Department of Medicine, Duke University, Durham, NC 27710, USA.
Proc Natl Acad Sci U S A. 2011 Jul 26;108(30):12509-14. doi: 10.1073/pnas.1109199108. Epub 2011 Jul 11.
Sodium appetite is an instinct that involves avid specific intention. It is elicited by sodium deficiency, stress-evoked adrenocorticotropic hormone (ACTH), and reproduction. Genome-wide microarrays in sodium-deficient mice or after ACTH infusion showed up-regulation of hypothalamic genes, including dopamine- and cAMP-regulated neuronal phosphoprotein 32 kDa (DARPP-32), dopamine receptors-1 and -2, α-2C- adrenoceptor, and striatally enriched protein tyrosine phosphatase (STEP). Both DARPP-32 and neural plasticity regulator activity-regulated cytoskeleton associated protein (ARC) were up-regulated in lateral hypothalamic orexinergic neurons by sodium deficiency. Administration of dopamine D1 (SCH23390) and D2 receptor (raclopride) antagonists reduced gratification of sodium appetite triggered by sodium deficiency. SCH23390 was specific, having no effect on osmotic-induced water drinking, whereas raclopride also reduced water intake. D1 receptor KO mice had normal sodium appetite, indicating compensatory regulation. Appetite was insensitive to SCH23390, confirming the absence of off-target effects. Bilateral microinjection of SCH23390 (100 nM in 200 nL) into rats' lateral hypothalamus greatly reduced sodium appetite. Gene set enrichment analysis in hypothalami of mice with sodium appetite showed significant enrichment of gene sets previously linked to addiction (opiates and cocaine). This finding of concerted gene regulation was attenuated on gratification with perplexingly rapid kinetics of only 10 min, anteceding significant absorption of salt from the gut. Salt appetite and hedonic liking of salt taste have evolved over >100 million y (e.g., being present in Metatheria). Drugs causing pleasure and addiction are comparatively recent and likely reflect usurping of evolutionary ancient systems with high survival value by the gratification of contemporary hedonic indulgences. Our findings outline a molecular logic for instinctive behavior encoded by the brain with possible important translational-medical implications.
钠欲是一种涉及强烈特定意图的本能。它由钠缺乏、应激引起的促肾上腺皮质激素 (ACTH) 和繁殖引起。在缺钠的小鼠或在 ACTH 输注后，全基因组微阵列显示下丘脑基因上调，包括多巴胺和 cAMP 调节的神经元磷蛋白 32 kDa (DARPP-32)、多巴胺受体-1 和 -2、α-2C-肾上腺素能受体和纹状体丰富的蛋白酪氨酸磷酸酶 (STEP)。DARPP-32 和神经可塑性调节剂活性调节细胞骨架相关蛋白 (ARC) 在外侧下丘脑食欲素能神经元中由钠缺乏而上调。多巴胺 D1 (SCH23390) 和 D2 受体 (raclopride) 拮抗剂的给药减少了由钠缺乏引发的钠欲满足。SCH23390 是特异性的，对渗透压引起的水饮无影响，而 raclopride 也减少了水的摄入。D1 受体 KO 小鼠有正常的钠欲，表明有代偿调节。SCH23390 对食欲不敏感，证实不存在脱靶效应。双侧微量注射 SCH23390 (100 nM 在 200 nL) 到大鼠的外侧下丘脑大大减少了钠欲。具有钠欲的小鼠下丘脑的基因集富集分析显示，先前与成瘾相关的基因集显著富集 (阿片类药物和可卡因)。这种基因调控的协同作用的发现减弱了满足感，令人费解的快速动力学仅为 10 分钟，早于从肠道吸收显著的盐。盐欲和盐味的快感已经进化了超过 1 亿年 (例如，在 Metatheria 中存在)。引起快感和成瘾的药物相对较新，可能反映了通过当代享乐放纵的满足感篡夺了具有高生存价值的古老系统。我们的发现概述了大脑编码的本能行为的分子逻辑，可能具有重要的转化医学意义。
