Bentué-Ferrer D, Reymann J M, Rousselle J C, Massot O, Bourin M, Allain H, Fillion G
Laboratoire de Pharmacologie, Faculté de Médecine, Rennes, France.
Eur J Pharmacol. 1998 Oct 2;358(2):129-37. doi: 10.1016/s0014-2999(98)00586-x.
5-Hydroxytryptamine-moduline (5-HT-moduline) is an endogenous tetrapeptide (Leu-Ser-Ala-Leu) recently isolated and characterized from mammalian brain. This compound interacts with 5-HT1B receptors as a non-competitive, high-affinity antagonist and has the properties of an allosteric modulator. 5-HT-moduline could play an important role in the regulation of serotonergic transmission and also, through heteroreceptors, dopaminergic transmission. The aim of this work was to examine the potential ability of 5-HT-moduline to modify the basal extracellular concentration of dopamine and its metabolites (3-methoxytyramine, dihydroxyphenylacetic acid and homovanillic acid), in the rat striatum and to determine its potential interaction with the stimulating activity of a specific 5-HT1B receptor agonist, 3-(1,2,5,6-tetrahydropyrid-4-yl) pyrrolo [3,2-b] pyrid-5-one (CP-93,129), on the release of dopamine. The technique is based on in vivo microdialysis using probes implanted in the striatum of the conscious rat. Results showed that the perfusion of 5-HT-moduline directly into this structure (1.25 mM) increased the striatal level of dopamine by two-fold (104% of the absolute basal release values, P = 0.0015) and that of 3-methoxytyramine by 3-fold (293%, P = 0.0001) without any change in the terminal metabolite concentrations. The intrastriatal administration of CP-93,129 induced a statistically significant, dose-dependent increase of dopamine levels (P < 0.0001). Coperfusion of 5-HT-moduline did not significantly alter the effect of CP-93,129 at 0.1 and 0.5 mM, but appeared to have an additive effect on the lowest dose (P = 0.0406). The results obtained show that 5-HT-moduline directly administered into the striatum increases the release of dopamine in this area. Presumably, this effect results from the desensitization of 5-HT1B receptors located on dopamine terminals. However, the fact that a 5-HT1B receptor agonist (CP-93,129) also increased the release of dopamine in the striatum and that 5-HT-moduline exhibited a slight additive effect with that of a low concentration of CP-93,129 suggests that the two substances interact with different mechanisms.
5-羟色胺调节素（5-HT调节素）是一种内源性四肽（亮氨酸-丝氨酸-丙氨酸-亮氨酸），最近从哺乳动物大脑中分离并鉴定出来。该化合物作为一种非竞争性、高亲和力拮抗剂与5-HT1B受体相互作用，并具有变构调节剂的特性。5-HT调节素可能在5-羟色胺能传递的调节中发挥重要作用，并且还可能通过异源受体对多巴胺能传递产生影响。这项工作的目的是研究5-HT调节素改变大鼠纹状体中多巴胺及其代谢产物（3-甲氧基酪胺、二羟基苯乙酸和高香草酸）基础细胞外浓度的潜在能力，并确定其与特定5-HT1B受体激动剂3-(1,2,5,6-四氢吡啶-4-基)吡咯并[3,2-b]吡啶-5-酮（CP-93,129）刺激多巴胺释放活性的潜在相互作用。该技术基于在清醒大鼠纹状体中植入探针进行体内微透析。结果表明，将5-HT调节素直接灌注到该结构中（1.25 mM）可使纹状体多巴胺水平增加两倍（绝对基础释放值的104%，P = 0.0015），使3-甲氧基酪胺水平增加3倍（293%，P = 0.0001），而终末代谢产物浓度没有任何变化。纹状体内注射CP-93,129可引起多巴胺水平具有统计学意义的剂量依赖性增加（P < 0.0001）。5-HT调节素的共灌注在0.1和0.5 mM时并未显著改变CP-93,129的作用，但在最低剂量时似乎具有相加作用（P = 0.0406）。获得的结果表明，直接注入纹状体的5-HT调节素会增加该区域多巴胺的释放。据推测，这种作用是由于多巴胺终末上的5-HT1B受体脱敏所致。然而，5-HT1B受体激动剂（CP-93,129）也增加了纹状体中多巴胺的释放，并且5-HT调节素与低浓度的CP-93,129表现出轻微的相加作用，这一事实表明这两种物质通过不同机制相互作用。
