Involvement of cannabinoid receptors in the regulation of neurotransmitter release in the rodent striatum:: A combined immunochemical and pharmacological analysis
Involvement of cannabinoid receptors in the regulation of neurotransmitter release in the rodent striatum:: A combined immunochemical and pharmacological analysis
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DOI：
10.1523/jneurosci.4232-04.2005
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发表时间：
2005-03-16
影响因子：
5.3
通讯作者：
Sperlágh, B
中科院分区：
文献类型：
--
作者：
Köfalvi, A;Rodrigues, RJ;Sperlágh, B
尽管大麻素对运动功能有深远的影响，以及它们在帕金森病和亨廷顿病中的治疗潜力，但纹状体CB 1受体的细胞和亚细胞分布还没有很好地确定。在这里，我们发现，CB 1受体主要位于GABA能（囊泡GABA转运蛋白阳性）和谷氨酸能[囊泡谷氨酸转运蛋白-1（VGLUT-1）-和VGLUT-2-阳性]纹状体神经末梢，并存在于突触前活动区，在突触后密度，以及在突触外膜。非选择性激动剂WIN 55212 -2 [（R）-（+）-[2，3-二氢-5-甲基-3-[（4-吗啉基）甲基]吡咯并[1，2，3-de]-1，4-苯并恶嗪基]-（1-萘基）甲酮甲磺酸盐]（EC 50，32 nM）和CB 1选择性激动剂ACEA [N-（2-chloroethyl）-5Z，8 Z，11 Z，14 Z-二十碳四烯酰胺]抑制大鼠纹状体脑片[H-3] GABA的释放。这些激动剂的作用被CB 1选择性拮抗剂SR 141716 A [N-（哌啶-1-基）-5-（4-氯苯基）-1-（2，4-二氯苯基）-4-甲基-1-H-吡唑-3-甲酰胺]（1 μ M）和AM 251 [1- 2，4-二氯苯基-5-（4-碘苯基）-4-甲基-N-1-哌啶基-1-H-吡唑-3-甲酰胺三氟乙酸盐]（1 μ M），表明大麻素通过激活突触前CB 1受体抑制GABA的释放。大麻素通过CB 1和非CB 1机制调节谷氨酸释放。大麻素激动剂和拮抗剂抑制25 mM K+诱发的[H-3]谷氨酸释放和钠依赖性[H-3]谷氨酸摄取。由于低浓度的SR 141716 A部分和AM 251完全阻止了WIN 55212 -2和CP 55940 [5-（1，1-二甲基庚基）-2-[5-羟基-2-（3-羟丙基）环己基]苯酚]的作用，因此提示CB 1受体部分参与。然而，CB 1激动剂和拮抗剂的影响持续在CB 1基因敲除小鼠，表明非CB 1，CB 1样受体的参与。相反，大麻素不调节[H-3]多巴胺释放或[H-3]多巴胺和[H-3] GABA摄取。我们的研究结果表明，不同的调制纹状体GABA能和cannabinoids的传输，并将促进大麻素系统在正常和病理运动功能的作用和重要性的理解。
Despite the profound effect of cannabinoids on motor function, and their therapeutic potential in Parkinson's and Huntington's diseases, the cellular and subcellular distributions of striatal CB1 receptors are not well defined. Here, we show that CB1 receptors are primarily located on GABAergic (vesicular GABA transporter-positive) and glutamatergic [vesicular glutamate transporter-1 (VGLUT-1)- and VGLUT-2-positive] striatal nerve terminals and are present in the presynaptic active zone, in the postsynaptic density, as well as in the extrasynaptic membrane. Both the nonselective agonist WIN55212-2 [(R)-(+)-[2,3-dihydro-5-methyl-3[(4-morpholinyl) methyl] pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate salt] (EC50, 32nM) and the CB1-selective agonist ACEA [N-(2-chloroethyl)-5Z, 8Z, 11Z, 14Z-eicosatetraenamide] inhibited [H-3] GABA release from rat striatal slices. The effect of these agonists was prevented by the CB1-selective antagonists SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1-Hpyrazole3- carboxamide] (1 mu M) and AM251 [1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1-H-pyrazole-3carboxamide trifluoroacetate salt] (1 mu M), indicating that cannabinoids inhibit the release of GABA via activation of presynaptic CB1 receptors. Cannabinoids modulated glutamate release via both CB1 and non-CB1 mechanisms. Cannabinoid agonists and antagonists inhibited 25mM K+-evoked [H-3] glutamate release and sodium-dependent [H-3] glutamate uptake. Partial involvement of CB1 receptors is suggested because low concentrations of SR141716A partly and AM251 fully prevented the effect of WIN55212-2 and CP55940 [5-(1,1-dimethylheptyl)- 2-[5-hydroxy-2-(3-hydroxypropyl) cyclohexyl] phenol]. However, the effect of CB1 agonists and antagonists persisted in CB1 knock-out mice, indicating the involvement of non-CB1, CB1-like receptors. In contrast, cannabinoids did not modulate [H-3] dopamine release or [H-3] dopamine and [H-3] GABA uptake. Our results indicate distinct modulation of striatal GABAergic and glutamatergic transmission by cannabinoids and will facilitate the understanding of the role and importance of the cannabinoid system in normal and pathological motor function.