Mncube K, Harvey B H
Centre of Excellence for Pharmaceutical Sciences (PharmaCen), Division of Pharmacology, School of Pharmacy, North-West University (Potchefstroom Campus), South Africa.
MRC Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry and Mental Health and Neuroscience Institute, University of Cape Town, South Africa.
IBRO Neurosci Rep. 2022 Sep 5;13:284-298. doi: 10.1016/j.ibneur.2022.08.009. eCollection 2022 Dec.
Exposure of Flinders Sensitive Line (FSL) rats to post-weaning social isolation rearing (SIR) causes depressive- and social anxiety-like symptoms resistant to, or worsened by, fluoxetine. SIR typically presents with psychotic-like symptoms, while the paradoxical response to fluoxetine suggests unaddressed psychotic-like manifestations. Psychotic depression (MDpsy) is invariably treatment resistant. To further explore the mood-psychosis continuum in fluoxetine resistant FSL-SIR rats (Mncube et al., 2021), mood-, psychotic-, anxiety-, and social-related behaviour and biomarker response to antidepressant/antipsychotic treatment was studied in FSL-SIR rats. Methods: Sprague Dawley (SD) and FSL pups were subjected to social rearing or SIR from postnatal day (PND) 21. Thereafter FSL-SIR rats received olanzapine (5 mg/kg x 14 days) or olanzapine+fluoxetine (OLZ+FLX; 5 mg/kg + 10 mg/kg for 14 days) from PND 63. Psychotic-like, depressive, anxiety, and social behaviour were assessed from PND 72, versus saline-treated FSL-SIR rats, using the prepulse inhibition (PPI), forced swim, open field and social interaction tests. Post-mortem cortico-hippocampal norepinephrine (NE), serotonin (5-HT), and dopamine (DA), as well as plasma corticosterone and dopamine-beta-hydroxylase levels were evaluated. Results: SD-SIR and FSL-SIR rats present with significant depressive-like behaviour ( < 0.01) as well as significantly reduced sensorimotor gating ( < 0.01), although exacerbation versus SIR alone was not observed. Anxiety was significant in FSL-SIR ( < 0.01) but not SD-SIR rats. No deficit in social behaviour was evident. Cortico-hippocampal monoamines (NE, 5-HT, DA; < .05) and dopamine beta hydroxylase ( = 1.13) were reduced in FSL-SIR rats, less so in SD-SIR rats. Except for dopamine-beta-hydroxylase, these deficits were reversed by both olanzapine and OLZ+FLX ( < 0.01). OLZ+FLX was superior to reverse hipocampal NE and DA changes ( < 0.01). However, OLZ (p < .05) and OLZ+FLX (p < .01) worsened depressive-like behaviour and failed to reverse PPI deficits in FSL-SIR rats.
SIR-exposed FSL rats display worsened anxiety, as well as depressive and psychotic-like symptoms, variably responsive to olanzapine or OLZ+FLX. Depleted monoamines are reversed by OLZ+FLX, less so by olanzapine. FSL-SIR rats show promising face and construct but limited predictive validity for MDpsy, perhaps more relevant for bipolar disorder.
将弗林德斯敏感品系（FSL）大鼠在断奶后进行社会隔离饲养（SIR），会导致出现抑郁样和社交焦虑样症状，这些症状对氟西汀有抗性或会因氟西汀而加重。SIR通常会出现类精神病症状，而对氟西汀的矛盾反应表明存在未得到解决的类精神病表现。精神病性抑郁症（MDpsy）总是对治疗有抗性。为了进一步探索氟西汀抗性FSL-SIR大鼠的情绪-精神病连续体（Mncube等人，2021年），对FSL-SIR大鼠的情绪、精神病、焦虑和社交相关行为以及对抗抑郁药/抗精神病药治疗的生物标志物反应进行了研究。方法：将斯普拉格-道利（SD）和FSL幼崽从出生后第21天开始进行社会饲养或SIR。此后，从出生后第63天开始，FSL-SIR大鼠接受奥氮平（5毫克/千克×14天）或奥氮平+氟西汀（OLZ+FLX；5毫克/千克+10毫克/千克，共14天）。与生理盐水处理的FSL-SIR大鼠相比，从出生后第72天开始使用前脉冲抑制（PPI）、强迫游泳、旷场和社交互动测试评估类精神病、抑郁、焦虑和社交行为。评估死后皮质-海马去甲肾上腺素（NE）、5-羟色胺（5-HT）和多巴胺（DA）以及血浆皮质酮和多巴胺-β-羟化酶水平。结果：SD-SIR和FSL-SIR大鼠表现出显著的抑郁样行为（<0.01）以及显著降低的感觉运动门控（<0.01），尽管未观察到与单独SIR相比有加重情况。焦虑在FSL-SIR大鼠中显著（<0.01），但在SD-SIR大鼠中不显著。社交行为没有明显缺陷。FSL-SIR大鼠的皮质-海马单胺（NE、5-HT、DA；<0.05）和多巴胺β羟化酶（=1.13）减少，SD-SIR大鼠减少程度较小。除了多巴胺-β-羟化酶外，奥氮平和OLZ+FLX均能逆转这些缺陷（<0.01）。OLZ+FLX在逆转海马NE和DA变化方面更具优势（<0.01）。然而，奥氮平（p<0.05）和OLZ+FLX（p<0.01）使FSL-SIR大鼠的抑郁样行为恶化，且未能逆转PPI缺陷。结论：经SIR处理的FSL大鼠表现出更严重的焦虑、抑郁和类精神病症状，对奥氮平或OLZ+FLX的反应各不相同。OLZ+FLX可逆转单胺耗竭，奥氮平的效果较差。FSL-SIR大鼠在表面效度和结构效度方面表现出潜力，但对MDpsy的预测效度有限，可能与双相情感障碍更相关。
