MECHANISMS OF SEROTONIN RECEPTOR AGONIST-INDUCED ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS IN THE RAT
MECHANISMS OF SEROTONIN RECEPTOR AGONIST-INDUCED ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS IN THE RAT
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DOI：
10.1210/endo-126-4-1888
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发表时间：
1990-04-01
期刊：
影响因子：
4.8
通讯作者：
CHROUSOS, GP
中科院分区：
文献类型：
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作者：
CALOGERO, AE;BAGDY, G;CHROUSOS, GP
大量的实验证据表明，5-羟色胺（5-HT）和几种合成的5-HT受体激动剂激活下丘脑-垂体-肾上腺（HPA）轴。为了探索5-HT或5-HT激动剂在体外增强HPA轴活性的机制，我们检测了5-HT 1a激动剂8-羟基-2-羟色胺（8-hydroxy-2）对HPA轴的刺激作用。（二正丙基氨基）四氢化萘（8-OH-DPAT）、针对间氯苯基哌嗪（m-CPP）的5-HT 1c/5-HT 1b和5-HT 2/5-HT 1c激动剂1-（2，5-二甲氧基-4-碘苯基）2-氨基丙烷（DOI）对大鼠血浆ACTH和皮质酮分泌的影响。为了测试8-OH-DPAT、m-CPP或DOI是否通过刺激内源性CRH的释放而增加血浆ACTH水平，用超免疫CRH兔血清（TS-6）或正常兔血清预处理插管的清醒雄性Sprague-Dawley大鼠，随后用最大刺激剂量的上述5-HT激动剂攻击。TS-6预处理可完全抑制ACTH对m-CPP的反应，并显著减弱对8-OH-DPAT或DOI的反应。为了研究是否剩余的ACTH反应8-OH-DPAT或DOI也介导的垂体网站的行动，我们管理这些代理人的垂体茎横断或假手术大鼠。与假手术大鼠相比，在茎横断大鼠中对8-OH-DPAT和DOI的ACTH反应被保留，尽管显着钝化。这表明，这两种5-HT激动剂也可以在垂体水平上起作用，以刺激体内ACTH的释放。虽然ACTH反应8-OH-DPAT，m-CPP，和DOI钝化后TS-6预处理和垂体柄横断，皮质酮的反应只有轻微的影响，这表明这些化合物中的一些可能会导致皮质酮释放大鼠通过另一种机制。为了评估这一假设，ACTH和皮质酮的反应，8-OH-DPAT，m-CPP，和DOI进行了检查大鼠的HPA轴已被抑制的单次高剂量注射地塞米松。与盐水预处理的大鼠相比，皮质酮对8 OH-DPAT和DOI的反应减弱，但与在这些大鼠中观察到的ACTH反应相比，皮质酮的反应不适当地高。另一方面，ACTH和皮质酮对m-CPP的反应被地塞米松完全消除。总之，本研究结果表明，5-HT 1a受体激动剂8-OH-DPAT和5-HT 2/5-HT 1c受体激动剂DOI可能通过刺激下丘脑CRH和垂体ACTH分泌引起ACTH释放，而ACTH对5-HT 1c/5-HT 1b受体激动剂m-CPP的反应似乎主要是CRH依赖性的。看来，8-OH-DPAT和DOI可能能够通过ACTH非依赖性机制刺激皮质酮分泌。
A substantial body of experimental evidence indicates that serotonin (5-HT) and several synthetic 5-HT receptor agonists activate the hypothalamic-pituitary-adrenal (HPA) axis. To explore the mechanism(s) by which 5-HT or 5-HT agonists enhance the activity of the HPA axis in vitro, we examined the stimulatory effects of the 5-HT1a agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT), THE 5-HT1c/5-HT1b against m-chlorophenylpiperazine (m-CPP), and the 5-HT2/5-HT1c agonist 1-(2,5-dimethoxy-4-iodophenyl)2-amino-propane (DOI) on plasma ACTH and corticosterone secretion in the rat. To test whether 8-OH-DPAT, m-CPP, or DOI increase plasma ACTH levels by stimulating the release of endogenous CRH, catheterized conscious male Sprague-Dawley rats were pretreated with hyperimmune CRH rabbit serum (TS-6) or normal rabbit serum and subsequently challenged with a maximally stimulatory dose of the above 5-HT agonists. Pretreatment with TS-6 completely suppressed the ACTH response to m-CPP and significantly blunted the responses to 8-OH-DPAT or DOI. To examine whether the remaining ACTH response to 8-OH-DPAT or DOI was also mediated by a pituitary site of action, we administered each of these agents to pituitary stalk-transected or sham-operated rats. The ACTH responses to 8-OH-DPAT and DOI in stalk-transected rats were preserved, although significantly blunted, compared to those in sham-operated rats. This suggested that both of these 5-HT agonists may also act at the pituitary level to stimulate ACTH release in vivo. Although the ACTH responses to 8-OH-DPAT, m-CPP, and DOI were blunted after both TS-6 pretreatment and pituitary stalk transection, corticosterone responses were only slightly affected, suggesting that some of these compounds may cause corticosterone release in the rat through another mechanism. To evaluate this hypothesis, ACTH and corticosterone responses to 8-OH-DPAT, m-CPP, and DOI were examined in rats whose HPA axis had been suppressed by a single high dose injection of dexamethasone. The corticosterone responses to 8 OH-DPAT and DOI were blunted compared to those of saline-pretreated rats, but were inappropriately high compared to the ACTH responses observed in these rats. On the other hand, both ACTH and corticosterone responses to m-CPP were completely abolished by dexamethasone. In conclusion, the present findings suggest that the 5-HT1a receptor agonist 8-OH-DPAT and the 5-HT2/5-HT1c receptor agonist DOI may cause ACTH release in vivo by stimulating both hypothalamic CRH and pituitary ACTH secretion, whereas the ACTH response to the 5-HT1c/5-HT1b receptor agonist m-CPP appears to be primarily CRH dependent. It appears that both 8-OH-DPAT and DOI may be capable of stimulating corticosterone secretion through an ACTH-independent mechanism.