Reches A, Burke R E, Kuhn C M, Hassan M N, Jackson V R, Fahn S
J Pharmacol Exp Ther. 1983 Jun;225(3):515-21.
Tetrabenazine (TBZ) is used in the treatment of hyperkinetic movement disorders. Its effect is thought to be mediated by depletion of dopamine (DA) stores. We studied other possible mechanisms of action of this drug. TBZ decreased DA concentration in rat striatum and nucleus accumbens in a dose-dependent manner with an IC50 of approximately 1.2 mg.kg-1. Maximal depletion was obtained within 30 min with only partial recovery at 8 hr. TBZ induced (at 40 mg . kg-1) 5- to 8-fold increases in 3,4-dihydroxyphenylacetic acid and homovanillic acid concentrations in both brain regions. Unlike reserpine, TBZ completely abolished the apomorphine-induced inhibition of DA synthesis under conditions in which this effect is mediated by presynaptic DA receptors. Both TBZ (5 mg . kg-1) and reserpine (5 mg . kg-1) depleted, at 1 hr, striatal DA content by approximately 90%. However, TBZ, but not reserpine, significantly stimulated in vivo tyrosine hydroxylase activity. TBZ also inhibited [3H]spiperone binding in the striatum with Ki = 2.1 X 10(-6) M. In rats, with unilateral destruction of the nigrostriatal pathway with 6-hydroxydopamine, pretreatment with TBZ significantly reduced the number of rotations induced by apomorphine. Finally, in rats treated with either TBZ (5 mg . kg-1) or reserpine (5 mg . kg-1), prolactin levels significantly increased as compared to control values. TBZ, but not reserpine, blocked apomorphine inhibition of prolactin secretion. We conclude that, in addition to depleting monoamines, TBZ also blocks both presynaptic and postsynaptic DA receptors in rat brain.
丁苯那嗪（TBZ）用于治疗运动亢进性运动障碍。其作用被认为是通过耗尽多巴胺（DA）储存来介导的。我们研究了这种药物其他可能的作用机制。TBZ以剂量依赖性方式降低大鼠纹状体和伏隔核中的DA浓度，IC50约为1.2mg·kg-1。在30分钟内可获得最大耗竭，8小时时仅有部分恢复。TBZ（40mg·kg-1）使两个脑区的3,4-二羟基苯乙酸和高香草酸浓度增加5至8倍。与利血平不同，在由突触前DA受体介导这种作用的条件下，TBZ完全消除了阿扑吗啡诱导的DA合成抑制。TBZ（5mg·kg-1）和利血平（5mg·kg-1）在1小时时均使纹状体DA含量耗尽约90%。然而，TBZ而非利血平显著刺激体内酪氨酸羟化酶活性。TBZ还抑制纹状体中[3H]螺哌隆结合，Ki = 2.1×10(-6)M。在大鼠中，用6-羟基多巴胺单侧破坏黑质纹状体通路后，用TBZ预处理可显著减少阿扑吗啡诱导的旋转次数。最后，在用TBZ（5mg·kg-1）或利血平（5mg·kg-1）治疗的大鼠中，催乳素水平与对照值相比显著升高。TBZ而非利血平阻断了阿扑吗啡对催乳素分泌的抑制。我们得出结论，除了耗尽单胺外，TBZ还阻断大鼠脑中的突触前和突触后DA受体。
