α2-肾上腺素能受体的体内外表征方法

A. L. Hudson, E. S. J. Robinson, M. D. Lalies, R. J. Tyacke, H. C. Jackson, D. J. Nutt
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引用次数: 28

摘要

为了更充分地了解α2肾上腺素能受体在脑功能中的作用,我们采用了放射配体结合、放射自显影、脑微透析和反义寡核苷酸等体外和体内结合技术。2结合研究表明,选择性α2-肾上腺素能受体拮抗剂RX821002(甲氧基-咪唑嗪)的tritriated形式在大鼠脑膜上具有高亲和力(1 nM)的单一位点,而吡唑嗪具有低亲和力(1107 nM)。对兔脑膜的类似研究发现,吡唑嗪和羟甲唑啉能够置换。[3H]-RX821002呈双相表达,表明存在α2-肾上腺素受体亚型。3受体放射自显影显示[3H]- rx821002结合在大鼠脑内的分布与所有% a2 -肾上腺素能受体亚型α2A/D-、α2B和α2C的标记一致。在大鼠中,体内脑透析实验表明,外周给药RX821002提高了额叶皮质的基础去甲肾上腺素,尽管程度较小,但也提高了腹侧海马的基础去甲肾上腺素。RX821002也能提高纹状体的细胞外多巴胺。5 . 7天静脉滴注一种靶向α2A/ d肾上腺素能受体的反义寡核苷酸,可显著降低[3H]-RX821002在特定脑区结合的放射自显影密度,尤其是中隔外侧核和下丘脑前部区。我们小组几年来的研究扩展了我们对α2肾上腺素能受体的药理学和功能的认识,并提供了该受体在控制单胺转换中的作用的证据。成功利用反义技术敲低α2A/D亚型的表达为未来探索该受体亚型的生理学提供了机会。
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In vitro and in vivo approaches to the characterization of the α2-adrenoceptor

1 In order to more fully understand the role of the α2-adrenoceptor in brain function, a combination of in vitro and in vivo techniques were utilized including radioligand binding, autoradiography, brain microdialysis and antisense oligonucleotides.

2 Binding studies showed the tritiated form of the selective α2-adrenoceptor antagonist, RX821002 (methoxy-idazoxan) labelled an apparent single population of sites in rat brain membranes with high affinity (1 nM), for which prazosin had low affinity (1107 nM). Similar studies in rabbit brain membranes found that prazosin and oxymetazoline were able to displace. [3H]-RX821002 in a biphasic manner indicating the presence of subtypes of α2-adrenoceptors.

3 Receptor autoradiography revealed a distribution of [3H]-RX821002 binding in rat brain consistent with the labelling of all %aL2-adrenoceptor subtypes, namely α2A/D-, α2B and α2C.

4 In rat, in vivo brain dialysis experiments demonstrated peripherally administered RX821002 elevated basal noradrenaline in frontal cortex and also, although to a lesser extent, in ventral hippocampus. RX821002 was also able to elevate extracellular dopamine in the striatum.

5 A 7-day i.c.v. infusion of an antisense oligonucleotide targeting the α2A/D-adrenoceptor, resulted in a significant reduction in the autoradiographic density of [3H]-RX821002 binding in specific brain areas, notably the lateral septal nuclei and anterior hypothalamic area.

6 Several years of research by our group has extended our knowledge of the pharmacology and function of the α2-adrenoceptor and has provided evidence of the roles of this receptor in the control of monoamine turnover. The successful use of antisense technology to knockdown expression of the α2A/D subtype provides future opportunities to explore the physiology of this receptor subtype.

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