Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, 09042 Monserrato, Italy.
J Neurosci. 2013 Apr 3;33(14):6203-11. doi: 10.1523/JNEUROSCI.4647-12.2013.
Ventral tegmental area dopamine neurons control reward-driven learning, and their dysregulation can lead to psychiatric disorders. Tonic and phasic activity of these dopaminergic neurons depends on cholinergic tone and activation of nicotinic acetylcholine receptors (nAChRs), particularly those containing the β2 subunit (β2*-nAChRs). Nuclear peroxisome proliferator-activated receptors type-α (PPARα) tonically regulate β2*-nAChRs and thereby control dopamine neuron firing activity. However, it is unknown how and when PPARα endogenous ligands are synthesized by dopamine cells. Using ex vivo and in vivo electrophysiological techniques combined with biochemical and behavioral analysis, we show that activation of α7-nAChRs increases in the rat VTA both the tyrosine phosphorylation of the β2 subunit of nAChRs and the levels of two PPARα endogenous ligands in a Ca(2+)-dependent manner. Accordingly, in vivo production of endogenous PPARα ligands, triggered by α7-nAChR activation, blocks in rats nicotine-induced increased firing activity of dopamine neurons and displays antidepressant-like properties. These data demonstrate that endogenous PPARα ligands are effectors of α7-nAChRs and that their neuromodulatory properties depend on phosphorylation of β2*-nAChRs on VTA dopamine cells. This reveals an autoinhibitory mechanism aimed at reducing dopamine cell overexcitation engaged during hypercholinergic drive. Our results unveil important physiological functions of nAChR/PPARα signaling in dopamine neurons and how behavioral output can change after modifications of this signaling pathway. Overall, the present study suggests PPARα as new therapeutic targets for disorders associated with unbalanced dopamine-acetylcholine systems.
腹侧被盖区多巴胺神经元控制奖赏驱动学习，其功能失调可导致精神疾病。这些多巴胺能神经元的紧张和相位活动依赖于胆碱能张力和烟碱型乙酰胆碱受体（nAChRs）的激活，特别是含有β2 亚基的受体（β2*-nAChRs）。核过氧化物酶体增殖物激活受体-α（PPARα）通过调节β2*-nAChRs 来调节多巴胺神经元的放电活动。然而，多巴胺细胞内源性 PPARα 配体的合成方式和时间尚不清楚。我们使用离体和在体电生理技术，结合生化和行为分析，发现激活α7-nAChRs 以 Ca2+依赖的方式增加大鼠 VTA 中 nAChRs 的β2 亚基酪氨酸磷酸化和两种 PPARα 内源性配体的水平。因此，α7-nAChR 激活在体内触发内源性 PPARα 配体的产生，阻断尼古丁诱导的大鼠多巴胺神经元放电活动增加，并显示出抗抑郁样特性。这些数据表明，内源性 PPARα 配体是α7-nAChRs 的效应物，其神经调节特性取决于 VTA 多巴胺细胞上β2*-nAChRs 的磷酸化。这揭示了一种自动抑制机制，旨在减少过度兴奋的胆碱能驱动期间多巴胺细胞的过度兴奋。我们的研究结果揭示了 nAChR/PPARα 信号在多巴胺神经元中的重要生理功能，以及该信号通路修饰后行为输出如何发生变化。总的来说，本研究表明 PPARα 是与多巴胺-乙酰胆碱系统失衡相关疾病的新治疗靶点。
