SKF83959 Produces Antidepressant Effects in a Chronic Social Defeat Stress Model of Depression through BDNF-TrkB Pathway

Background:

{"type":"entrez-protein","attrs":{"text":"SKF83959","term_id":"1155968032","term_text":"SKF83959"}}SKF83959 stimulates the phospholipase Cβ/inositol phosphate 3 pathway, resulting in the activation of Ca²⁺/calmodulin-dependent kinase IIα, which affects the synthesis of brain-derived neurotrophic factor, a neurotrophic factor critical for the pathophysiology of depression. Previous reports showed that {"type":"entrez-protein","attrs":{"text":"SKF83959","term_id":"1155968032","term_text":"SKF83959"}}SKF83959 elicited antidepressant activity in the forced swim test and tail suspension test as a novel triple reuptake inhibitor. However, there are no studies showing the effects of {"type":"entrez-protein","attrs":{"text":"SKF83959","term_id":"1155968032","term_text":"SKF83959"}}SKF83959 in a chronic stress model of depression and the role of phospholipase C/inositol phosphate 3/calmodulin-dependent kinase IIα/brain-derived neurotrophic factor pathway in {"type":"entrez-protein","attrs":{"text":"SKF83959","term_id":"1155968032","term_text":"SKF83959"}}SKF83959-mediated antidepressant effects.

Methods:

In this study, {"type":"entrez-protein","attrs":{"text":"SKF83959","term_id":"1155968032","term_text":"SKF83959"}}SKF83959 was firstly investigated in the chronic social defeat stress model of depression. The changes in hippocampal neurogenesis, dendrite spine density, and brain-derived neurotrophic factor signaling pathway after chronic social defeat stress and {"type":"entrez-protein","attrs":{"text":"SKF83959","term_id":"1155968032","term_text":"SKF83959"}}SKF83959 treatment were then investigated. Pharmacological inhibitors and small interfering RNA/short hairpin RNA methods were further used to explore the antidepressive mechanisms of {"type":"entrez-protein","attrs":{"text":"SKF83959","term_id":"1155968032","term_text":"SKF83959"}}SKF83959.

Results:

We found that {"type":"entrez-protein","attrs":{"text":"SKF83959","term_id":"1155968032","term_text":"SKF83959"}}SKF83959 produced antidepressant effects in the chronic social defeat stress model and also restored the chronic social defeat stress-induced decrease in hippocampal brain-derived neurotrophic factor signaling pathway, dendritic spine density, and neurogenesis. By using various inhibitors and siRNA/shRNA methods, we further demonstrated that the hippocampal dopamine D₅ receptor, phospholipase C/inositol phosphate 3/ calmodulin-dependent kinase IIα pathway, and brain-derived neurotrophic factor system are all necessary for the {"type":"entrez-protein","attrs":{"text":"SKF83959","term_id":"1155968032","term_text":"SKF83959"}}SKF83959 effects.

Conclusion:

These results suggest that {"type":"entrez-protein","attrs":{"text":"SKF83959","term_id":"1155968032","term_text":"SKF83959"}}SKF83959 can be developed as a novel antidepressant and produces antidepressant effects via the hippocampal D₅/ phospholipase C/inositol phosphate 3/calmodulin-dependent kinase IIα/brain-derived neurotrophic factor pathway.     

逍遥散不同提取部位对慢性轻度不可预知应激模型大鼠行为学及海马中单胺类神经递质的影响

建立了慢性轻度不可预知应激(CUMS)模型大鼠,分别灌胃给予逍遥散石油醚部位(1)、95%乙醇部位(2)、1+2及盐酸文拉法辛(阳性药),考察大鼠行为学和海马中单胺类神经递质(去甲肾上腺素、5-羟色胺和5-羟基吲哚乙酸)的变化。采用旷场试验和糖水消耗试验结果及大鼠体重评价其行为学改变,并以HPLC-电化学方法检测海马内单胺类神经递质的含量。结果表明,单用1及1+2联用与阳性药具有相似的抗抑郁效果,对大鼠行为学和3种神经递质的回调均有显著改善;而单用2的疗效不显著,在3种神经递质中仅对去甲肾上腺素有显著的回调作用。     

Too Much of a Good Thing: Blocking Noradrenergic Facilitation in Medial Prefrontal Cortex Prevents the Detrimental Effects of Chronic Stress on Cognition

