Serotonin reduces the hyperpolarization-activated current (Ih) in ventral tegmental area dopamine neurons: involvement of 5-HT2 receptors and protein kinase C.
Serotonin reduces the hyperpolarization-activated current (Ih) in ventral tegmental area dopamine neurons: involvement of 5-HT2 receptors and protein kinase C.
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DOI：
10.1152/jn.00281.2003
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发表时间：
2003-11
影响因子：
2.5
通讯作者：
Zhaoping Liu;E. Bunney;S. B. Appel;M. Brodie
中科院分区：
文献类型：
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作者：
Zhaoping Liu;E. Bunney;S. B. Appel;M. Brodie
腹侧被盖区（VTA）的多巴胺能神经元与药物滥用的奖励特性和精神分裂症的病因有关;这些神经元的5-羟色胺调制可能在这些现象中发挥作用。在大鼠脑切片的全细胞膜片记录被用来调查调制的超极化激活的阳离子电流Ih的5-羟色胺在这些神经元。5-羟色胺（50-500 μ M）以浓度依赖性方式降低Ih的振幅;这种作用在5-羟色胺长期洗脱后是可逆的。这种作用被5-HT 2激动剂α-甲基血清素（25 μ M）模拟，并被5-HT 2拮抗剂酮色林（25 μ M）逆转。5-羟色胺降低最大Ih电流和电导（在-130 mV下测量），并导致Ih激活的电压依赖性负移。通过细胞内给予非特异性蛋白激酶抑制剂H-7（75 μ M）和选择性蛋白激酶C抑制剂白屈菜红碱（25 μ M），可拮抗乌洛宁诱导的Ih振幅降低。蛋白激酶C激活剂佛波醇12，13二乙酸酯（PDA，2 μ M）降低Ih幅度;当PDA和5-羟色胺一起使用时，对Ih的影响小于相加。这些数据支持以下结论：5-羟色胺通过作用于5-羟色胺5-HT 2受体（其激活蛋白激酶C）降低多巴胺能腹侧被盖区神经元中的Ih。这种Ih的减少可能在生理学上是重要的，因为Ih的选择性抑制剂ZD 7288显著增加了多巴胺能VTA神经元放电率的多巴胺抑制，这是我们先前用5-羟色胺证明的效果。
Dopaminergic neurons of the ventral tegmental area (VTA) have been implicated in the rewarding properties of drugs of abuse and in the etiology of schizophrenia; serotonin modulation of these neurons may play a role in these phenomena. Whole cell patch-in-the-slice recording in rat brain slices was used to investigate modulation of the hyperpolarization-activated cationic current Ih by serotonin in these neurons. Serotonin (50-500 microM) reduced the amplitude of Ih in a concentration-dependent manner; this effect was reversible after prolonged washout of serotonin. This effect was mimicked by the 5-HT2 agonist alpha-methylserotonin (25 microM) and reversed by the 5-HT2 antagonist ketanserin (25 microM). Serotonin reduced the maximal Ih current and conductance (measured at -130 mV) and caused a negative shift in the voltage dependence of Ih activation. The serotonin-induced reduction in Ih amplitude was antagonized by intracellular administration of the nonspecific protein kinase inhibitor H-7 (75 microM) and the selective protein kinase C inhibitor chelerythrine (25 microM). The protein kinase C activator phorbol 12, 13 diacetate (PDA, 2 microM) reduced Ih amplitude; when PDA and serotonin were applied together, the effect on Ih was less than additive. These data support the conclusion that serotonin reduces Ih in dopaminergic VTA neurons by acting at serotonin 5-HT2 receptors, which activate protein kinase C. This reduction of Ih may be physiologically important, as the selective inhibitor of Ih, ZD7288, significantly increased dopamine inhibition of firing rate of dopaminergic VTA neurons, an effect that we previously demonstrated with serotonin.