Dopamine D3 receptor-preferring agonists increase dendrite arborization of mesencephalic dopaminergic neurons via extracellular signal-regulated kinase phosphorylation
Dopamine D3 receptor-preferring agonists increase dendrite arborization of mesencephalic dopaminergic neurons via extracellular signal-regulated kinase phosphorylation
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DOI：
10.1111/j.1460-9568.2008.06423.x
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发表时间：
2008-10-01
影响因子：
3.4
通讯作者：
Spano, PierFranco
中科院分区：
文献类型：
--
作者：
Collo, Ginetta;Zanetti, Silvia;Spano, PierFranco
多巴胺 D3 受体偏好激动剂对帕金森病的临床改善与其神经保护作用有关，最近又与其神经再生特性有关。然而，尚不清楚多巴胺激动剂是通过直接作用于中脑多巴胺能神经元表达的受体产生神经营养作用，还是通过释放神经营养因子间接作用于星形胶质细胞表达的受体产生神经营养作用。在这项研究中，我们研究了多巴胺 D3 受体偏好激动剂喹吡罗和 7-羟基-N,N-二丙基-2-氨基四氢化萘 (7-OH-DPAT) 以及间接激动剂安非他明对酪氨酸羟化酶免疫反应性 (TH-IR) 鉴定的多巴胺能神经元的影响。实验在从小鼠胚胎中脑制备的含有少于 0.5% 星形胶质细胞的神经元富集原代培养物上进行。孵育3天后，喹吡罗（1-10μm）和7-OH-DPAT（5-500nm）剂量依赖性地增加TH-IR阳性中脑神经元的最大树突长度（P<0.001）、初级树突数量（P<0.01）和[H-3]多巴胺摄取（P<0.01）。使用 10 μM 安非他明观察到类似的效果。所有神经营养作用均被非选择性 D2/D3 受体拮抗剂舒必利 (5 μM) 和低剂量 (50 nm) 选择性 D3 受体拮抗剂 SB-277011-A 阻断。 Quinpirole 和 7-OH-DPAT 还在几分钟内增加了细胞外信号调节激酶 (ERK) 的磷酸化，而用 SB-277011-A 预处理可阻断这种作用。 PD98059、GF109203 或 LY294002 抑制 D2/D3 受体信号通路至 ERK，从而阻断神经营养作用。这些数据表明，多巴胺激动剂通过对 D2/D3 受体的直接作用，优先涉及 D3 受体依赖性神经传递，增加中脑多巴胺能神经元的树突状树枝化。
Clinical improvements in Parkinson's disease produced by dopamine D3 receptor-preferring agonists have been related to their neuroprotective actions and, more recently, to their neuroregenerative properties. However, it is unclear whether dopamine agonists produce their neurotrophic effects by acting directly on receptors expressed by the mesencephalic dopaminergic neurons or indirectly on receptors expressed by astrocytes, via release of neurotrophic factors. In this study, we investigated the effects of the dopamine D3 receptor-preferring agonists quinpirole and 7-hydroxy- N,N-di-propyl-2-aminotetralin (7-OH-DPAT), as well as of the indirect agonist amphetamine, on dopaminergic neurons identified by tyrosine hydroxylase immunoreactivity (TH-IR). Experiments were performed on neuronal-enriched primary cultures containing less than 0.5% of astrocytes prepared from the mouse embryo mesencephalon. After 3 days of incubation, both quinpirole (1-10 mu m) and 7-OH-DPAT (5-500 nm) dose-dependently increased the maximal dendrite length (P < 0.001), number of primary dendrites (P < 0.01) and [H-3] dopamine uptake ( P < 0.01) of TH-IR-positive mesencephalic neurons. Similar effects were observed with 10 mu M amphetamine. All neurotrophic effects were blocked by the unselective D2/D3 receptor antagonist sulpiride (5 mu M) and by the selective D3 receptor antagonist SB-277011-A at a low dose (50 nm). Quinpirole and 7-OH-DPAT also increased the phosphorylation of extracellular signal-regulated kinase (ERK) within minutes, an effect blocked by pretreatment with SB-277011-A. Inhibition of the D2/D3 receptor signalling pathway to ERK was obtained with PD98059, GF109203 or LY294002, resulting in blockade of neurotrophic effects. These data suggest that dopamine agonists increase dendritic arborizations of mesencephalic dopaminergic neurons via a direct effect on D2/D3 receptors, preferentially involving D3 receptor-dependent neurotransmission.