Laboratory of Molecular Pharmacology, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University.
Biol Pharm Bull. 2021;44(5):724-731. doi: 10.1248/bpb.b21-00137.
Nicotine enhances attention, working memory and recognition. One of the brain regions associated with these effects of nicotine is the medial prefrontal cortex (mPFC). However, cellular mechanisms that induce the enhancing effects of nicotine remain unclear. To address this issue, we performed whole-cell patch-clamp recordings from mPFC layer 5 pyramidal neurons in slices of C57BL/6J mice. Shortly (approx. 2 min) after bath application of nicotine, the number of action potentials, which were elicited by depolarizing current injection, was increased, and this increase persisted for over 5 min. The effect of nicotine was blocked by the α4β2 nicotinic acetylcholine receptor (nAChR) antagonist dihydro-β-erythroidine, α7 nAChR antagonist methyllycaconitine, or intracellular perfusion with the Ca chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). Additionally, the voltage-dependent potassium 7 (Kv7) channel blocker, 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone dihydrochloride (XE-991), as well as nicotine, shortened the spike threshold latency and increased the spike numbers. By contrast, the Kv7 channel opener, retigabine reduced the number of firings, and the addition of nicotine did not increase the spike numbers. These results indicate that nicotine induces long-lasting enhancement of firing activity in mPFC layer 5 pyramidal neurons, which is mediated by the stimulation of the α4β2 and α7 nAChRs and subsequent increase in intracellular Ca levels followed by the suppression of the Kv7 channels. The novel effect of nicotine might underlie the nicotine-induced enhancement of attention, working memory and recognition.
尼古丁增强注意力、工作记忆和识别能力。与尼古丁这些作用相关的脑区之一是前额叶皮质中间区（mPFC）。然而，诱导尼古丁增强作用的细胞机制仍不清楚。为了解决这个问题，我们在 C57BL/6J 小鼠脑片的 mPFC 第 5 层锥体神经元上进行全细胞膜片钳记录。尼古丁经浴槽给药后不久（约 2 分钟），由去极化电流注入引发的动作电位数量增加，并且这种增加持续超过 5 分钟。尼古丁的作用被 α4β2 烟碱型乙酰胆碱受体（nAChR）拮抗剂二氢-β-石蒜碱、α7 nAChR 拮抗剂甲基-6-氯烟碱、或细胞内灌流 Ca 螯合剂 1,2-双(2-氨苯氧基)乙烷-N,N,N',N'-四乙酸（BAPTA）阻断。此外，电压依赖性钾 7 (Kv7) 通道阻滞剂 10,10-双(4-吡啶基甲基)-9(10H)-蒽酮二盐酸盐（XE-991）以及尼古丁缩短了尖峰阈值潜伏期并增加了尖峰数量。相比之下，Kv7 通道开放剂瑞替加滨减少了放电次数，并且添加尼古丁不会增加尖峰数量。这些结果表明，尼古丁通过刺激 α4β2 和 α7 nAChRs 并随后增加细胞内 Ca 水平，随后抑制 Kv7 通道，诱导 mPFC 第 5 层锥体神经元的长时程放电活动增强。尼古丁的这种新作用可能是尼古丁增强注意力、工作记忆和识别能力的基础。