Cognitive impairments associated with dysfunction of the medial prefrontal cortex (mPFC) are prominent in stress-related psychiatric disorders. We have shown that enhancing noradrenergic tone acutely in the rat mPFC facilitated extra-dimensional (ED) set-shifting on the attentional set-shifting test (AST), whereas chronic unpredictable stress (CUS) impaired ED. In this study, we tested the hypothesis that the acute facilitatory effect of norepinephrine (NE) in mPFC becomes detrimental when activated repeatedly during CUS. Using microdialysis, we showed that the release of NE evoked in mPFC by acute stress was unchanged at the end of CUS treatment. Thus, to then determine if repeated elicitation of this NE activity in mPFC during CUS may have contributed to the ED deficit, we infused a cocktail of α₁-, β₁-, and β₂-adrenergic receptor antagonists into the mPFC prior to each CUS session, then tested animals drug free on the AST. Antagonist treatment prevented the CUS-induced ED deficit, suggesting that NE signaling during CUS compromised mPFC function. We confirmed that this was not attributable to sensitization of adrenergic receptor function following chronic antagonist treatment, by administering an additional microinjection into the mPFC immediately prior to ED testing. Acute antagonist treatment did not reverse the beneficial effects of chronic drug treatment during CUS, nor have any effect on baseline ED performance in chronic vehicle controls. Thus, we conclude that blockade of noradrenergic receptors in mPFC protected against the detrimental cognitive effects of CUS, and that repeated elicitation of noradrenergic facilitatory activity is one mechanism by which chronic stress may promote mPFC cognitive dysfunction.     

Dopamine Response to Psychosocial Stress in Chronic Cannabis Users: A PET Study With [11C]-(+)-PHNO

A number of addictions have been linked with decreased striatal dopamine (DA) receptor availability and DA release. Stress has a key role in cannabis craving, as well as in modulation of dopaminergic signaling. The present study aimed to assess DA release in response to a laboratory stress task with [¹¹C]-(+)-PHNO positron emission tomography in cannabis users (CU). Thirteen healthy CU and 12 healthy volunteers (HV) were scanned during a sensorimotor control task (SMCT) and under a stress condition using the validated Montreal imaging stress task (MIST). The simplified reference tissue model (SRTM) was used to obtain binding potential (BP_ND) in striatal subdivisions: limbic striatum (LST), associative striatum (AST), and sensorimotor striatum (SMST). Stress-induced DA release (indexed as a percentage of reduction in [¹¹C]-(+)-PHNO BP _ND) between CU and HV was tested with analysis of variance. SMCT BP_ND was significantly higher in CU compared with HV in the AST (F=10.38, p=0.003), LST (F=4.95, p=0.036), SMST (F=4.33, p=0.048), and whole striatum (F=9.02, p=0.006). Percentage of displacement (change in BP_ND between SMCT and MIST PET scans) was not significantly different across groups in any brain region, except in the GP (−5.03±14.6 in CU, compared with 6.15±12.1 in HV; F=4.39, p=0.049). Duration of cannabis use was significantly associated with stress-induced [¹¹C]-(+)-PHNO displacement by endogenous DA in the LST (r=0.566, p=0.044), with no effect in any other brain region. In conclusion, despite an increase in striatal BP_ND observed during the control task, chronic cannabis use is not associated with alterations in stress-induced DA release.     

The Role of Glutathione in Chronic Adaptation to Oxidative Stress: Studies in a Normal Rat Kidney Epithelial (NRK52E) Cell Model of Sustained Upregulation of Glutathione Biosynthesis

Reduced glutathione (GSH) is considered to play a central role in protection of cells from oxidant injury. However, the question remains as to whether sustained elevation of intracellular GSH levels, as compared with the ability to rapidly upregulate GSH synthesis, is more important with respect to protection of cell constituents from oxidative stress. To address this question, we conducted studies to evaluate the direct influence of chronically increased endogenous GSH content on chemically induced intracellular free radical formation and oxidative stress using a kidney epithelial cell model adapted to sustain intracellular GSH concentrations in excess of eightfold that observed in unadapted parent kidney cells. Elevated GSH levels in adapted cells were found to be attributable, at least in part, to coordinately increased amounts of both the regulatory and catalytic subunits of gamma-glutamylcysteine synthetase (GCS), the rate-limiting enzyme in GSH synthesis. Studies using electron spin resonance (ESR) spectroscopy and scanning laser cytometry demonstrated that cells having sustained elevation of GSH levels did not attenuate free radical formation and associated oxidative stress compared with parent cells when treated with the prooxidant chemicals, menadione or potassium dichromate. In contrast, nonadapted kidney parent cells treated 18 h after initial prooxidant challenge displayed significantly attenuated free radical signals. Additionally, cells adapted to sustain excess GSH were somewhat more sensitive than parent cells in terms of resistance to prooxidant (chromate) toxicity, as determined by cell viability assays. These findings suggest that the capacity of cells to rapidly upregulate GSH synthesis, rather the ability to chronically sustain elevated intracellular GSH levels, may play a more important role in terms of protection from cytotoxicity associated with prooxidant chemical exposures.