促甲状腺激素释放激素（TRH）及其类似物DN-1417对大鼠伏隔核和纹状体中多巴胺释放的一种可能作用机制。

A possible mechanism of action of thyrotropin-releasing hormone (TRH) and its analog DN-1417 on the release of dopamine from the nucleus accumbens and striatum in rats.

作者信息

Narumi S, Nagai Y, Saji Y, Nagawa Y

出版信息

Jpn J Pharmacol. 1985 Dec;39(4):425-35. doi: 10.1254/jjp.39.425.

DOI:10.1254/jjp.39.425

Abstract

Slices of the nucleus accumbens, the terminus of the mesolimbic dopaminergic system and the striatum, the terminus of the nigrostriatal dopaminergic system obtained from rats, were used for analyzing the dopamine releasing effects of TRH and its analog DN-1417 (gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate). (1) Dopamine release: The addition of DN-1417 (5 X 10(-5) M) or TRH (5 X 10(-4) M) stimulated the release of prelabelled [3H]-dopamine (DA) from the superfused nucleus accumbens slices, and 100 or 20 times higher concentrations of each compound stimulated DA release from the striatal slices. The omission of Ca2+ from the superfusion medium or the addition of ouabain (5 X 10(-3) M), a (Na+ + K+) stimulated adenosine triphosphate (ATP) phosphohydrolase [(Na+ + K+)-ATPase] inhibitor, almost completely abolished the DN-1417- or TRH-induced DA releasing effect. (2) 45Ca2+ uptake: The addition of DN-1417 (10(-4) M) or TRH (10(-4) M) stimulated 45Ca2+ uptake into the nucleus accumbens slices in a time-dependent manner from 1 to 5 min at 30 degrees C. On the other hand, both drugs (10(-4) M) had no effect on 45Ca2+ uptake into the striatal slices. A Ca2+ ionophore, A-23187 (10(-6) M), stimulated 45Ca2+ uptake into slices of the nucleus accumbens and striatum. Ouabain abolished the DN-1417-, TRH- and A-23187-induced effects. (3) Cyclic AMP formation: The addition of DN-1417 (10(-4) M) or TRH (10(-4) and 10(-3) M) accelerated cyclic AMP formation in the nucleus accumbens, but not in the striatal slices. A Ca2+ antagonist, methoxyverapamil (D-600, 10(-6) M) almost completely abolished the DN-1417- and TRH-effects. (4) (Na+ + K+)-ATPase activity: The addition of DN-1417 (10(-5) and 10(-4) M) or TRH (10(-4) M) activated (Na+ + K+)-ATPase in the P1 fraction (cell debris, nuclei) of the nucleus accumbens, but had little effect on the same activity in the striatum. (5) [3H]-TRH binding: The addition of 10(-6) to 10(-4) M of DN-1417 and TRH inhibited concentration-dependently [3H]-TRH binding in the nucleus accumbens and striatal slices. Ouabain (5 X 10(-3) M) almost completely abolished [3H]-TRH binding in both types of slices.(ABSTRACT TRUNCATED AT 400 WORDS)

摘要

取大鼠脑伏隔核切片（中脑边缘多巴胺能系统的终末部分）和纹状体切片（黑质纹状体多巴胺能系统的终末部分），用于分析促甲状腺激素释放激素（TRH）及其类似物DN - 1417（γ - 丁内酯 - γ - 羰基 - L - 组氨酰 - L - 脯氨酰胺柠檬酸盐）的多巴胺释放效应。（1）多巴胺释放：加入DN - 1417（5×10⁻⁵M）或TRH（5×10⁻⁴M）可刺激预标记的[³H] - 多巴胺（DA）从灌流的伏隔核切片中释放，而每种化合物浓度提高100倍或20倍时可刺激纹状体切片释放DA。灌流液中去除Ca²⁺或加入哇巴因（5×10⁻³M），一种（Na⁺ + K⁺）刺激的三磷酸腺苷（ATP）磷酸水解酶[（Na⁺ + K⁺）-ATP酶]抑制剂，几乎完全消除了DN - 1417或TRH诱导的DA释放效应。（2）⁴⁵Ca²⁺摄取：加入DN - 1417（10⁻⁴M）或TRH（10⁻⁴M）在30℃下1至5分钟内以时间依赖性方式刺激⁴⁵Ca²⁺摄取到伏隔核切片中。另一方面，两种药物（10⁻⁴M）对纹状体切片的⁴⁵Ca²⁺摄取无影响。钙离子载体A - 23187（10⁻⁶M）刺激⁴⁵Ca²⁺摄取到伏隔核和纹状体切片中。哇巴因消除了DN - 1417、TRH和A - 23187诱导的效应。（3）环磷酸腺苷（cAMP）生成：加入DN - 1417（10⁻⁴M）或TRH（10⁻⁴和10⁻³M）可加速伏隔核中cAMP生成，但对纹状体切片无此作用。钙离子拮抗剂甲氧基维拉帕米（D - 600，10⁻⁶M）几乎完全消除了DN - 1417和TRH的作用。（4）（Na⁺ + K⁺）-ATP酶活性：加入DN - 1417（10⁻⁵和10⁻⁴M）或TRH（10⁻⁴M）可激活伏隔核P1组分（细胞碎片、细胞核）中的（Na⁺ + K⁺）-ATP酶，但对纹状体中相同活性影响很小。（5）[³H] - TRH结合：加入10⁻⁶至10⁻⁴M的DN - 1417和TRH浓度依赖性地抑制[³H] - TRH在伏隔核和纹状体切片中的结合。哇巴因（5×10⁻³M）几乎完全消除了两种类型切片中的[³H] - TRH结合。（摘要截断于400字）