Zhang Yahong, Gray Thackery S, D'Souza Deborah N, Carrasco Gonzalo A, Damjanoska Katerina J, Dudas Bertalan, Garcia Francisca, Zainelli Gina M, Sullivan Hanley Nicole R, Battaglia George, Muma Nancy A, Van de Kar Louis D
Center for Serotonin Disorders Research and Department of Pharmacology, Loyola University of Chicago, Stritch School of Medicine, Maywood, Illinois 60153, USA.
J Pharmacol Exp Ther. 2004 Jul;310(1):59-66. doi: 10.1124/jpet.103.062224. Epub 2004 Apr 2.
An imbalance between serotonin-2A (5-HT2A) and 5-HT1A receptors may underlie several mood disorders. The present studies determined whether 5-HT2A receptors interact with 5-HT1A receptors in the rat hypothalamic paraventricular nucleus (PVN). The sensitivity of the hypothalamic 5-HT1A receptors was measured as oxytocin and adrenocorticotropic hormone (ACTH) responses to the 5-HT1A receptor agonist (+)-8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide [(+)8-OH-DPAT] (40 microg/kg s.c.). The 5-HT(2A/2C) receptor agonist (-)DOI [(-)-1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane HCl] (1 mg/kg s.c.) injected 2 h prior to (+)8-OH-DPAT significantly reduced the oxytocin and ACTH responses to (+)8-OH-DPAT, producing a heterologous desensitization of the 5-HT1A receptors. Microinjection of the 5-HT2A receptor antagonist MDL100,907 [(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol; 0, 10, or 20 nmol, 15 min prior to (-)DOI] into the PVN dose-dependently prevented the desensitization of 5-HT1A receptors induced by the 5-HT2A receptor agonist (-)DOI. Double-label immunocytochemistry revealed a high degree of colocalization of 5-HT1A and 5-HT2A receptors in the oxytocin and corticotropin-releasing factor neurons of the PVN. Thus, activation of 5-HT2A receptors in the PVN may directly induce a heterologous desensitization of 5-HT1A receptors within individual neuroendocrine cells. These findings may provide insight into the long-term adaptation of 5-HT1A receptor signaling after changes in function of 5-HT2A receptors; for example, during pharmacotherapy of mood disorders.
血清素 - 2A（5 - HT2A）和5 - HT1A受体之间的失衡可能是多种情绪障碍的潜在原因。本研究确定了5 - HT2A受体是否与大鼠下丘脑室旁核（PVN）中的5 - HT1A受体相互作用。下丘脑5 - HT1A受体的敏感性通过催产素和促肾上腺皮质激素（ACTH）对5 - HT1A受体激动剂（+）-8 - 羟基 - 2 - （二正丙基氨基）四氢溴化萘[（+）8 - OH - DPAT]（40微克/千克皮下注射）的反应来测量。在（+）8 - OH - DPAT注射前2小时皮下注射5 - HT（2A/2C）受体激动剂（ - ）DOI [（ - ）-1 - （2,5 - 二甲氧基 - 4 - 碘苯基）2 - 氨基丙烷盐酸盐]（1毫克/千克）可显著降低催产素和ACTH对（+）8 - OH - DPAT的反应，导致5 - HT1A受体的异源脱敏。在（ - ）DOI注射前15分钟，将5 - HT2A受体拮抗剂MDL100,907 [（+）-α - （2,3 - 二甲氧基苯基）-1 - [2 - （4 - 氟苯基乙基）]-4 - 哌啶甲醇；0、10或20纳摩尔]微量注射到PVN中，可剂量依赖性地防止5 - HT2A受体激动剂（ - ）DOI诱导的5 - HT1A受体脱敏。双标免疫细胞化学显示PVN的催产素和促肾上腺皮质激素释放因子神经元中5 - HT1A和5 - HT2A受体高度共定位。因此，PVN中5 - HT2A受体的激活可能直接诱导单个神经内分泌细胞内5 - HT1A受体的异源脱敏。这些发现可能有助于深入了解5 - HT2A受体功能改变后5 - HT1A受体信号的长期适应性；例如，在情绪障碍的药物治疗期间。
