Transcriptional Regulation of L-Type Calcium Channel Subtypes Cav1.2 and Cav1.3 by Nicotine and Their Potential Role in Nicotine Sensitization
Transcriptional Regulation of L-Type Calcium Channel Subtypes Cav1.2 and Cav1.3 by Nicotine and Their Potential Role in Nicotine Sensitization
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DOI：
10.1093/ntr/ntt274
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发表时间：
2014-06-01
影响因子：
4.7
通讯作者：
Hansson, Anita C.
中科院分区：
文献类型：
--
作者：
Bernardi, Rick E.;Uhrig, Stefanie;Hansson, Anita C.
脑中的L型钙通道（LTCC）活性由2种亚型Ca（v）1.2和Ca（v）1.3介导。采用定量原位杂交技术，我们检测了用尼古丁（0.175mg/kg）或生理盐水处理1或14天的小鼠前脑区Ca（v）1.2和Ca（v）1.3的表达水平，并在最后一次注射后24小时或7天处死。此外，我们用尼古丁处理小鼠14天，然后在7天的戒断期内每天两次给予非特异性LTCC拮抗剂硝苯地平，然后测试尼古丁致敏性以确定LTCC阻断对致敏性的影响。尼古丁处理14天和禁欲24小时后，Ca（v）1.2 mRNA在整个检查区域下调，而Ca（v）1.3 mRNA大部分恢复到对照值。禁欲7天后，观察到Ca（v）1.2转录物的强烈上调，而Ca（v）1.3 mRNA基本不受影响。在我们的致敏研究中，尼古丁戒断期间服用硝苯地平会损害随后的尼古丁致敏作用。我们的数据表明，Ca（v）1.2和Ca（v）1.3在尼古丁相关过程中的参与程度不同。Ca（v）1.3似乎主要在早期暴露于尼古丁期间参与。Ca（v）1.2似乎在慢性尼古丁和戒烟后发生的长期分子和行为变化中发挥作用。硝苯地平可能会抵消尼古丁诱导的LTCC活性的改变，损害尼古丁的敏感性。
L-type calcium channel (LTCC) activity in the brain is mediated by 2 subtypes, Ca(v)1.2 and Ca(v)1.3. The individual contributions of these LTCC subtypes to the long-term pharmacological and behavioral effects of nicotine are unknown.Using quantitative in situ hybridization, we examined expression levels of Ca(v)1.2 and Ca(v)1.3 in forebrain regions of mice treated with nicotine (0.175mg/kg) or saline for 1 or 14 days and sacrificed 24hr or 7 days following the last injection. Additionally, we treated mice with nicotine for 14 days and then administered the nonspecific LTCC antagonist nifedipine twice daily during a 7-day abstinence period prior to testing for nicotine sensitization to determine the effect of LTCC blockade on sensitization.Ca(v)1.2 mRNA was unaffected 24hr following a single nicotine exposure, whereas Ca(v)1.3 mRNA was upregulated in several brain regions. Following 14 days of nicotine treatment and 24hr of abstinence, Ca(v)1.2 mRNA was downregulated throughout the areas examined, whereas Ca(v)1.3 mRNA had mostly returned to control values. Following 7 days of abstinence, a strong upregulation of Ca(v)1.2 transcripts was observed, whereas Ca(v)1.3 mRNA was largely unaffected. In our sensitization study, nifedipine administered during nicotine abstinence impaired subsequent nicotine sensitization.Our data suggest a differential involvement of Ca(v)1.2 and Ca(v)1.3 in nicotine-related processes. Ca(v)1.3 seems to be involved primarily during early exposure to nicotine. Ca(v)1.2 appears to play a role in the long-term molecular and behavioral changes that occur following chronic nicotine and abstinence. Nifedipine may counteract those nicotine-induced alterations in LTCC activity to impair nicotine sensitization.