Molecular Neuropsychiatry Unit, Shaar Menashe Brain Behavior Laboratory, Shaar Menashe MHC and Technion-Faculty of Medicine, Mobile Post, 38814, Haifa, Israel.
Psychopharmacology (Berl). 2012 Apr;220(4):763-70. doi: 10.1007/s00213-011-2530-y. Epub 2011 Oct 12.
The combination of selective serotonin reuptake inhibitor (SSRI) antidepressants and antipsychotics is currently used for the treatment of negative symptoms of schizophrenia. However, the biochemical mechanism mediating the clinical effectiveness of this treatment remains obscure. Previously, we have reported that acute haloperidol (HALO)-fluvoxamine (FLU) in vivo and in vitro treatment regulated GABA-Aβ2/3 receptor subunits, and protein kinase C (PKC) and mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) signaling pathways.
In the present study, we demonstrated that chronic HALO-FLU treatment, but not each drug alone, significantly decreased GABA-Aβ2/3 receptor expression (25 ± 6.2% vs. control) and caused receptor translocation from the membrane to the cytosol in rat prefrontal cortex. Phosphorylation of PKC and ERK2 was affected differently by HALO-FLU combination than by the individual drug treatments. HALO and FLU each given alone increased PKC phosphorylation levels (29 ± 15% and 40 ± 11.8%, vs. control, respectively) and did not affect ERK2 phosphorylation, while HALO-FLU combined treatment did not alter PKC phosphorylation levels and significantly decreased ERK2 phosphorylation levels (58 ± 4.4% vs. control). GABA-A receptor downregulation in the brain was accompanied by a decrease in GABA-A function, as shown in muscimol-induced loss of righting reflex (22 ± 9.8 min).
We provide a brief heuristic overview of our preclinical and clinical studies with the SSRI-antipsychotic combination and argue that the finding that it causes similar dynamic changes in laboratory and clinical domains, specifically in GABA-A β2/3 receptor and PKC, strongly supports the hypothesis that the GABA-A receptors and their regulatory systems are involved in the molecular mechanisms underlying the clinical effectiveness of SSRI augmentation.
目前，选择性 5-羟色胺再摄取抑制剂（SSRIs）抗抑郁药与抗精神病药联合使用，用于治疗精神分裂症的阴性症状。然而，介导这种治疗临床疗效的生化机制仍不清楚。先前，我们已经报道了氟伏沙明（FLU）与氟哌啶醇（HALO）在体内和体外治疗可调节 GABA-Aβ2/3 受体亚基以及蛋白激酶 C（PKC）和丝裂原活化蛋白激酶/细胞外信号调节激酶（ERK）信号通路。
在本研究中，我们证实慢性 HALO-FLU 治疗（而非单独用药）可显著降低 GABA-Aβ2/3 受体表达（与对照组相比，降低 25%±6.2%），并导致受体从膜向细胞质易位。HALO-FLU 联合治疗对 PKC 和 ERK2 的磷酸化作用的影响与单一药物处理不同。单独给予 HALO 和 FLU 会分别增加 PKC 磷酸化水平（与对照组相比，分别增加 29%±15%和 40%±11.8%），但不影响 ERK2 磷酸化，而 HALO-FLU 联合治疗不会改变 PKC 磷酸化水平，反而会显著降低 ERK2 磷酸化水平（与对照组相比，降低 58%±4.4%）。大脑中 GABA-A 受体下调伴随着 GABA-A 功能下降，如 muscimol 诱导的翻正反射丧失（22±9.8 分钟）。
我们对 SSRI-抗精神病药联合治疗的临床前和临床研究进行了简要的启发式概述，并认为发现其在实验室和临床领域引起类似的动态变化，特别是在 GABA-Aβ2/3 受体和 PKC 中，强烈支持 GABA-A 受体及其调节系统参与 SSRI 增效治疗的临床疗效的分子机制这一假说。
