Sustained treatment with a 5-HT(2A) receptor agonist causes functional desensitization and reductions in agonist-labeled 5-HT(2A) receptors despite increases in receptor protein levels in rats.
Sustained treatment with a 5-HT(2A) receptor agonist causes functional desensitization and reductions in agonist-labeled 5-HT(2A) receptors despite increases in receptor protein levels in rats.
复制标题
尽管大鼠体内受体蛋白水平增加，但持续使用 5-HT(2A) 受体激动剂治疗会导致功能性脱敏和激动剂标记的 5-HT(2A) 受体减少。
DOI：
10.1016/j.neuropharm.2008.06.001
复制
发表时间：
2008
影响因子：
4.7
通讯作者：
Muma,NancyA
中科院分区：
文献类型：
--
作者：
Shi,Ju;Landry,Michelle;Carrasco,GonzaloA;Battaglia,George;Muma,NancyA
5-羟色胺2A (5-HT2A) 受体信号的适应性变化与多种精神药物的临床反应相关，包括非典型抗精神病药和选择性5-羟色胺再摄取抑制剂。本研究探讨了大鼠下丘脑室旁核（PVN）用 1mg/kg (−)-1-(2,5-二甲氧基-4-碘苯基)-2-氨基丙烷 HCl (DOI) 治疗 4 和 7 天后激动剂诱导的 5-HT2A 受体脱敏的可能机制。 DOI 治疗 4 天后，5-HT2A 受体介导的催产素释放量减少了 78%，7 天后减少了 61%。同样，1mg/kg DOI 后的 ACTH 释放量在 DOI 治疗 4 天后下降了 31%，在 7 天后下降了 38%。与盐水处理的对照大鼠相比，用DOI处理4或7天导致高亲和力5-HT 2A 受体结合显着降低(约50％)，如通过125 I-DOI结合测量的。相比之下，蛋白质印迹分析表明，DOI 治疗 4 天或 7 天后，5-HT2A 受体蛋白水平显着增加，分别达到对照水平的 167% 和 191%。实时定量 RT-PCR 分析显示，用 DOI 处理 4 或 7 天后，5-HT2AmRNA 水平出现小幅但不显着的增加。总而言之，5-HT2A 受体刺激的激素反应、激动剂结合数据和蛋白质印迹数据表明，尽管激动剂处理增加了细胞膜中 5-HT2A 受体蛋白的水平，但能够高亲和力结合并介导功能反应的 5-HT2A 受体群体减少。
Adaptive changes in serotonin2A (5-HT2A) receptor signaling are associated with the clinical response to a number of psychiatric drugs including atypical antipsychotics and selective serotonin reuptake inhibitors. The present study examined possible mechanisms of agonist-induced desensitization of 5-HT2Areceptors in rat hypothalamic paraventricular nucleus (PVN) after 4 and 7 days of treatment with 1mg/kg (−)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI). The magnitude of 5-HT2Areceptor-mediated oxytocin release decreased 78% after 4 days and 61% after 7 days of DOI treatment. Similarly, the magnitude of ACTH release following 1mg/kg DOI decreased by 31% after 4 days and 38% after 7 days of DOI treatment. Treatment with DOI for either 4 or 7 days caused a significant decrease (by approximately 50%) in the high-affinity 5-HT2Areceptor binding as measured by125I-DOI binding compared to saline-treated control rats. In contrast, western blot analysis demonstrated a significant increase in 5-HT2Areceptor protein levels with 4 or 7 days of DOI treatment to 167% and 191% of control levels, respectively. Real time quantitative RT-PCR analysis revealed a small but nonsignificant increase in the levels of 5-HT2AmRNA following treatment with DOI for 4 or 7 days. Taken together, the 5-HT2Areceptor-stimulated hormone responses, agonist binding data and western blot data suggest that although agonist treatment increases the levels of 5-HT2Areceptor protein in the cell membrane, there is a reduction in the population of 5-HT2Areceptors capable of high-affinity binding and mediating a functional response.