Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA, USA.
Neuropsychopharmacology. 2011 Apr;36(5):1021-32. doi: 10.1038/npp.2010.240. Epub 2011 Feb 2.
Nicotine activation of nicotinic acetylcholine receptors (nAChRs) within the dopaminergic (DAergic) neuron-rich ventral tegmental area (VTA) is necessary and sufficient for nicotine reinforcement. In this study, we show that rewarding doses of nicotine activated VTA DAergic neurons in a region-selective manner, preferentially activating neurons in the posterior VTA (pVTA) but not in the anterior VTA (aVTA) or in the tail VTA (tVTA). Nicotine (1 μM) directly activated pVTA DAergic neurons in adult mouse midbrain slices, but had little effect on DAergic neurons within the aVTA. Quantification of nAChR subunit gene expression revealed that pVTA DAergic neurons expressed higher levels of α4, α6, and β3 transcripts than did aVTA DAergic neurons. Activation of nAChRs containing the α4 subunit (α4() nAChRs) was necessary and sufficient for activation of pVTA DAergic neurons: nicotine failed to activate pVTA DAergic neurons in α4 knockout animals; in contrast, pVTA α4() nAChRs were selectively activated by nicotine in mutant mice expressing agonist-hypersensitive α4() nAChRs (Leu9'Ala mice). In addition, whole-cell currents induced by nicotine in DAergic neurons were mediated by α4() nAChRs and were significantly larger in pVTA neurons than in aVTA neurons. Infusion of an α6() nAChR antagonist into the VTA blocked activation of pVTA DAergic neurons in WT mice and in Leu9'Ala mice at nicotine doses, which only activate the mutant receptor indicating that α4 and α6 subunits coassemble to form functional receptors in these neurons. Thus, nicotine selectively activates DAergic neurons within the pVTA through α4α6() nAChRs. These receptors represent novel targets for smoking-cessation therapies.
尼古丁激活富含多巴胺能（DAergic）神经元的腹侧被盖区（VTA）中的烟碱型乙酰胆碱受体（nAChRs）对于尼古丁强化是必要且充分的。在这项研究中，我们表明，奖赏剂量的尼古丁以区域选择性的方式激活 VTA 的 DAergic 神经元，优先激活后腹侧被盖区（pVTA）中的神经元，而不激活前腹侧被盖区（aVTA）或尾部腹侧被盖区（tVTA）中的神经元。尼古丁（1μM）直接激活成年小鼠中脑切片中的 pVTA DAergic 神经元，但对 aVTA 中的 DAergic 神经元几乎没有影响。nAChR 亚基基因表达的定量分析表明，pVTA DAergic 神经元表达的 α4、α6 和 β3 转录本水平高于 aVTA DAergic 神经元。含有 α4 亚基的 nAChR（α4() nAChRs）的激活对于 pVTA DAergic 神经元的激活是必要且充分的：尼古丁在 α4 敲除动物中不能激活 pVTA DAergic 神经元；相反，在表达激动剂敏感受体（Leu9'Ala 小鼠）的突变小鼠中，pVTA α4() nAChRs 被尼古丁选择性激活。此外，尼古丁在 DAergic 神经元中诱导的全细胞电流是由 α4() nAChRs 介导的，并且在 pVTA 神经元中比在 aVTA 神经元中大得多。在 WT 小鼠和 Leu9'Ala 小鼠中，将 α6() nAChR 拮抗剂注入 VTA 可阻断 pVTA DAergic 神经元的激活，在这些小鼠中，只有激活突变受体的尼古丁剂量才会发生这种情况，这表明 α4 和 α6 亚基在这些神经元中共同组装形成功能性受体。因此，尼古丁通过 α4α6(*) nAChRs 选择性地激活 pVTA 中的 DAergic 神经元。这些受体代表了戒烟治疗的新靶点。
