Griffon N, Pilon C, Sautel F, Schwartz J C, Sokoloff P
Unité de Neurobiologie et Pharmacologie de l'INSERM, Centre Paul Broca, Paris, France.
J Neural Transm (Vienna). 1996;103(10):1163-75. doi: 10.1007/BF01271201.
In NG 108-15 cells expressing the recombinant human D3 receptor, dopamine agonists enhance [3H]thymidine incorporation and decrease cAMP accumulation. In these cells, but not in wild type cells, haloperidol, fluphenazine, and various other antipsychotics inhibited basal [3H]thymidine incorporation in a concentration-dependent manner. In contrast, other dopamine antagonists such as nafadotride or (+)AJ 76, two D3-preferring antagonists, were without effect. The concentration-response curve of haloperidol was shifted to the right in presence of nafadotride, with a potency compatible with its nanomolar apparent affinity as neutral antagonist. Pertussis toxin treatment abolished or markedly reduced the responses to haloperidol or fluphenazine. In contrast, no significant enhancement of cAMP accumulation could be observed, under the influence of haloperidol or eticlopride. These data indicate that some dopamine antagonists behave as inverse agonists, and thus appear to inhibit an agonist-independent activity of the D3 receptor on [3H]thymidine incorporation pathway, but not on the cAMP pathway.
在表达重组人D3受体的NG 108-15细胞中，多巴胺激动剂可增强[3H]胸腺嘧啶核苷掺入并减少环磷酸腺苷（cAMP）积累。在这些细胞中，而非野生型细胞中，氟哌啶醇、氟奋乃静及其他多种抗精神病药物以浓度依赖性方式抑制基础[3H]胸腺嘧啶核苷掺入。相比之下，其他多巴胺拮抗剂如萘法朵屈或（+）AJ 76（两种对D3受体有偏好的拮抗剂）则无此作用。在萘法朵屈存在的情况下，氟哌啶醇的浓度-反应曲线向右移动，其效力与其作为中性拮抗剂的纳摩尔表观亲和力相符。百日咳毒素处理消除或显著降低了对氟哌啶醇或氟奋乃静的反应。相比之下，在氟哌啶醇或依替必利的影响下，未观察到cAMP积累有明显增强。这些数据表明，一些多巴胺拮抗剂表现为反向激动剂，因此似乎抑制了D3受体在[3H]胸腺嘧啶核苷掺入途径上而非cAMP途径上的非激动剂依赖性活性。
