Sullivan Nicole R, Crane James W, Damjanoska Katerina J, Carrasco Gonzalo A, D'Souza Deborah N, Garcia Francisca, Van de Kar Louis D
Center for Serotonin Disorders Research and Department of Pharmacology, Stritch School of Medicine, Loyola University of Chicago, 2160 South First Avenue, Maywood, IL 60153, USA.
Naunyn Schmiedebergs Arch Pharmacol. 2005 Jan;371(1):18-26. doi: 10.1007/s00210-004-1005-7. Epub 2005 Jan 18.
Tandospirone, an azapirone, is a selective serotonin(1A) (5-HT(1A)) receptor agonist. The effects of tandospirone on plasma hormones and on mitogen-activated protein (MAP) kinase activity in the brain of male rats were studied. Tandospirone produced a time- and dose-dependent increase in plasma levels of oxytocin, adrenocorticotropin (ACTH), corticosterone, and prolactin. The minimal dose of tandospirone that led to a significant elevation of plasma oxytocin, ACTH, and prolactin levels was 1.0 mg/kg (s.c.), while the minimal dose for corticosterone release was 3.0 mg/kg (s.c.). The ED(50) of tandospirone was 1.3 mg/kg for oxytocin, 1.2 mg/kg for ACTH, 3.0 mg/kg for corticosterone, and 0.24 mg/kg for prolactin. Pretreatment with the specific 5-HT(1A) receptor antagonist WAY 100,635 (0.3 mg/kg, s.c.) completely blocked the effects of tandospirone on plasma levels of oxytocin, ACTH, and corticosterone but shifted the dose-response curve for prolactin to the right. Tandospirone injection (10 mg/kg, s.c.) stimulated the MAP kinase signaling cascade, specifically the phosphorylation of p42/44 extracellular signal-regulated kinase (ERK). Western blot analysis revealed a significant increase in phosphorylated ERK (p-ERK) levels in the hypothalamic paraventricular nucleus (PVN) as well as the dorsal raphe nucleus 5 min following tandospirone injection. These increases were blocked by pretreatment with WAY 100,635 (0.3 mg/kg). The results are the first evidence that systemic 5-HT(1A) receptor agonist administration produces a rapid increase in p-ERK levels in vivo, providing further insight into the signaling mechanisms of the 5-HT(1A) receptor.
坦度螺酮是一种氮杂螺环癸烷二酮，是一种选择性5-羟色胺（1A）（5-HT（1A））受体激动剂。研究了坦度螺酮对雄性大鼠血浆激素及脑内丝裂原活化蛋白（MAP）激酶活性的影响。坦度螺酮可使血浆中催产素、促肾上腺皮质激素（ACTH）、皮质酮和催乳素水平呈时间和剂量依赖性升高。导致血浆催产素、ACTH和催乳素水平显著升高的坦度螺酮最小剂量为1.0mg/kg（皮下注射），而皮质酮释放的最小剂量为3.0mg/kg（皮下注射）。坦度螺酮对催产素的半数有效剂量（ED50）为1.3mg/kg，对ACTH为1.2mg/kg，对皮质酮为3.0mg/kg，对催乳素为0.24mg/kg。用特异性5-HT（1A）受体拮抗剂WAY 100635（0.3mg/kg，皮下注射）预处理可完全阻断坦度螺酮对血浆催产素、ACTH和皮质酮水平的影响，但使催乳素的剂量反应曲线右移。注射坦度螺酮（10mg/kg，皮下注射）可刺激MAP激酶信号级联反应，特别是p42/44细胞外信号调节激酶（ERK）的磷酸化。蛋白质印迹分析显示，注射坦度螺酮5分钟后，下丘脑室旁核（PVN）以及中缝背核中磷酸化ERK（p-ERK）水平显著升高。这些升高被WAY 100635（0.3mg/kg）预处理所阻断。这些结果首次证明，全身性给予5-HT（1A）受体激动剂可使体内p-ERK水平迅速升高，为深入了解5-HT（1A）受体的信号传导机制提供了进一步的线索。
