Svensson A, Carlsson M L, Carlsson A
Department of Pharmacology, University of Göteborg, Sweden.
J Neural Transm Gen Sect. 1995;101(1-3):127-48. doi: 10.1007/BF01271551.
Previous work, based on systemic drug administration, has shown that neurotransmitter interactions between dopaminergic, adrenergic, glutamatergic and cholinergic systems are involved in locomotor control in mice. In an attempt to identify the target sites in the brain of these interactions, we have started a series of experiments, where the drugs are administered intracerebrally in mice. The locomotor threshold doses of the competitive NMDA antagonist AP-5 and the noncompetitive NMDA antagonist MK-801 were investigated by means of local application in the accumbens nucleus of monoamine-depleted and monoaminergically intact mice, respectively. The threshold dose of AP-5 was lower in depleted than in intact animals, whereas the threshold dose of MK-801 was lower in monoaminergically intact than monoamine-depleted mice. The locomotor effects of AP-5 and the AMPA-kainate receptor antagonist CNQX were registered in monamine-depleted mice after local application in the accumbens or entopeduncular nucleus (= medial pallidum). Both AP-5 and CNQX stimulated locomotor activity in the accumbens, but had no effects in the entopeduncular nucleus. We have previously shown synergistic interactions with regard to locomotor stimulation in monoamine-depleted mice, between an NMDA antagonist and an alpha 2-adrenoceptor agonist or a dopamine D1 agonist (all drugs given systemically). In the present study the alpha 2-adrenoceptor agonist alpha-methylnoradrenaline was applied intracerebrally in combination with a subthreshold dose of MK-801 given intraperitoneally: Locomotor stimulation was produced after alpha-methyl-noradrenaline injection into the accumbens nucleus, but not after injection into the dorsal striatum, prefrontal cortex or thalamus. Likewise, local application of the D1 agonist SKF 38393, in combination with a subthreshold dose of MK-801 given intraperitoneally, point to an important role of the accumbens nucleus in motor control. Previous experiments based on systemic drug administration have also shown a synergistic interaction between a muscarine antagonist and an alpha 2-adrenoceptor agonist in monoamine-depleted mice. Local application of the muscarine antagonist methscopolamine, in combination with the alpha 2-adrenoceptor agonist clonidine given intraperitoneally, showed that the striatum, in this case both the ventral and dorsal parts of the striatum, is an important target for the muscarine antagonist. Unilateral injection of AP-5 into the accumbens nucleus of mice induces rotational behaviour: Previous findings have shown that the rotation is ipsilateral in monoaminergically intact animals, whereas monoamine-depleted animals rotate contralaterally. In addition, these findings have shown that dopamine D2 receptor stimulation seems to determine whether AP-5 will induce ipsilateral or contralateral rotation. In the present study we report further evidence for a crucial role of the D2 receptor in this respect. Finally, the rotational effects of AP-5 injected into the dorsal striatum or hippocampus were investigated: As after AP-5 application into the accumbens nucleus, monoaminergically intact mice rotated ipsilaterally, whereas monoamine-depleted animals rotated contralaterally, following AP-5 application in the dorsal striatum or the hippocampus. The present data show that the accumbens nucleus has an important role in motor control. Both glutamatergic, muscarine cholinergic, dopaminergic and alpha-adrenergic systems are involved in the control of motor functions in the accumbens nucleus.
以往基于全身给药的研究表明，多巴胺能、肾上腺素能、谷氨酸能和胆碱能系统之间的神经递质相互作用参与了小鼠的运动控制。为了确定大脑中这些相互作用的靶点，我们开展了一系列实验，将药物脑内注射到小鼠体内。分别通过在单胺耗竭和单胺能正常的小鼠伏隔核局部应用，研究了竞争性NMDA拮抗剂AP - 5和非竞争性NMDA拮抗剂MK - 801的运动阈值剂量。AP - 5在耗竭小鼠中的阈值剂量低于正常动物，而MK - 801在单胺能正常小鼠中的阈值剂量低于单胺耗竭小鼠。在伏隔核或内侧苍白球（= 内苍白球核）局部应用后，记录了AP - 5和AMPA - 海人藻酸受体拮抗剂CNQX在单胺耗竭小鼠中的运动效应。AP - 5和CNQX均能刺激伏隔核中的运动活动，但在内侧苍白球核中无作用。我们之前已经表明，在单胺耗竭小鼠中，NMDA拮抗剂与α2 - 肾上腺素能受体激动剂或多巴胺D1激动剂（所有药物均全身给药）在运动刺激方面存在协同相互作用。在本研究中，将α2 - 肾上腺素能受体激动剂α - 甲基去甲肾上腺素脑内注射，并与腹腔注射的亚阈值剂量MK - 801联合应用：向伏隔核注射α - 甲基去甲肾上腺素后产生了运动刺激，但向背侧纹状体、前额叶皮质或丘脑注射后未产生运动刺激。同样，局部应用D1激动剂SKF 38393并与腹腔注射的亚阈值剂量MK - 801联合应用，表明伏隔核在运动控制中起重要作用。以往基于全身给药的实验还表明，在单胺耗竭小鼠中，毒蕈碱拮抗剂与α2 - 肾上腺素能受体激动剂之间存在协同相互作用。局部应用毒蕈碱拮抗剂甲基东莨菪碱并与腹腔注射的α2 - 肾上腺素能受体激动剂可乐定联合应用，表明在这种情况下，纹状体，即腹侧和背侧纹状体，是毒蕈碱拮抗剂的重要靶点。向小鼠伏隔核单侧注射AP - 5会诱导旋转行为：以往的研究结果表明，在单胺能正常的动物中旋转是同侧的，而单胺耗竭的动物则是对侧旋转。此外，这些研究结果表明，多巴胺D2受体刺激似乎决定了AP - 5是否会诱导同侧或对侧旋转。在本研究中，我们报告了进一步的证据，证明D2受体在这方面起关键作用。最后，研究了注射到背侧纹状体或海马体中的AP - 5的旋转效应：与向伏隔核注射AP - 5后一样，在背侧纹状体或海马体中应用AP - 5后，单胺能正常的小鼠同侧旋转，而单胺耗竭的动物则对侧旋转。目前的数据表明，伏隔核在运动控制中起重要作用。谷氨酸能、毒蕈碱胆碱能、多巴胺能和α - 肾上腺素能系统均参与伏隔核中运动功能的控制。
