Department of Cognitive Neuroscience, Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behaviour, Nijmegen, the Netherlands.
Department of Pharmacological and Biomolecular Sciences 'Rodolfo Paoletti', Università degli Studi di Milano, Milan, Italy.
J Affect Disord. 2024 Apr 15;351:128-142. doi: 10.1016/j.jad.2024.01.186. Epub 2024 Jan 26.
Bipolar disorder (BD) is a highly burdensome psychiatric disorder characterized by alternating states of mania and depression. A major challenge in the clinic is the switch from depression to mania, which is often observed in female BD patients during antidepressant treatment such as imipramine. However, the underlying neural basis is unclear.
To investigate the potential neuronal pathways, serotonin transporter knockout (SERT KO) rats, an experimental model of female BD patients, were subjected to a battery of behavioral tests under chronic treatment of the antidepressant imipramine. In addition, the expression of brain-derived neurotrophic factor (BDNF) and its downstream signaling was examined in the prefrontal cortex.
Chronic exposure to imipramine reduced anxiety and sociability and problem-solving capacity, and increased thigmotaxis and day/night activity in all animals, but specifically in female SERT KO rats, compared to female wild-type (WT) rats. Further, we found an activation of BDNF-TrkB-Akt pathway signaling in the infralimbic, but not prelimbic, cortex after chronic imipramine treatment in SERT KO, but not WT, rats.
Repeated testing behaviors could potentially affect the results. Additionally, the imipramine induced changes in behavior and in the BDNF system were measured in separate animals.
Our study indicates that female SERT KO rats, which mirror the female BD patients with the 5-HTTLPR s-allele, are at higher risk of a switch to mania-like behaviors under imipramine treatment. Activation of the BDNF-TrkB-Akt pathway in the infralimbic cortex might contribute to this phenotype, but causal evidence remains to be provided.
双相情感障碍（BD）是一种高度负担的精神疾病，其特征是躁狂和抑郁状态交替出现。临床上的一个主要挑战是从抑郁到躁狂的转变，这在接受抗抑郁药如丙咪嗪治疗的女性 BD 患者中经常观察到。然而，其潜在的神经基础尚不清楚。
为了研究潜在的神经元途径，使用 5-羟色胺转运体敲除（SERT KO）大鼠，这是一种女性 BD 患者的实验模型，在慢性抗抑郁药丙咪嗪治疗下进行了一系列行为测试。此外，还检测了前额叶皮层中脑源性神经营养因子（BDNF）及其下游信号的表达。
慢性暴露于丙咪嗪可减少所有动物的焦虑和社交性以及解决问题的能力，并增加触壁行为和昼夜活动，但在雌性 SERT KO 大鼠中比雌性野生型（WT）大鼠更为明显。此外，我们发现慢性丙咪嗪处理后 SERT KO 大鼠而非 WT 大鼠的下边缘皮层中 BDNF-TrkB-Akt 信号通路被激活。
重复测试行为可能会影响结果。此外，BDNF 系统在行为中的变化是在单独的动物中测量的。
我们的研究表明，女性 SERT KO 大鼠，其与携带 5-HTTLPR s-等位基因的女性 BD 患者相似，在丙咪嗪治疗下更有可能出现躁狂样行为的转变。下边缘皮层中 BDNF-TrkB-Akt 信号通路的激活可能促成了这种表型，但仍需要提供因果证据。
