Direct angiotensin II type 2 receptor stimulation decreases dopamine synthesis in the rat striatum

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• 作者：Birgit Mertens ; Patrick V ; erheyden ; Yvette Michotte ; Sophie Sarre
• 关键词：Renin angiotensin system ; Dopaminergic system ; Striatum ; AT₂ receptor agonist ; Tyrosine hydroxylase activity ; In vivo microdialysis
• 刊名：Neuropharmacology
• 出版年：2010
• 出版时间：June 2010
• 年：2010
• 卷：58
• 期：7
• 页码：1038-1044
• 全文大小：309 K

文摘

A relationship between the central renin angiotensin system and the dopaminergic system has been described in the striatum. However, the role of the angiotensin II type 2 (AT₂) receptor in this interaction has not yet been established. The present study examined the outcome of direct AT₂ receptor stimulation on dopamine (DA) release and synthesis by means of the recently developed nonpeptide AT₂ receptor agonist, compound 21 (C21). The effects of AT₂ receptor agonism on the release of DA and its major metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) and on the activity of tyrosine hydroxylase (TH), the rate-limiting enzyme in the catecholamine biosynthesis, were investigated using in vivo microdialysis. Local administration of C21 (0.1 and 1 μM) resulted in a decrease of the extracellular DOPAC levels, whereas extracellular DA concentrations remained unaltered, suggesting a reduced synthesis of DA. This effect was mediated by the AT₂ receptor since it could be blocked by the AT₂ receptor antagonist PD123319 (1 μM). A similar effect was observed after local striatal (10 nM) as well as systemic (0.3 and 3 mg/kg i.p.) administration of the AT₁ receptor antagonist, candesartan. TH activity as assessed by accumulation of extracellular levels of l-DOPA after inhibition of amino acid decarboxylase with NSD1015, was also reduced after local administration of C21 (0.1 and 1 μM) and candesartan (10 nM). Together, these data suggest that AT₁ and AT₂ receptors in the striatum exert an opposite effect on the modulation of DA synthesis rather than DA release.