Department of Pharmacology, University of the Basque Country, UPV/EHU, Leioa, Bizkaia, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain.
Department of Pharmacology, University of the Basque Country, UPV/EHU, Leioa, Bizkaia, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain; Biocruces Bizkaia Health Research Institute, Barakaldo, Bizkaia, Spain.
Eur Neuropsychopharmacol. 2021 Nov;52:3-11. doi: 10.1016/j.euroneuro.2021.05.012. Epub 2021 Jun 20.
Previous evidence suggests that α-adrenoceptors (α-AR) may be involved in the pathophysiology of schizophrenia. However, postmortem brain studies on α-AR expression and functionality in schizophrenia are scarce. The aim of our work was to evaluate α-AR and α-AR expression in different subcellular fractions of prefrontal cortex postmortem tissue from antipsychotic-free (absence of antipsychotics in blood at the time of death) (n = 12) and antipsychotic-treated (n = 12) subjects with schizophrenia, and matched controls (n = 24). Functional coupling of α-AR to G proteins induced by the agonist UK14304 was also tested. Additionally, G protein expression was also evaluated. In antipsychotic-free schizophrenia subjects, α-AR and α-AR protein expression was similar to controls in all the subcellular fractions. Conversely, in antipsychotic-treated schizophrenia subjects, increased α-AR expression was found in synaptosomal plasma membrane and postsynaptic density (PSD) fractions (+60% and +79% vs controls, respectively) with no significant changes in α-AR. [S]GTPγS SPA experiments showed a significant lower stimulation of G and G proteins by UK14304 in antipsychotic-treated schizophrenia subjects, whereas stimulation in antipsychotic-free schizophrenia subjects remained unchanged. G protein stimulation was significantly decreased in both antipsychotic-free and antipsychotic-treated schizophrenia subjects compared to controls. Expression of G protein did not differ between groups, whereas G levels were increased in PSD of schizophrenia subjects, both antipsychotic-free and antipsychotic-treated. G protein expression was increased in PSD of antipsychotic-treated subjects and in the presynaptic fraction of antipsychotic-free schizophrenia subjects. The present results suggest that antipsychotic treatment is able to modify in opposite directions both the protein expression and the functionality of α-AR in the cortex of schizophrenia patients.
先前的证据表明，α-肾上腺素受体（α-AR）可能参与精神分裂症的病理生理学。然而，精神分裂症死后大脑中α-AR 表达和功能的研究很少。我们的工作旨在评估抗精神病药物治疗（死亡时血液中无抗精神病药物）（n=12）和未治疗（n=12）的精神分裂症患者和匹配对照者（n=24）前额叶皮质组织不同亚细胞部分的α-AR 和 α-AR 表达。还测试了激动剂 UK14304 诱导的 α-AR 与 G 蛋白的功能偶联。此外，还评估了 G 蛋白的表达。在未用抗精神病药物治疗的精神分裂症患者中，所有亚细胞部分的 α-AR 和 α-AR 蛋白表达与对照组相似。相反，在用抗精神病药物治疗的精神分裂症患者中，突触体质膜和突触后密度（PSD）部分的 α-AR 表达增加（分别增加 60%和 79%，与对照组相比），而 α-AR 没有明显变化。[S]GTPγS SPA 实验表明，用 UK14304 刺激 G 和 G 蛋白的刺激在用抗精神病药物治疗的精神分裂症患者中显著降低，而未用抗精神病药物治疗的精神分裂症患者的刺激保持不变。与对照组相比，未用抗精神病药物治疗和用抗精神病药物治疗的精神分裂症患者的 G 蛋白刺激均显著降低。各组之间 G 蛋白的表达没有差异，而 PSD 中的 G 水平在未用抗精神病药物治疗和用抗精神病药物治疗的精神分裂症患者中均增加。G 蛋白表达在抗精神病药物治疗患者的 PSD 和未用抗精神病药物治疗的精神分裂症患者的突触前部分增加。这些结果表明，抗精神病药物治疗能够以相反的方式调节精神分裂症患者皮质中 α-AR 的蛋白表达和功能。
