NMDAR-independent, cAMP-dependent antidepressant actions of ketamine.
Wray Nathan H,Schappi Jeffrey M,Singh Harinder,Senese Nicolas B,Rasenick Mark M
Molecular psychiatry
Ketamine produces rapid and robust antidepressant effects in depressed patients within hours of administration, often when traditional antidepressant compounds have failed to alleviate symptoms. We hypothesized that ketamine would translocate Gα from lipid rafts to non-raft microdomains, similarly to other antidepressants but with a distinct, abbreviated treatment duration. C6 glioma cells were treated with 10 µM ketamine for 15 min, which translocated Gα from lipid raft domains to non-raft domains. Other NMDA antagonist did not translocate Gα from lipid raft to non-raft domains. The ketamine-induced Gα plasma membrane redistribution allows increased functional coupling of Gα and adenylyl cyclase to increase intracellular cyclic adenosine monophosphate (cAMP). Moreover, increased intracellular cAMP increased phosphorylation of cAMP response element-binding protein (CREB), which, in turn, increased BDNF expression. The ketamine-induced increase in intracellular cAMP persisted after knocking out the NMDA receptor indicating an NMDA receptor-independent effect. Furthermore, 10 µM of the ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) also induced Gα redistribution and increased cAMP. These results reveal a novel antidepressant mechanism mediated by acute ketamine treatment that may contribute to ketamine's powerful antidepressant effect. They also suggest that the translocation of Gα from lipid rafts is a reliable hallmark of antidepressant action that might be exploited for diagnosis or drug development.
10.1038/s41380-018-0083-8
N-Methyladenosine Modification of Fatty Acid Amide Hydrolase Messenger RNA in Circular RNA STAG1-Regulated Astrocyte Dysfunction and Depressive-like Behaviors.
Biological psychiatry
BACKGROUND:N-methyladenosine (mA) is the most abundant epigenetic modification in eukaryotic messenger RNAs and is essential for multiple RNA processing events in physiological and pathological processes. However, precisely how mA methylation is involved in major depressive disorder (MDD) is not fully understood. METHODS:Circular RNA STAG1 (circSTAG1) was screened from the hippocampus of chronic unpredictable stress-treated mice using high-throughput RNA sequencing. Microinjection of circSTAG1 lentivirus into the mouse hippocampus was used to observe the role of circSTAG1 in depression. Sucrose preference, forced swim, and tail suspension tests were performed to evaluate the depressive-like behaviors of mice. Astrocyte dysfunction was examined by GFAP immunostaining and 3D reconstruction. Methylated RNA immunoprecipitation sequence analysis was used to identify downstream targets of circSTAG1/ALKBH5 (alkB homolog 5) axis. Cell Counting Kit-8 assay was performed to evaluate astrocyte viability in vitro. RESULTS:circSTAG1 was significantly decreased in the chronic unpredictable stress-treated mouse hippocampus and in peripheral blood of patients with MDD. Overexpression of circSTAG1 notably attenuated astrocyte dysfunction and depressive-like behaviors induced by chronic unpredictable stress. Further examination indicated that overexpressed circSTAG1 captured ALKBH5 and decreased the translocation of ALKBH5 into the nucleus, leading to increased mA methylation of fatty acid amide hydrolase (FAAH) messenger RNA and degradation of FAAH in astrocytes with subsequent attenuation of depressive-like behaviors and astrocyte loss induced by corticosterone in vitro. CONCLUSIONS:Our findings dissect the functional link between circSTAG1 and mA methylation in the context of MDD, providing evidence that circSTAG1 may be a novel therapeutic target for MDD.
10.1016/j.biopsych.2020.02.018
Angiotensin-Converting Enzyme Inhibitor Rapidly Ameliorates Depressive-Type Behaviors via Bradykinin-Dependent Activation of Mammalian Target of Rapamycin Complex 1.
