cAMP-mediated upregulation of HCN channels in VTA dopamine neurons promotes cocaine reinforcement.
cAMP-mediated upregulation of HCN channels in VTA dopamine neurons promotes cocaine reinforcement.
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DOI：
10.1038/s41380-023-02290-x
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发表时间：
2023-09
影响因子：
11
通讯作者：
Liu, Qing-song
中科院分区：
文献类型：
--
作者：
Mu, Lianwei;Liu, Xiaojie;Yu, Hao;Vickstrom, Casey R.;Friedman, Vladislav;Kelly, Thomas J.;Hu, Ying;Su, Wantang;Liu, Shuai;Mantsch, John R.;Liu, Qing-song
慢性可卡因暴露诱导持久的神经适应，促进有动机的吸毒。超极化激活的环核苷酸门控（HCN）通道被认为可以调节腹侧被盖区（VTA）多巴胺神经元的放电和起搏活动。然而，可卡因自我给药是否影响HCN通道功能以及HCN通道活性是否调节有动机的药物服用仍然是未知的。我们报告，大鼠腹侧被盖区多巴胺神经元主要表达Hcn3 - 4 mRNA，而腹侧被盖区GABA神经元表达Hcn1 - 4 mRNA。这两种神经元类型显示类似的超极化激活电流（Ih），这是促进急性增加cAMP。急性可卡因应用减少电压依赖性激活Ih在腹侧被盖区多巴胺神经元，但不是在GABA神经元。出乎意料的是，慢性可卡因自我管理的结果在增强Ih选择性腹侧被盖区多巴胺神经元。Ih电流的这种差异调节可能是由D2自身受体诱导的cAMP减少介导的，因为D2（Drd2）mRNA主要在多巴胺神经元中表达，而D1（Drd1）mRNA在VTA中几乎检测不到。此外，通过Gi-DREADD刺激慢性降低cAMP导致腹侧被盖区多巴胺神经元中Ih增加，并增强HCN 3/HCN 4与含有tetratricopeptide重复序列的Rab8b相互作用蛋白（TRIP8b）的结合，TRIP8b是一种辅助亚基，已知可促进HCN通道表面转运。最后，我们表明，HCN阻滞剂伊伐布雷定的全身注射和VTA内输注减少了递增比例方案下的可卡因自我给药，并使可卡因剂量-反应曲线下移。我们的研究结果表明，可卡因自我管理诱导上调Ih腹侧被盖区多巴胺神经元，而HCN抑制减少可卡因摄入的动机。
Chronic cocaine exposure induces enduring neuroadaptations that facilitate motivated drug taking. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are known to modulate neuronal firing and pacemaker activity in ventral tegmental area (VTA) dopamine neurons. However, it remained unknown whether cocaine self-administration affects HCN channel function and whether HCN channel activity modulates motivated drug taking. We report that rat VTA dopamine neurons predominantly express Hcn3-4 mRNA, while VTA GABA neurons express Hcn1–4 mRNA. Both neuronal types display similar hyperpolarization-activated currents (Ih), which are facilitated by acute increases in cAMP. Acute cocaine application decreases voltage-dependent activation of Ih in VTA dopamine neurons, but not in GABA neurons. Unexpectedly, chronic cocaine self-administration results in enhanced Ih selectively in VTA dopamine neurons. This differential modulation of Ih currents is likely mediated by a D2 autoreceptor-induced decrease in cAMP as D2 (Drd2) mRNA is predominantly expressed in dopamine neurons, whereas D1 (Drd1) mRNA is barely detectable in the VTA. Moreover, chronically decreased cAMP via Gi-DREADD stimulation leads to an increase in Ih in VTA dopamine neurons and enhanced binding of HCN3/HCN4 with tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b), an auxiliary subunit that is known to facilitate HCN channel surface trafficking. Finally, we show that systemic injection and intra-VTA infusion of the HCN blocker ivabradine reduces cocaine self-administration under a progressive ratio schedule and produces a downward shift of the cocaine dose-response curve. Our results suggest that cocaine self-administration induces an upregulation of Ih in VTA dopamine neurons, while HCN inhibition reduces the motivation for cocaine intake.
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DOI：
10.1126/science.1249240
发表时间：
2014-04-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Friedman AK;Walsh JJ;Juarez B;Ku SM;Chaudhury D;Wang J;Li X;Dietz DM;Pan N;Vialou VF;Neve RL;Yue Z;Han MH
通讯作者：
Han MH
影响因子：
1.6
作者：
Felker, GM;Hu, WM;Kasper, EK
通讯作者：
Kasper, EK
影响因子：
16.2
作者：
Lammel, Stephan;Hetzel, Andrea;Roeper, Jochen
通讯作者：
Roeper, Jochen
影响因子：
5.3
作者：
Ford, CP;Mark, GP;Williams, JT
通讯作者：
Williams, JT
影响因子：
5.6
作者：
通讯作者：
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