Haloperidol-induced catalepsy is absent in dopamine D2 but maintained in dopamine D3 receptor knock-out mice
Haloperidol-induced catalepsy is absent in dopamine D2 but maintained in dopamine D3 receptor knock-out mice
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DOI：
10.1016/s0014-2999(99)00916-4
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发表时间：
2000-03-10
影响因子：
5
通讯作者：
Perrault, G
中科院分区：
文献类型：
--
作者：
Boulay, D;Depoortere, R;Perrault, G
在本研究中，我们先前发现，多巴胺D-2受体基因缺失的纯合子小鼠（D-2（-/-）小鼠）在“条形试验”中测试时不会出现自发性猝倒。我们试图分析D-2受体突变小鼠对多巴胺D-2样或d -1样受体拮抗剂的催化作用的反应性。同时，我们评估了这些拮抗剂在多巴胺D-3受体突变小鼠中的催化作用。D-2（-/-）小鼠对多巴胺D-2样受体拮抗剂氟哌啶醇（0.125-2 mg/kg i.p）的猝厥作用完全没有反应，而D-2（-/-）小鼠在氟哌啶醇最高剂量下的猝厥水平约为野生型对照的一半。氟哌啶醇诱导的猝睡程度与纹状体多巴胺D-2受体的表达水平成正比(在0.25 nM [H-3]spiperone下，D-2(+)/（+)、D-2（+/-）和D-2（-/-）小鼠的蛋白水平分别为0.50、0.30和0.08 pmol/mg）。然而，D-2（-/-）和D-2（+/-）小鼠与野生型小鼠一样，对多巴胺d- 1样受体拮抗剂R-(+)-7-氯-8-羟基-3-甲基-1-苯基-2,3,4,5-四氢-1 H-3-benzazepine hydrochloride （SCH 23390）的催化作用敏感。0.03-0.6 mg/kg s.c)。纹状体多巴胺D受体表达（通过[H-3]SCH 23390结合测定）不受基因型的显著影响。SCH 23390在D-2（-/-）小鼠中诱导猝睡的能力表明，它们对氟哌啶醇诱导的猝睡的抵抗是由于缺乏多巴胺D-2受体，而不是由于纹状体突触可塑性异常，而其他研究表明纹状体突触可塑性异常发生在这些小鼠中。多巴胺D-2和多巴胺D-1受体在D-3（+/+）、D-3（+/-）和D-3（-/-）小鼠中的表达基本相同，多巴胺D-3受体纯合子和杂合子突变小鼠在给予氟哌啶醇（0.5-2 mg/kg i.p）或SCH 23390 （0.03-0.6 mg/kg s.c）后处于痉挛位置的时间总体上与对照组没有差异。同时，多巴胺D-3受体突变小鼠在同时给予阈下剂量的氟哌啶醇（0.125 mg/kg）和SCH 23390 （0.03 mg/kg）时，其反应并不比野生型小鼠更敏感，这表明多巴胺D-3受体敲除小鼠对该模型中多巴胺D-2和多巴胺D-1受体同时阻断的协同效应并不比野生型小鼠更敏感。这些结果表明，多巴胺D-3受体亚型是氟哌啶醇产生猝睡所必需的，多巴胺D-3受体亚型似乎对多巴胺产生的猝睡没有可观察到的控制。
We have previously found that mice homozygous for the deletion of the dopamine D-2 receptor gene (D-2(-/-) mice) do not present spontaneous catalepsy when tested in a "bar test'', in the present study. we sought to analyse the reactivity of D-2 receptor mutant mice to the cataleptogenic effects of dopamine D-2-like or D-1-like receptor antagonists. in parallel, we assessed the cataleptogenic effects of these antagonists in dopamine D-3 receptor mutant mice. D-2(-/-) mice were totally unresponsive to the cataleptogenic effects of the dopamine D-2-like receptor antagonist haloperidol (0.125-2 mg/kg i.p.), while D-2(-/-) mice, at the highest haloperidol doses tested, showed a level of catalepsy about half that of wild-type controls. The degree of haloperidol-induced catalepsy was thus proportional to the level of striatal dopamine D-2 receptor expression (0.50, 0.30 and 0.08 pmol/mg protein as measured at 0.25 nM [H-3]spiperone for D-2(+)/(+), D-2(+/-) and D-2(-/-) mice, respectively). However, D-2(-/-) and D-2(+/-) mice were as sensitive as their wild-type counterparts to the cataleptogenic effects of the dopamine D-1-like receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine hydrochloride (SCH 23390. 0.03-0.6 mg/kg s.c.). Striatal dopamine D, receptor expression (as measured using [H-3]SCH 23390 binding) was not significantly affected by the genotype. Tne ability of SCH 23390 to induce catalepsy in D-2(-/-) mice suggests that their resistance to haloperidol-induced catalepsy is due to the absence of dopamine D-2 receptors, and not to the abnormal striatal synaptic plasticity that has been shown by others to occur in these mice. In agreement with the observation that dopamine D-2 and dopamine D-1 receptor expression was essentially identical in D-3(+/+), D-3(+/-) and D-3(-/-) mice, dopamine D-3 receptor homozygous and heterozygous mutant mice, on the whole, did not differ from their controls in the time spent in a cataleptic position following administration of either haloperidol (0.5-2 mg/kg i.p.) or SCH 23390 (0.03-0.6 mg/kg s.c.). Also, dopamine D-3 receptor mutant mice were no more responsive than wild-type controls when co-administered subthreshold doses of haloperidol (0.125 mg/kg) and SCH 23390 (0.03 mg/kg), suggesting that dopamine D-3 receptor knock-out mice are not more sensitive than wild-types to the synergistic effects of concurrent blockade of dopamine D-2 and dopamine D-1 receptors in this model. These results suggest that the dopamine D-3 receptor subtype is necessary for haloperidol to produce catalepsy, and that the dopamine D-3 receptor subtype appears to exert no observable control over the catalepsy produced by dopamine.