Luo Han,Wu Peng-Fei,Cao Yu,Jin Ming,Shen Tian-Tian,Wang Ji,Huang Jian-Geng,Han Qian-Qian,He Jin-Gang,Deng Si-Long,Ni Lan,Hu Zhuang-Li,Long Li-Hong,Wang Fang,Chen Jian-Guo
Biological psychiatry
BACKGROUND:Angiotensin-converting enzyme inhibitors (ACEIs) are widely prescribed antihypertensive agents. Intriguingly, case reports and clinical trials have indicated that ACEIs, including captopril and lisinopril, may have a rapid mood-elevating effect in certain patients, but few experimental studies have investigated their value as fast-onset antidepressants. METHODS:The present study consisted of a series of experiments using biochemical assays, immunohistochemistry, and behavioral techniques to examine the effect and mechanism of captopril on depressive-like behavior in 2 animal models, the chronic unpredictable stress model and the chronic social defeat stress model. RESULTS:Captopril (19.5 or 39 mg/kg, intraperitoneal injection) exerted rapid antidepressant activity in mice treated under the chronic unpredictable stress model and mice treated under the chronic social defeat stress model. Pharmacokinetic analysis revealed that captopril crossed the blood-brain barrier and that lisinopril, another ACEI with better blood-brain barrier permeability, exerted a faster and longer-lasting effect at a same molar equivalent dose. This antidepressant effect seemed to be independent of the renin-angiotensin system, but dependent on the bradykinin (BK) system, since the decreased BK detected in the stressed mice could be reversed by captopril. The hypofunction of the downstream effector of BK, Cdc42 (cell division control protein 42) homolog, contributed to the stress-induced loss of dendritic spines, which was rapidly reversed by captopril via activating the mTORC1 (mammalian target of rapamycin complex 1) pathway. CONCLUSIONS:Our findings indicate that the BK-dependent activation of mTORC1 may represent a promising mechanism underlying antidepressant pharmacology. Considering their affordability and availability, ACEIs may emerge as a novel fast-onset antidepressant, especially for patients with comorbid depression and hypertension.
10.1016/j.biopsych.2020.02.005
Hippocampal extracellular matrix alterations contribute to cognitive impairment associated with a chronic depressive-like state in rats.
Riga Danai,Kramvis Ioannis,Koskinen Maija K,van Bokhoven Pieter,van der Harst Johanneke E,Heistek Tim S,Jaap Timmerman A,van Nierop Pim,van der Schors Roel C,Pieneman Anton W,de Weger Anouk,van Mourik Yvar,Schoffelmeer Anton N M,Mansvelder Huib D,Meredith Rhiannon M,Hoogendijk Witte J G,Smit August B,Spijker Sabine
Science translational medicine
Patients with depression often suffer from cognitive impairments that contribute to disease burden. We used social defeat-induced persistent stress (SDPS) to induce a depressive-like state in rats and then studied long-lasting memory deficits in the absence of acute stressors in these animals. The SDPS rat model showed reduced short-term object location memory and maintenance of long-term potentiation (LTP) in CA1 pyramidal neurons of the dorsal hippocampus. SDPS animals displayed increased expression of synaptic chondroitin sulfate proteoglycans in the dorsal hippocampus. These effects were abrogated by a 3-week treatment with the antidepressant imipramine starting 8 weeks after the last defeat encounter. Next, we observed an increase in the number of perineuronal nets (PNNs) surrounding parvalbumin-expressing interneurons and a decrease in the frequency of inhibitory postsynaptic currents (IPSCs) in the hippocampal CA1 region in SDPS animals. In vivo breakdown of the hippocampus CA1 extracellular matrix by the enzyme chondroitinase ABC administered intracranially restored the number of PNNs, LTP maintenance, hippocampal inhibitory tone, and memory performance on the object place recognition test. Our data reveal a causal link between increased hippocampal extracellular matrix and the cognitive deficits associated with a chronic depressive-like state in rats exposed to SDPS.
10.1126/scitranslmed.aai8753
Ketamine ameliorates severe traumatic event-induced antidepressant-resistant depression in a rat model through ERK activation.
Lee Chi-Wei,Chen Yi-Ju,Wu Han-Fang,Chung Yueh-Jung,Lee Yi-Chao,Li Cheng-Ta,Lin Hui-Ching
Progress in neuro-psychopharmacology & biological psychiatry
Treatment-resistant depression (TRD) is a major public health issue, as it is common for patients with depression to fail to respond to adequate trials of antidepressants. However, a well-established animal model of TRD is still warranted. The present study focused on selective serotonin reuptake inhibitor (SSRI) resistance, and aimed to investigate whether higher levels of traumatic stress caused by greater numbers of foot-shocks may lead to severe depression and to examine the feasibility of this as an animal model of SSRI-resistant depression. To reveal the correlation between traumatic stress and severe depression, rats received 3, 6 and 10 tone (conditioned stimulus, CS)-shock (unconditioned stimulus, US) pairings to mimic mild, moderate, and severe traumatic events, and subsequent depressive-like behaviors and protein immunocontents were analyzed. The antidepressant efficacy was assessed for ketamine and SSRI (i.e., fluoxetine) treatment. We found that only the severe stress group presented depressive-like behaviors. Phosphorylation of extracellular signal-regulated kinases (ERKs) was decreased in the amygdala and prefrontal cortex (PFC). The immunocontents of GluA1 and PSD 95 were increased in the amygdala and decreased in the PFC. Moreover, the glutamate-related abnormalities in the amygdala and PFC were normalized by single-dose (10 mg/kg, i.p.) ketamine treatment. In contrast, the depressive-like behaviors were not reversed by 28 days of fluoxetine treatment (10 mg/kg, i.p.) in the severe stress group. Our data demonstrated that high levels of traumatic stress could lead to SSRI-resistant depressive symptoms through impacts on the glutamatergic system, and that this rat model has the potential to be a feasible animal model of SSRI-resistant depression.
