Mishra R, Leith N J, Steranka L, Sulser F
Naunyn Schmiedebergs Arch Pharmacol. 1981 Jun;316(3):218-24. doi: 10.1007/BF00505652.
The present studies were undertaken to ascertain whether or not an alteration in the availability of serotonin (5HT) can modify central noradrenergic function at the level of the noradrenaline (NA) receptor coupled adenylate cyclase system in brain. The chronic but not acute administration of the 5HT uptake inhibitors amitriptyline and chlorimipramine reduced the sensitivity of the cyclic AMP generating system to NA in the limbic forebrain. This subsensitivity was linked to a decrease in the Bmax value of beta-adrenergic binding sites without appreciable changes in the Kd values, as assessed by specific 3H-dihydroalprenolol binding. The specific 5HT uptake inhibitor fluoxetine did not change either the responsiveness of the cyclic AMP generating system to NA or the density of beta-adrenergic receptor sites. Raphé lesions which selectively reduced the level of 5HT also did not cause any changes in the neurohormonal responsiveness or the density of beta-adrenergic receptor sites. In contrast, medial forebrain bundle lesions which reduced the levels of both 5HT and catecholamines (NA and dopamine) in the forebrain, increased the responsiveness of the cyclic AMP generating system to NA. It can thus be concluded that a selective change in the availability of 5HT per se does not modify noradrenergic receptor function at the level of the NA receptor coupled adenylate cyclase system. The subsensitivity of the noradrenergic receptor system developed following amitriptyline and chlorimipramine may in all likelihood be due to the in vivo conversion to the secondary amines, nortriptyline and desmethylchlorimipramine respectively. These secondary amine metabolites are potent inhibitors of the NA reuptake and consequently could be responsible for the demonstrated in vivo down-regulation of central adrenergic receptor function (homospecific down-regulation).
本研究旨在确定血清素（5HT）可用性的改变是否会在大脑中去甲肾上腺素（NA）受体偶联腺苷酸环化酶系统水平上改变中枢去甲肾上腺素能功能。5HT摄取抑制剂阿米替林和氯米帕明的慢性而非急性给药降低了边缘前脑中环磷酸腺苷生成系统对NA的敏感性。通过特异性3H-二氢阿普洛尔结合评估，这种亚敏感性与β-肾上腺素能结合位点的Bmax值降低有关，而Kd值没有明显变化。特异性5HT摄取抑制剂氟西汀既没有改变环磷酸腺苷生成系统对NA的反应性，也没有改变β-肾上腺素能受体位点的密度。选择性降低5HT水平的中缝核损伤也没有引起神经激素反应性或β-肾上腺素能受体位点密度的任何变化。相反，降低前脑中5HT和儿茶酚胺（NA和多巴胺）水平的内侧前脑束损伤增加了环磷酸腺苷生成系统对NA的反应性。因此可以得出结论，5HT可用性的选择性改变本身不会在NA受体偶联腺苷酸环化酶系统水平上改变去甲肾上腺素能受体功能。阿米替林和氯米帕明后出现的去甲肾上腺素能受体系统亚敏感性很可能是由于体内分别转化为仲胺去甲替林和去甲氯米帕明。这些仲胺代谢产物是NA再摄取的有效抑制剂，因此可能是体内中枢肾上腺素能受体功能下调（同特异性下调）的原因。
