通过在大鼠中使用微透析测量海马细胞外5-羟色胺来评估8-羟基二丙胺可能的体内5-羟色胺再摄取阻断特性。
Possible in vivo 5-HT reuptake blocking properties of 8-OH-DPAT assessed by measuring hippocampal extracellular 5-HT using microdialysis in rats.
作者信息
Assié M B, Koek W
机构信息
Neurobiology Division II, Centre de Recherche Pierre Fabre, Castres, France.
出版信息
Br J Pharmacol. 1996 Nov;119(5):845-50. doi: 10.1111/j.1476-5381.1996.tb15749.x.
Abstract
- The 5-hydroxytryptamine (5-HT)1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), has been shown to label 5-HT reuptake sites. 2. To study the functional consequences of this property, the effects of 8-OH-DPAT were compared with those of the 5-HT reuptake inhibitors, paroxetine and clomipramine, and of the 5-HT1A receptor agonist flesinoxan, in vitro on 5-HT reuptake, and in vivo on the extracellular concentration of 5-HT by use of microdialysis, in rat hippocampus. Because 5-HT reuptake inhibitors reportedly attenuate the ability of (+)-fenfluramine to increase the extracellular concentration of 5-HT, the possible reversal of these effects of 8-OH-DPAT and by paroxetine were examined. 3. 8-OH-DPAT, paroxetine and clomipramine inhibited [3H]-5-HT reuptake in rat hippocampal synaptosomes (pIC50: 6.00, 8.41 and 7.00, respectively). In contrast, flesinoxan did not alter 5-HT reuptake (pIC50 < 5). 4. 8-OH-DPAT (10 and 100 microM), paroxetine (0.1 microM) and clomipramine (1 microM), administered through the dialysis probe, significantly increased the hippocampal extracellular concentration of 5-HT. In contrast, flesinoxan (100 microM) did not alter extracellular 5-HT. Moreover, the effects of 100 microM 8-OH-DPAT were not blocked by the 5-HT1A receptor antagonist, WAY-100635 (0.16 mg kg-1, s.c.). 5. The increase in extracellular 5-HT induced by 10 mg kg-1, i.p., (+)-fenfluramine was prevented not only by 0.1 microM paroxetine, but also by 100 microM 8-OH-DPAT. In addition, systemic administration of 10 mg kg-1, but not 2.5 mg kg-1, i.p. 8-OH-DPAT attenuated the increase in extracellular 5-HT induced by 2.5 mg kg-1, i.p., (+)-fenfluramine. 6. These findings suggest that the increase in extracellular 5-HT produced by local administration of 8-OH-DPAT does not involve its 5-HT1A receptor agonist properties, but may result, at least in part, from its 5-HT reuptake blocking properties.
摘要
- 5-羟色胺（5-HT）1A受体激动剂8-羟基-2-（二正丙基氨基）四氢萘（8-OH-DPAT）已被证明可标记5-HT再摄取位点。2. 为研究该特性的功能后果，在体外对5-HT再摄取以及在体内通过微透析对大鼠海马中5-HT的细胞外浓度进行研究，比较了8-OH-DPAT与5-HT再摄取抑制剂帕罗西汀和氯米帕明以及5-HT1A受体激动剂氟辛克生的作用。由于据报道5-HT再摄取抑制剂可减弱（+）-芬氟拉明增加5-HT细胞外浓度的能力，因此研究了8-OH-DPAT和帕罗西汀这些作用的可能逆转情况。3. 8-OH-DPAT、帕罗西汀和氯米帕明抑制大鼠海马突触体中[3H]-5-HT的再摄取（pIC50分别为6.00、8.41和7.00）。相比之下，氟辛克生未改变5-HT再摄取（pIC50 < 5）。4. 通过透析探针给予8-OH-DPAT（10和100 microM）、帕罗西汀（0.1 microM）和氯米帕明（1 microM），可显著增加海马中5-HT的细胞外浓度。相比之下，氟辛克生（100 microM）未改变细胞外5-HT。此外，5-HT1A受体拮抗剂WAY-100635（0.16 mg kg-1，皮下注射）未阻断100 microM 8-OH-DPAT的作用。5. 腹腔注射10 mg kg-1（+）-芬氟拉明诱导的细胞外5-HT增加不仅被0.1 microM帕罗西汀阻止，也被100 microM 8-OH-DPAT阻止。此外，腹腔注射10 mg kg-1而非2.5 mg kg-1的8-OH-DPAT可减弱腹腔注射2.5 mg kg-1（+）-芬氟拉明诱导的细胞外5-HT增加。6. 这些发现表明，局部给予8-OH-DPAT所产生的细胞外5-HT增加并不涉及其5-HT1A受体激动剂特性，而是可能至少部分源于其5-HT再摄取阻断特性。
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