10.1016/j.pnpbp.2019.03.015
Hippocampal proteomic changes of susceptibility and resilience to depression or anxiety in a rat model of chronic mild stress.
Tang Min,Huang Haojun,Li Shuiming,Zhou Mi,Liu Zhao,Huang Rongzhong,Liao Wei,Xie Peng,Zhou Jian
Translational psychiatry
Chronic stressful occurrences are documented as a vital cause of both depression and anxiety disorders. However, the stress-induced molecular mechanisms underlying the common and distinct pathophysiology of these disorders remains largely unclear. We utilized a chronic mild stress (CMS) rat model to differentiate and subgroup depression-susceptible, anxiety-susceptible, and insusceptible rats. The hippocampus was analyzed for differential proteomes by combining mass spectrometry and the isobaric tags for relative and absolute quantitation (iTRAQ) labeling technique. Out of 2593 quantified proteins, 367 were aberrantly expressed. These hippocampal protein candidates might be associated with susceptibility to stress-induced depression or anxiety and stress resilience. They provide the potential protein systems involved in various metabolic pathways as novel investigative protein targets. Further, independent immunoblot analysis identified changes in Por, Idh2 and Esd; Glo1, G6pdx, Aldh2, and Dld; Dlat, Ogdhl, Anxal, Tpp2, and Sdha that were specifically associated to depression-susceptible, anxiety-susceptible, or insusceptible groups respectively, suggesting that identical CMS differently impacted the mitochondrial and metabolic processes in the hippocampus. Collectively, the observed alterations to protein abundance profiles of the hippocampus provided significant and novel insights into the stress regulation mechanism in a CMS rat model. This might serve as the molecular basis for further studies that would contributed to a better understanding of the similarities and differences in pathophysiologic mechanisms underlying stress-induced depression or anxiety, and stress resiliency.
10.1038/s41398-019-0605-4
Interleukin-6: Its role and mechanisms in rescuing depression-like behaviors in rat models of depression.
Wang Peng,Feng Ya-Bo,Wang Liyan,Li Ye,Fan Cuiqin,Song Qiqi,Yu Shu Yan
Brain, behavior, and immunity
Neuronal injury within specific brain regions is considered a critical risk factor in the pathophysiology of depression. However, the underlying mechanisms of this process, and thus the potential for development of novel therapeutic strategies in the treatment of depression, remain largely unknown. Here, we report that Il-6 protects against neuronal anomalies related with depression, in part, by suppressing oxidative stress and consequent autophagic and apoptotic hyperactivity. Specifically, we show that IL-6 is downregulated within the CA1 hippocampus in two animal models of depression and upregulated by antidepressants. Increasing levels of IL-6 in the CA1 region result in pleiotropic protective actions including reductions in oxidative stress and modulation of autophagy, anti-immuno-inflammatory activation and anti-apoptotic effects in CA1 neurons, all of which are associated with the rescue of depression-like behaviors. In contrast, IL-6 downregulation exacerbates neuronal anomalies within the CA1 region and facilitates the genesis of depression phenotypes in rats. Interestingly, in addition to attenuating oxidative damage, the antioxidant, N-acetylcysteine (NAC), is also associated with significantly decreased neuronal deficits and the display of depressive behaviors in rats. These results suggest that IL-6 may exert neuroprotection within CA1 neurons via pleiotropic mechanisms and may serve as a potential therapeutic target for the treatment of depression.
10.1016/j.bbi.2019.08.002
Silibinin prevents depression-like behaviors in a single prolonged stress rat model: the possible role of serotonin.
