Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts 01604, USA.
Mol Pharmacol. 2012 Apr;81(4):541-8. doi: 10.1124/mol.111.076661. Epub 2012 Jan 5.
Nicotine is reinforcing because it activates dopaminergic (DAergic) neurons within the ventral tegmental area (VTA) of the brain's mesocorticolimbic reward circuitry. This increase in activity can occur for a period of several minutes up to an hour and is thought to be a critical component of nicotine dependence. However, nicotine concentrations that are routinely self-administered by smokers are predicted to desensitize high-affinity α4β2 neuronal nicotinic acetylcholine receptors (nAChRs) in seconds. Thus, how physiologically relevant nicotine concentrations persistently activate VTA DAergic neurons is unknown. Here we show that nicotine can directly and robustly increase the firing frequency of VTA DAergic neurons for several minutes. In mouse midbrain slices, 300 nM nicotine elicited a persistent inward current in VTA DAergic neurons that was blocked by α-conotoxin MII[H9A;L15A], a selective antagonist of nAChRs containing the α6 subunit. α-conotoxin MII[H9A;L15A] also significantly reduced the long-lasting increase in DAergic neuronal activity produced by low concentrations of nicotine. In addition, nicotine failed to significantly activate VTA DAergic neurons in mice that did not express either α4 or α6 nAChR subunits. Conversely, selective activation of nAChRs containing the α4 subunit in knock-in mice expressing a hypersensitive version of these receptors yielded a biphasic response to nicotine consisting of an acute desensitizing increase in firing frequency followed by a sustained increase that lasted several minutes and was sensitive to α-conotoxin MII[H9A;L15A]. These data indicate that nicotine persistently activates VTA DAergic neurons via nAChRs containing α4 and α6 subunits.
尼古丁具有强化作用，因为它能激活大脑中边缘奖赏回路的腹侧被盖区（VTA）中的多巴胺能（DAergic）神经元。这种活性的增加可持续几分钟到一个小时，被认为是尼古丁依赖的一个关键组成部分。然而，吸烟者通常自行摄入的尼古丁浓度预计会在几秒钟内使高亲和力α4β2 神经元烟碱型乙酰胆碱受体（nAChRs）脱敏。因此，生理相关浓度的尼古丁如何持续激活 VTA DAergic 神经元尚不清楚。在这里，我们展示尼古丁可以直接且强烈地增加 VTA DAergic 神经元的放电频率几分钟。在小鼠中脑切片中，300 nM 尼古丁在 VTA DAergic 神经元中引起持续的内向电流，该电流被α-芋螺毒素 MII[H9A;L15A]阻断，这是一种含有α6 亚基的 nAChRs 的选择性拮抗剂。α-芋螺毒素 MII[H9A;L15A]也显著降低了由低浓度尼古丁产生的持久 DAergic 神经元活性增加。此外，在不表达α4 或α6 nAChR 亚基的小鼠中，尼古丁不能显著激活 VTA DAergic 神经元。相反，在表达这些受体超敏版本的敲入小鼠中选择性激活含有α4 亚基的 nAChRs，导致对尼古丁的双相反应，包括急性脱敏的放电频率增加，随后是持续几分钟的持续增加，对α-芋螺毒素 MII[H9A;L15A]敏感。这些数据表明，尼古丁通过含有α4 和α6 亚基的 nAChRs 持续激活 VTA DAergic 神经元。
