Mechanisms involved in systemic nicotine-induced glutamatergic synaptic plasticity on dopamine neurons in the ventral tegmental area.
Mechanisms involved in systemic nicotine-induced glutamatergic synaptic plasticity on dopamine neurons in the ventral tegmental area.
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DOI：
10.1523/jneurosci.1943-10.2010
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发表时间：
2010-10-13
期刊：
影响因子：
--
通讯作者：
Wu J
中科院分区：
文献类型：
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作者：
Gao M;Jin Y;Yang K;Zhang D;Lukas RJ;Wu J
系统暴露于尼古丁可诱导腹侧被盖区（VTA）多巴胺（DA）神经元的谷氨酸能突触可塑性，但其机制尚不清楚。在这里，我们报告了单次、全身暴露于尼古丁（0.17 mg/kg游离碱）的大鼠，根据切片贴片记录，24小时后评估的AMPA介导的DA神经元电流相对于NMDA受体的比率（AMPA/NMDA比率）增加。AMPA/NMDA比值在尼古丁暴露后1小时内明显增加，并持续至少72小时（重复给药后8天）。这种作用不能通过全身注射α - 7- nachr选择性（甲基莱卡乌碱，MLA）或β2*- nachr选择性（甲胺胺，MEC）拮抗剂来阻止，但可以通过MLA和MEC共同注射来阻止。在nAChR α7或β2亚基敲除小鼠中，系统暴露于尼古丁仍会增加AMPA/NMDA比值。在大鼠中预注射NMDA受体拮抗剂（MK801），但DA受体拮抗剂（SCH23390加氟哌啶醇）和钙调磷酸酶抑制剂（环孢素）都不能阻止尼古丁诱导的AMPA/NMDA比值的增加。在系统暴露于尼古丁后，谷氨酸能（而不是gaba能）传递到大鼠VTA DA神经元输入增强。相应地，在体内使用细胞外单单位记录法测量尼古丁暴露24小时后的DA神经元放电明显更快，并且沉默的DA神经元向活跃的DA神经元转化。综上所述，这些研究结果表明，系统性尼古丁通过α7-或β2*- nachr增加突触前和突触后的谷氨酸能功能，从而启动谷氨酸能突触可塑性，这可能是尼古丁奖励和强化中重要的早期神经元适应。
Systemic exposure to nicotine induces glutamatergic synaptic plasticity on dopamine (DA) neurons in the ventral tegmental area (VTA), but mechanisms are largely unknown. Here, we report that single, systemic exposure in rats to nicotine (0.17 mg/kg free base) increases the ratio of DA neuronal currents mediated by AMPA relative to NMDA receptors (AMPA/NMDA ratio) assessed 24 hr later, based on slice patch recording. The AMPA/NMDA ratio increase is evident within 1 hr and lasts for at least 72 hr after nicotine exposure (and up to 8 days after repeated nicotine administration). This effect cannot be prevented by systemic injection of either α7-nAChR-selective (methyllycaconitine, MLA) or β2*-nAChR-selective (mecamylamine, MEC) antagonists but is prevented by co-injection of MLA and MEC. In either nAChR α7 or β2 subunit knock-out mice, systemic exposure to nicotine still increases the AMPA/NMDA ratio. Pre-injection in rats of a NMDA receptor antagonist (MK801), but neither DA receptor antagonists (SCH23390 plus haloperidol) nor a calcineurin inhibitor (cyclosporine), prevents the nicotine-induced increase in AMPA/NMDA ratio. After systemic exposure to nicotine, glutamatergic (but not GABAergic) transmission onto rat VTA DA neuronal inputs is enhanced. Correspondingly, DA neuronal firing measured 24 hr after nicotine exposure using extracellular single unit recording in vivo is significantly faster, and there is conversion of silent to active DA neurons. Collectively, these findings demonstrate that systemic nicotine acting via either α7- or β2*-nAChRs increases pre- and post-synaptic glutamatergic function, and consequently initiates glutamatergic synaptic plasticity, which may be an important, early neuronal adaptation in nicotine reward and reinforcement.