Lee Bombi,Choi Gwang Muk,Sur Bongjun
BMC complementary medicine and therapies
BACKGROUND:Post-traumatic stress disorder (PTSD) is an extreme mood disorder that occurs after experiencing extreme stress, and patients with this disorder are known to accompany with symptoms of depression, anxiety, and memory impairments. Silibinin (SIL) is a natural polyphenolic flavonoid and is the main active ingredient of silymarin, which is primarily extracted from the milk thistle. Although some studies have assessed the properties of this flavonoid, the potential of SIL as a treatment for PTSD patients and its mechanisms of action have yet to be fully elucidated. METHODS:After exposure to a model of single prolonged stress (SPS), the open field test (OFT) and forced swimming test (FST), were used to investigate the effects of SIL on anxiety- and depression-like symptoms in male rats. The rats received of SIL (25, 50, and 100 mg/kg) for 14 days following exposure to SPS. RESULTS:Administration of SIL significantly improved anxiety-like behaviors in the OFT, depression-like behaviors in the FST, and freezing behavior in fear conditioning test. SIL also increased levels of serotonin in the hippocampus (Hipp) and amygdala, and enhanced expression of tryptophan hydroxylase-1 mRNA in the Hipp. The administration of SIL also inhibited SPS-induced decreases dopamine levels and increases norepinephrine levels in the Hipp. CONCLUSIONS:Taken together, the present findings suggest that SIL can be a useful therapeutic ingredient for the treatment of trauma stress-associated symptoms, including PTSD-induced anxiety and depression caused by PTSD.
10.1186/s12906-020-2868-y
Direct Interaction of PP2A Phosphatase with GABA Receptors Alters Functional Signaling.
The Journal of neuroscience : the official journal of the Society for Neuroscience
Addictive drugs usurp the brain's intrinsic mechanism for reward, leading to compulsive and destructive behaviors. In the ventral tegmental area (VTA), the center of the brain's reward circuit, GABAergic neurons control the excitability of dopamine (DA) projection neurons and are the site of initial psychostimulant-dependent changes in signaling. Previous work established that cocaine/methamphetamine exposure increases protein phosphatase 2A (PP2A) activity, which dephosphorylates the GABAR2 subunit, promotes internalization of the GABA receptor (GABAR) and leads to smaller GABAR-activated G-protein-gated inwardly rectifying potassium (GIRK) currents in VTA GABA neurons. How the actions of PP2A become selective for a particular signaling pathway is poorly understood. Here, we demonstrate that PP2A can associate directly with a short peptide sequence in the C terminal domain of the GABAR1 subunit, and that GABARs and PP2A are in close proximity in rodent neurons (mouse/rat; mixed sexes). We show that this PP2A-GABAR interaction can be regulated by intracellular Ca Finally, a peptide that potentially reduces recruitment of PP2A to GABARs and thereby limits receptor dephosphorylation increases the magnitude of baclofen-induced GIRK currents. Thus, limiting PP2A-dependent dephosphorylation of GABARs may be a useful strategy to increase receptor signaling for treating diseases. Dysregulation of GABA receptors (GABARs) underlies altered neurotransmission in many neurological disorders. Protein phosphatase 2A (PP2A) is involved in dephosphorylating and subsequent internalization of GABARs in models of addiction and depression. Here, we provide new evidence that PP2A B55 regulatory subunit interacts directly with a small region of the C-terminal domain of the GABAR1 subunit, and that this interaction is sensitive to intracellular Ca We demonstrate that a short peptide corresponding to the PP2A interaction site on GABAR1 competes for PP2A binding, enhances phosphorylation GABAR2 S783, and affects functional signaling through GIRK channels. Our study highlights how targeting PP2A dependent dephosphorylation of GABARs may provide a specific strategy to modulate GABAR signaling in disease conditions.
10.1523/JNEUROSCI.2654-19.2020
Astrocytes in rapid ketamine antidepressant action.
Stenovec Matjaž,Li Baoman,Verkhratsky Alexei,Zorec Robert
Neuropharmacology
Ketamine, a general anaesthetic and psychotomimetic drug, exerts rapid, potent and long-lasting antidepressant effect, albeit the cellular and molecular mechanisms of this action are yet to be discovered. Besides targeting neuronal NMDARs fundamental for synaptic transmission, ketamine affects the function of astroglia the key homeostatic cells of the central nervous system that contribute to pathophysiology of psychiatric diseases including depression. Here we review studies revealing that (sub)anaesthetic doses of ketamine elevate intracellular cAMP concentration ([cAMP]) in astrocytes, attenuate stimulus-evoked astrocyte calcium signalling, which regulates exocytotic secretion of gliosignalling molecules, and stabilize the vesicle fusion pore in a narrow configuration possibly hindering cargo discharge or vesicle recycling. Next we discuss how ketamine affects astroglial capacity to control extracellular K by reducing cytoplasmic mobility of vesicles delivering the inward rectifying potassium channel (Kir4.1) to the plasmalemma. Modified astroglial K buffering impacts upon neuronal excitability as demonstrated in the lateral habenula rat model of depression. Finally, we highlight the recent discovery that ketamine rapidly redistributes cholesterol in the plasmalemma of astrocytes, but not in fibroblasts nor in neuronal cells. This alteration of membrane structure may modulate a host of processes that synergistically contribute to ketamine's rapid and prominent antidepressant action.
