Piletz J E, Halaris A, Nelson J, Qu Y, Bari M
Department of Psychiatry, University of Mississippi Medical Center, Jackson 39216-4505, USA.
J Psychiatr Res. 1996 May-Jun;30(3):147-68. doi: 10.1016/0022-3956(96)00005-2.
Depressed patients have been reported to have a higher than normal density of platelet binding sites for 3H-clonidine, an alpha 2-adrenoceptor agonist. Paradoxically, other studies using 3H-alpha 2, antagonists have found no differences from controls. Because 3H-clonidine interacts with platelet alpha 2-adrenoceptors to form G-protein complexes, whereas 3H-alpha 2-antagonists bind with uncoupled receptors, an elevation in G-protein coupling might explain this paradox. Another possibility is that depression might be associated with increased non-adrenergic I1-imidazoline binding sites, which are also clonidine sensitive. To distinguish these possibilities, we utilized p125I-clonidine to measure density (Bmax) and affinity (KD) of platelet G-protein coupled alpha 2-adrenoceptors as well as platelet I1 binding sites, and compared diagnostic groups of major depressive disorder (MDD), generalized anxiety disorder (GAD) and healthy subjects. Specific inhibition of binding by norepinephrine (NE = 10 microM) was used to selectively quantify alpha 2-adrenoceptors, whereas inhibition by 10 microM moxonidine (a > 100-fold selective I1 ligand) quantified I1 binding sites under a NE mask. I1 sites were found to be markedly elevated by, on average, +136% in MDD patients (p = .0007), whereas there was only a marginal increase in alpha 2-adrenoceptor Bmax values in MDD patients (p = .08; GAD and healthy subjects did not differ). Treatment of MDD patients for 6-8 weeks with desipramine downregulated I1 sites as well as alpha 2-adrenoceptors. Positive correlations were also noted for both sites: (a) between Bmax values and the severity of depression (using the Hamilton Depression Rating Scale); and (b) between end-of-treatment plasma desipramine concentrations and the extent of downregulation in Bmax values when subject groups were pooled. None of the binding parameters was associated with plasma catecholamine concentrations. The results suggest that an increased density of platelet I1 binding sites may partially explain the utility of radiolabeled clonidine as a potential biological marker for depressive illness, although an additional increase in G-protein coupling cannot be excluded.
据报道，抑郁症患者血小板上3H-可乐定（一种α2肾上腺素能受体激动剂）的结合位点密度高于正常水平。矛盾的是，其他使用3H-α2拮抗剂的研究发现与对照组没有差异。由于3H-可乐定与血小板α2肾上腺素能受体相互作用形成G蛋白复合物，而3H-α2拮抗剂与未偶联的受体结合，G蛋白偶联的升高可能解释了这一矛盾。另一种可能性是，抑郁症可能与增加的非肾上腺素能I1-咪唑啉结合位点有关，这些位点也对可乐定敏感。为了区分这些可能性，我们利用125I-可乐定测量血小板G蛋白偶联α2肾上腺素能受体以及血小板I1结合位点的密度（Bmax）和亲和力（KD），并比较了重度抑郁症（MDD）、广泛性焦虑症（GAD）诊断组和健康受试者。用去甲肾上腺素（NE = 10 microM）特异性抑制结合用于选择性定量α2肾上腺素能受体，而用10 microM莫索尼定（一种选择性超过100倍的I1配体）抑制在NE掩盖下定量I1结合位点。发现MDD患者的I1位点平均显著升高+136%（p = 0.0007），而MDD患者的α2肾上腺素能受体Bmax值仅略有增加（p = 0.08；GAD和健康受试者无差异）。用去甲丙咪嗪治疗MDD患者6 - 8周可下调I1位点以及α2肾上腺素能受体。还注意到两个位点的正相关：（a）Bmax值与抑郁严重程度之间（使用汉密尔顿抑郁量表）；（b）当合并受试者组时，治疗结束时血浆去甲丙咪嗪浓度与Bmax值下调程度之间。没有一个结合参数与血浆儿茶酚胺浓度相关。结果表明，血小板I1结合位点密度的增加可能部分解释了放射性标记可乐定作为抑郁症潜在生物标志物的效用，尽管不能排除G蛋白偶联的额外增加。
