Kesić Maja, Mokrović Gordana, Tvrdeić Ante, Miše Branko, Štefulj Jasminka, Čičin-Šain Lipa
Laboratory for Neurochemistry and Molecular Neurobiology, Department of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia.
Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia.
Front Psychiatry. 2021 Oct 1;12:741222. doi: 10.3389/fpsyt.2021.741222. eCollection 2021.
Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed medications for the treatment of mood disorders. Yet, individual response to SSRIs is highly variable, with only a portion of patients showing the desired therapeutic effect. To better understand the molecular basis underlying individual variability in response to SSRIs, here we comparatively studied behavioral and molecular consequences of chronic treatment with fluoxetine, a widely used SSRI, in two sublines of rats with constitutionally different serotonin (5HT) homeostasis: the high-5HT and low-5HT sublines. Platelet 5HT levels, a recognized indicator of SSRI efficacy, were decreased by fluoxetine treatment in both 5HT-sublines. On the other hand, biologically active plasma 5HT levels were reduced only in high-5HT rats. The anxiolytic effect of fluoxetine was also evident only in high-5HT rats, as supported by spatio-temporal and ethological behavioral measures in the elevated plus maze (EPM) test and exploratory behavior measures in the open field (OF) test. None of the behavioral EPM or OF measures were significantly altered by fluoxetine treatment in low-5HT rats. Unexpectedly, 5HT levels in cerebral cortices tended to be reduced only in low-5HT rats. Moreover, the effects of fluoxetine on cortical expression levels of 5HT-related proteins were also present only in low-5HT rats, with serotonin transporter () and serotonin receptor type 1a () being down-regulated, while serotonin receptor type 4 () was up-regulated by fluoxetine treatment. The obtained results support a role of individual 5HT tone as an important influencing factor on the biological actions of SSRI antidepressants.
选择性5-羟色胺再摄取抑制剂（SSRIs）是治疗情绪障碍最常用的处方药。然而，个体对SSRIs的反应差异很大，只有一部分患者显示出预期的治疗效果。为了更好地理解个体对SSRIs反应差异的分子基础，我们比较研究了广泛使用的SSRI氟西汀对具有不同5-羟色胺（5HT）内稳态的两个大鼠亚系进行慢性治疗后的行为和分子效应：高5HT亚系和低5HT亚系。血小板5HT水平是公认的SSRI疗效指标，氟西汀治疗使两个5HT亚系的血小板5HT水平均降低。另一方面，具有生物活性的血浆5HT水平仅在高5HT大鼠中降低。氟西汀的抗焦虑作用也仅在高5HT大鼠中明显，高架十字迷宫（EPM）试验中的时空和行为学行为测量以及旷场（OF）试验中的探索行为测量均支持这一点。氟西汀治疗对低5HT大鼠的行为EPM或OF测量均无显著影响。出乎意料的是，仅在低5HT大鼠中，大脑皮质中的5HT水平有降低趋势。此外，氟西汀对5HT相关蛋白皮质表达水平的影响也仅存在于低5HT大鼠中，5-羟色胺转运体（）和5-羟色胺1a型受体（）被下调，而5-羟色胺4型受体（）在氟西汀治疗后上调。所得结果支持个体脑内5HT水平是影响SSRI类抗抑郁药生物学作用的重要因素。
