Fuxe K, Fredholm B B, Agnati L F, Corrodi H
Brain Res. 1978 May 12;146(2):295-311. doi: 10.1016/0006-8993(78)90975-7.
The actions of a new type of ergolene derivative, MPME ((5R, 8R)-8-(4-p-methoxyphenyl-1-piperazinyl methyl)-6-methylergolene), have been evaluated on central catecholamine (CA) neurons in the rat by means of a combined biochemical, histochemical and behavioural analysis. The evidence suggests that this ergolene derivative is a preferential agonist at subcortical limbic dopamine (DA) receptors and at DA receptors belonging to the neostriatal DA islands. (1) MPME does not change the DA and noradrenaline (NA) levels 4 h after the injection in doses ranging from 0.1 to 5 mg/kg. MPME significantly reduced DA turnover in doses from 0.5 to 5 mg/kg, whereas the NA turnover was increased in the same dose range. (2) Histochemically, using quantitative microfluorometry, DA levels were unchanged, except in the islands of the nucleus caudatus following administration of MPME. The drug selectively reduced DA turnover in the subcortical limbic regions (tuberculum olfactorium and nucleus accumbens) and in the DA terminal islands of the nucleus caudatus in doses of 1-5 mg/kg, whereas the large diffuse DA terminal systems of the nucleus caudatus were unaffected. Using this ergolene derivative the islandic small neostriatal DA system can be excellently demonstrated also in the adult rat. The effects of MPME on DA turnover, are blocked by haloperiodol but not by methergoline (which blocks 5-HT receptors). (3) Studies on uptake of tritiated DA in the nucleus caudatus and tuberculum olfactorium reveal a weak inhibition of DA uptake and retention only in high concentrations (10(-5)-10(-6) M). Such actions therefore can probably not explain the changes in DA turnover observed. (4) Behavioural effects of MPME were evaluated in the rotometer model of Ungerstedt25. This model will reveal actions on supersensitive striatal DA receptors. MPME was found to mimic the action of apomorphine and cause a prolonged rotational behaviour towards the nonoperated side in doses of 0.25-0.5 mg/kg. A marked potentiation of the action of MPME was obtained by means of pretreatment with phosphodiesterase inhibitors suggesting that the effect of MPME might be mediated by cyclic AMP. Studies with the DA receptor blocking agent pimozide indicated a high affinity of MPME for the supersensitive striatal DA receptors, since only very high doses of pimozide (15 mg/kg) were capable of blocking the actions of MPME. (5) Studies on the effect of MPME on DA sensitive adenylate cyclase in the nucleus caudatus and the subcortical limbic system (mainly tuberculum olfactorium and nucleus accumbens) suggested that MPME is a partial DA receptor agonist with different intrinsic activity on the DA receptors of the subcortical limbic system and of the nucleus caudatus, the effects in the subcortical limbic system being considerably larger than in the nucleus caudatus. Thus, the present paper gives evidence that the various DA receptor populations in the brain are sufficiently different to allow their preferential activation by drugs.
通过生物化学、组织化学和行为学相结合的分析方法，对一种新型麦角灵衍生物MPME（(5R, 8R)-8-(4-对甲氧基苯基-1-哌嗪基甲基)-6-甲基麦角灵）作用于大鼠中枢儿茶酚胺（CA）神经元的情况进行了评估。有证据表明，这种麦角灵衍生物是皮质下边缘多巴胺（DA）受体以及属于新纹状体DA岛的DA受体的优先激动剂。（1）注射剂量为0.1至5mg/kg后4小时，MPME不会改变DA和去甲肾上腺素（NA）的水平。MPME剂量为0.5至5mg/kg时可显著降低DA周转率，而在相同剂量范围内NA周转率会升高。（2）组织化学方面，采用定量显微荧光测定法，除了给予MPME后尾状核岛外，DA水平未发生变化。该药物在剂量为1 - 5mg/kg时可选择性降低皮质下边缘区域（嗅觉结节和伏隔核）以及尾状核DA终末岛中的DA周转率，而尾状核中大量弥散的DA终末系统未受影响。使用这种麦角灵衍生物，在成年大鼠中也能很好地显示出岛状小新纹状体DA系统。MPME对DA周转率的影响可被氟哌啶醇阻断，但不能被美西麦角（阻断5 - HT受体）阻断。（3）对尾状核和嗅觉结节中氚标记DA摄取的研究表明，只有在高浓度（10⁻⁵ - 10⁻⁶M）时才对DA摄取和保留有微弱抑制作用。因此，此类作用可能无法解释所观察到的DA周转率变化。（4）在Ungerstedt25的旋转试验模型中评估了MPME的行为学效应。该模型可揭示对超敏纹状体DA受体的作用。发现MPME在剂量为0.25 - 0.5mg/kg时可模拟阿扑吗啡的作用，并导致向未手术侧的长时间旋转行为。通过用磷酸二酯酶抑制剂预处理可显著增强MPME的作用，提示MPME的作用可能由环磷酸腺苷介导。使用DA受体阻断剂匹莫齐特的研究表明，MPME对超敏纹状体DA受体具有高亲和力，因为只有非常高剂量的匹莫齐特（15mg/kg）才能阻断MPME的作用。（5）对MPME对尾状核和皮质下边缘系统（主要是嗅觉结节和伏隔核）中DA敏感腺苷酸环化酶影响的研究表明，MPME是一种部分DA受体激动剂，对皮质下边缘系统和尾状核的DA受体具有不同的内在活性，在皮质下边缘系统中的作用明显大于在尾状核中的作用。因此，本文提供的证据表明，大脑中不同的DA受体群体差异足够大，使得药物能够优先激活它们。
