MODULATION OF BRAIN OPIOIDS AND TACHYKININS BY PSYCHOACTIVE DRUGS

该项目的目标是：1）了解基本的 阿片和速激肽系统的生物合成过程， 采用分子生物学和免疫化学技术， 2)来阐明经典的神经递质系统 由于多巴胺（DA）与阿片肽和速激肽相互作用， 在基底神经节多巴胺能神经元的扰动后， 传输 使用的方法包括定量 特异性mRNA和前体含量以及稳定的 说明肽浓度。 DA长期阻断 受体与DA拮抗剂，氟哌啶醇（一种抗精神病药 药物），引起了有趣的变化，表达 纹状体中的神经肽：（Met 5）-脑啡肽增加 (ME)但速激肽减少。 这一发现不仅表明 DA系统对这两个方面发挥着重要的调节作用， 肽系统，但也提出了一个有趣的概念，基因 神经肽系统的表达可能是一个潜在的位点， 抗精神病药物的作用。 氟哌啶醇对 这两种肽通过黑质内注射6- 羟多巴胺，它选择性地破坏黑质纹状体 DA途径。 这些结果进一步证实了 DA在调节代谢中起着重要作用， 我和速激肽。 为了确定是否增强 多巴胺能传递会产生相反的效果， 使用这些肽，阿扑吗啡，一种DA激动剂。 重复注射阿扑吗啡增加了 速激肽和强啡肽的mRNA和肽含量，但 未能改变基底神经节中的ME含量。 这一发现加上 上述结果有力地表明：1）DA 对ME的生物合成具有强烈的抑制作用， 这种紧张性抑制作用在生理条件下是最大的 条件下，2）DA增强速激肽的生物合成， 强啡肽和这种紧张性兴奋作用不是最大的下 生理条件。 将采用纹状体细胞培养 以确定连接DA受体的亚细胞事件 激活阿片肽和速激肽的基因表达。

The objectives of this project were: 1) to understand the basic biosynthetic process of opioid and tachykinin systems by employing molecular biological and immunochemical techniques, 2) to elucidate how the classical neurotransmitter systems such as dopamine (DA) interact with opioid peptides and tachykinins in the basal ganglia following the perturbation of dopaminergic transmission. The methods used include the quantitation of specific mRNA and the precursor content as well as the steady state peptide concentration. Long-term blockade of DA receptors with a DA antagonist, haloperidol (an antipsychotic drug), caused interesting changes in the expression of neuropeptides in the striatum: increases in (Met5)-enkephalin (ME) but decreases in tachykinin. This finding not only suggests that the DA system exerts important regulation on these two peptide systems, but also raises an interesting concept that gene expression of neuropeptide systems may be a potential site of action for antipsychotic drugs. The effects of haloperidol on these two peptides were mimicked by intranigral injection of 6- hydroxydopamine which selectively destroys the nigral-striatal DA pathway. These results add further credence to the concept that DA plays an important role in regulating the metabolism of ME and tachykinin. To determine if enhancement of dopaminergic transmission would produce opposite effects on these peptides, apomorphine, a DA agonist, was employed. Repeated injections of apomorphine increased the abundance of mRNA and peptide content of tachykinin and dynorphin, but failed to alter ME content in the basal ganglia. This finding plus the aforementioned results strongly suggest the following: 1) DA exerts strong inhibitory influence on the biosynthesis of ME and this tonic inhibitory effect is maximal under physiological conditions, 2) DA enhances the biosynthesis of tachykinin and dynorphin and this tonic excitatory effect is not maximal under physiological conditions. Striatal cell cultures will be employed to determine the subcellular events which link the DA receptor activation to gene expression of opioid peptides and tachykinins.