Gáborján A, Lendvai B, Vizi E S
Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences and Haynal Imre University of Health Sciences, Budapest.
Neuroscience. 1999 Apr;90(1):131-8. doi: 10.1016/s0306-4522(98)00461-8.
In this study, using an in vitro superfusion technique for the first time, we provide direct neurochemical evidence of the transmitter role of dopamine at the level of lateral olivocochlear efferent fibres of the guinea-pig cochlea. Our results revealed that nerve terminals are able to take up and release dopamine upon axonal stimulation. Since dopamine is thought to protect the afferent nerve fibres from damage due to acoustic trauma or ischaemia, enhancement of the release of dopamine, a potential therapeutic site of these injuries, was investigated. Positive modulation of dopamine release has been shown by a D1 dopamine receptor agonist, an antagonist and piribedil. Furthermore, negative feedback on the stimulation-evoked release of dopamine via D2 dopamine receptors has been excluded. Electrical stimulation of the cochlear tissue produced a significant and reproducible release of [3H]dopamine, which could be blocked by tetrodotoxin (1 microM) and cadmium (100 microM), proving that axonal activity releases dopamine and its dependence on Ca2+ influx verifies its neuronal origin. Nomifensine, a high-affinity dopamine uptake blocker, prevented the tissue from taking up [3H]dopamine from the bathing solution, also indicating the neural origin of dopamine released in response to stimulation. SKF-38393 (a selective D1 agonist) increased both the resting and electrically evoked release of dopamine. Piribedil (a D3/D2/D1 agonist), a drug under investigation, known to prevent acoustic trauma or ischaemia-induced hearing loss, had a similar and concentration-dependent increasing effect on both resting and evoked release of dopamine. The effect of both drugs on stimulation-evoked release could be prevented by SKF-83566 (a selective D1 antagonist). However, SKF-83566 alone enhanced the resting and axonal conduction-associated release of dopamine. D2 agonists and antagonists failed to modulate the release of dopamine, indicating the lack of negative feedback modulation of dopamine release. Our results suggest that the release of dopamine was subjected to modulation by a D1 receptor agonist and an antagonist. In addition, it is concluded that D2 receptors are not involved in the modulation of dopamine release. This observation may have clinical relevance in the prevention or therapy of particular types of hearing loss, because enhanced dopaminergic input into the primary auditory neuron may inhibit the (over)excitation of this neuron by glutamatergic input from inner hair cells.
在本研究中，我们首次使用体外灌流技术，在豚鼠耳蜗外侧橄榄耳蜗传出纤维水平上提供了多巴胺作为递质作用的直接神经化学证据。我们的结果显示，神经末梢在轴突刺激时能够摄取并释放多巴胺。由于多巴胺被认为可保护传入神经纤维免受声损伤或缺血损伤，因此我们研究了增强多巴胺释放这一这些损伤潜在治疗靶点的情况。D1多巴胺受体激动剂、拮抗剂和匹莫齐特已显示出对多巴胺释放的正向调节作用。此外，已排除通过D2多巴胺受体对刺激诱发的多巴胺释放的负反馈作用。耳蜗组织的电刺激产生了显著且可重复的[3H]多巴胺释放，该释放可被河豚毒素（1微摩尔）和镉（100微摩尔）阻断，这证明轴突活动释放多巴胺，且其对Ca2+内流的依赖性证实了其神经元来源。诺米芬辛是一种高亲和力多巴胺摄取阻滞剂，可阻止组织从浴液中摄取[3H]多巴胺，这也表明刺激后释放的多巴胺的神经来源。SKF-38393（一种选择性D1激动剂）增加了多巴胺的静息释放和电诱发释放。匹莫齐特（一种D3/D2/D1激动剂）是一种正在研究的药物，已知可预防声损伤或缺血性听力损失，对多巴胺的静息释放和诱发释放具有类似的浓度依赖性增加作用。两种药物对刺激诱发释放的作用均可被SKF-83566（一种选择性D1拮抗剂）阻断。然而，单独使用SKF-83566可增强多巴胺的静息释放和与轴突传导相关的释放。D2激动剂和拮抗剂未能调节多巴胺的释放，表明不存在对多巴胺释放的负反馈调节。我们的结果表明，多巴胺的释放受到D1受体激动剂和拮抗剂的调节。此外，得出的结论是D2受体不参与多巴胺释放的调节。这一观察结果可能在特定类型听力损失的预防或治疗中具有临床意义，因为增强对初级听觉神经元的多巴胺能输入可能抑制来自内毛细胞的谷氨酸能输入对该神经元的（过度）兴奋作用。
