slice preparations was significantly attenuated in OP rats, not only in the nucleus accumbens but also in additional terminal sites of dopamine neurons such as the accumbens shell, dorsal striatum, and medial prefrontal cortex, suggesting that there may be a widespread dysfunction in mechanisms regulating dopamine release in this obesity model. Moreover, dopamine impairment in OP rats was apparent at birth and associated with changes in expression of several factors regulating dopamine synthesis and release: vesicular monoamine transporter-2, tyrosine hydroxylase, dopamine transporter, and dopamine receptor-2 short-form. Taken together, these results suggest that an attenuated central dopamine system would reduce the hedonic response associated with feeding and induce compensatory hyperphagia, leading to obesity.