10.1016/j.neuropharm.2020.108158
Depression and anxiety behaviour in a rat model of chronic migraine.
Zhang Mingjie,Liu Yufei,Zhao Mangsuo,Tang Wenjing,Wang Xiaolin,Dong Zhao,Yu Shengyuan
The journal of headache and pain
BACKGROUND:Epidemiological and clinical studies have demonstrated comorbidity between migraine and affective disorders. However, it is unclear whether chronic migraine can lead to affective disorders in other animals. METHODS:A classical chronic migraine rat model (repeated dura mater inflammatory soup [IS] infusion) was used to evaluate depression and anxiety behaviour via weight, sucrose preference test, open field test and elevated plus maze test. RESULTS:We found that sucrose preference, locomotor and rearing behaviours, inner zoon distance percent, open-arm entries percent and serotonin and dopamine levels in the prefrontal cortex decreased significantly in the IS group compared with those in the control group; co-administration of low-dose amitriptyline ameliorated these deficits. However, no differences in weight, inner zone time percent, or open-arm time percent between the IS and control groups. These results were used to create new depression and anxiety scales to comprehensively assess and evaluate the degree of affective disorders in rats. Most of chronic migraine animals showed depression and anxiety like behaviors but a few didn't. CONCLUSIONS:Most of the chronic migraine rats were present depression and anxiety like behaviors. The new scales we created are expected to use in the future studies to find out the potential mechanism of affective disorders' comorbidity.
10.1186/s10194-017-0736-z
Effects of Baihe Dihuang powder on chronic stress depression rat models.
Miao Mingsan,Peng Mengfan,Chen Hongbao,Liu Baosong
Saudi journal of biological sciences
PURPOSE:Explore the effect of Baihe Dihuang powder on chronic stress depression rat models. METHODS:Chronic stress depression rat models were established with different stimuli for 21 days. At the same time, the drug was administered for 21 consecutive days. The animals were weighed once a week after the start of the formal experiment. On the second day after the end of drug administration, conduct sugar water consumption test and open-filed box experiment, and conduct behavioral observation; At the end of behavioral testing, blood was taken from the eyeball and plasma was separated to measure MDA level and erythrocyte SOD activity; Take brain for homogenate, then measure the contents of 5-HT, NE and DA in brain tissue homogenate; Take the thymus and spleen, stained with 10% formalin fixation, embedding and HE staining, then use microscope to observe the histopathological changes. RESULTS:Chronic stress depression rats model replicated successfully. Each group of given drugs could increase the weight, the consumption of sugar water, and improve the behavioral score, increase erythrocytes SOD activity and decrease MDA level of plasma, increase the content of 5-HT, NE and DA of brain homogenate, and improve the pathological changes of thymus and spleen of chronic stress depression model animals. CONCLUSION:Chronic stress depression rat model replicates successfully. Baihe Dihuang powder can interfere chronic stress depression rats model through different action pathways.
10.1016/j.sjbs.2018.12.002
Impaired Cognitive Flexibility and Working Memory Precedes Depression: A Rat Model to Study Depression.
Neuropsychobiology
INTRODUCTION:Depressive disorders are the 4th leading cause of health problems and the 2nd leading cause of burden among all diseases. Almost all depressive disorder patients have cognitive impairments to a certain extend. Studies about cognitive impairments in depression had been conducted, but whether cognitive dysfunctions are the cause or the effect is still not clear. OBJECTIVES:To analyze the process of working memory and cognitive flexibility impairments in a rat model of depression. METHODS:In this experimental study, chronic unpredictable mild stress (CUMS) was used as a model of depression in 30 rats (Rattus novergicus). Cognitive function was assessed with the Morris water maze and attentional set shifting test. RESULTS:This study found a significant difference on day 21 in working memory (p = 0.002) and cognitive flexibility (p = 0.036), which continued to day 41 in working memory (p = 0.001) and cognitive flexibility (p = 0.020). In the CUMS model of depression, parameters peak on day 41 and reveal parameter changes in weight gain (p = 0.018), food intake (p < 0.001), changes in food intake (p = 0.001), and the sucrose preference (p = 0.005), elevated plus maze (p = 0.001), and light dark box tests (p = 0.020). CONCLUSION:In a rat model of depression, cognitive impairment preceded depression, but it might be caused by anxiety-like behavior that occurred in early stimulation of chronic unpredictable mild stress.
10.1159/000508682