McGill University, Department of Psychiatry and Douglas Mental Health University Institute, 6875 Lasalle Boulevard, Montreal, Quebec H4H 1R3, Canada.
Neuroscience. 2011 Mar 10;176:225-36. doi: 10.1016/j.neuroscience.2010.12.037. Epub 2010 Dec 25.
High caloric intake during early postnatal development can have long term consequences for the offspring. We previously reported that the adult offspring of dams fed a high-fat diet during the last week of gestation and throughout lactation display blunted locomotor response to amphetamine (AMP) and reduced sensitization to the drug compared to offspring of control diet dams. Here, we report that the subsensitivity of high-fat offspring to AMP's locomotor stimulant action reflects, at least in part, altered regulation of nucleus accumbens (NAc) dopamine (DA) transmission. When compared to controls, the DA response of high-fat animals to AMP, as measured with microdialysis, was attenuated in the NAc, but unaffected in the prefrontal cortex (PFC). A relatively higher activity of NAc synaptosomal DA transporter sites without changes in vesicular monoamine transporter (VMAT) uptake capacity was also observed in high-fat offspring. Moreover, ventral tegmental area (VTA) D(2) receptor mRNA levels were decreased in high-fat offspring, suggesting a reduction in DA release-regulating D(2) autoreceptors in terminal regions such as the NAc. The magnitude of locomotor response to D(2/3) receptor activation (with quinpirole) was greater in high-fat than in control animals despite having comparable postsynaptic D(2) mRNA levels in the NAc. Finally, while operant responding for a sugar-enriched food reward did not differ between diet groups, high-fat offspring displayed increased operant responding for a fat-enriched reward compared to controls. These findings add to mounting evidence that early life exposure to elevated dietary maternal fat can lead to long lasting changes in DA-mediated behavioral responses to stimulant drugs and fat-enriched foods.
在产后早期发展过程中高热量的摄入会对后代产生长期影响。我们之前曾报道过，在妊娠最后一周和哺乳期期间用高脂肪饮食喂养的母鼠的成年后代对安非他命（AMP）的运动反应迟钝，并且对药物的敏感性降低，与对照饮食母鼠的后代相比。在这里，我们报告说高脂肪后代对 AMP 的运动刺激作用的敏感性降低至少部分反映了伏隔核（NAc）多巴胺（DA）传递的调节改变。与对照组相比，用微透析测量时，高脂肪动物对 AMP 的 DA 反应在 NAc 中减弱，但在前额叶皮层（PFC）中不受影响。还观察到高脂肪后代的 NAc 突触小体 DA 转运蛋白位点的相对较高活性，而囊泡单胺转运蛋白（VMAT）摄取能力没有变化。此外，高脂肪后代的腹侧被盖区（VTA）D2 受体 mRNA 水平降低，表明终端区域（如 NAc）的 DA 释放调节 D2 自身受体减少。尽管 NAc 中的突触后 D2 mRNA 水平相当，但高脂肪动物对 D2/3 受体激活（用喹吡罗）的运动反应幅度大于对照动物。最后，虽然两组饮食之间的操作反应性对富含糖的食物奖励没有差异，但高脂肪后代对富含脂肪的奖励的操作反应性高于对照组。这些发现增加了越来越多的证据表明，生命早期暴露于升高的饮食性母体脂肪会导致对兴奋剂药物和富含脂肪的食物的多巴胺介导的行为反应的持久变化。
