Chang Celene H, Chen Michael C, Lu Jun
Department of Neurology and Division of Sleep Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
Department of Neurology and Division of Sleep Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
Neuropharmacology. 2015 May;92:116-24. doi: 10.1016/j.neuropharm.2015.01.010. Epub 2015 Jan 28.
Our recent study indicates that the lesions of the prefrontal cortex in rats result in depressive-like behavior in forced swim test and REM sleep alterations, two well-established biomarkers of depression disorder. We hypothesized that antidepressants may target the PFC to reverse depression. Systemic injections of antidepressants: the tricyclic antidepressant desipramine (DMI), the selective serotonin reuptake inhibitor fluoxetine, and the NMDA-antagonist ketamine selectively increased cFos expression (a marker of neuronal activity) in the deep layers of the ventromedial PFC (vmPFC) in rats. Of the vmPFC's limbic system targets, only the nucleus accumbens (NAc) was also activated by DMI. Using a retrograde tracer and a neuronal toxin, we also found that DMI-activated vmPFC neurons project to the NAc and that NAc activation by DMI was lost following vmPFC lesion. These results suggest that the vmPFC may be an essential target of antidepressant drugs, its projections to the NAc may be a key circuit regulating antidepressant action, and dysfunction of this pathway may contribute to depression.
我们最近的研究表明，大鼠前额叶皮质的损伤会导致强迫游泳试验中的抑郁样行为和快速眼动睡眠改变，这是抑郁症的两个公认的生物标志物。我们假设抗抑郁药可能靶向前额叶皮质以逆转抑郁。全身性注射抗抑郁药：三环类抗抑郁药地昔帕明（DMI）、选择性5-羟色胺再摄取抑制剂氟西汀和N-甲基-D-天冬氨酸拮抗剂氯胺酮，可选择性增加大鼠腹内侧前额叶皮质（vmPFC）深层的cFos表达（神经元活动的标志物）。在vmPFC的边缘系统靶点中，只有伏隔核（NAc）也被DMI激活。使用逆行示踪剂和神经元毒素，我们还发现DMI激活的vmPFC神经元投射到NAc，并且在vmPFC损伤后，DMI对NAc的激活作用消失。这些结果表明，vmPFC可能是抗抑郁药物的重要靶点，其向NAc的投射可能是调节抗抑郁作用的关键回路，并且该通路的功能障碍可能导致抑郁症。
