Sertraline promotes hippocampus-derived neural stem cells differentiating into neurons but not glia and attenuates LPS-induced cellular damage

Sertraline is one of the most commonly used antidepressants in clinic. Although it is well accepted that sertraline exerts its action through inhibition of the reuptake of serotonin at presynaptic site in the brain, its effect on the neural stem cells (NSCs) has not been well elucidated. In this study, we utilized NSCs separated from the hippocampus of fetal rat to investigate the effect of sertraline on the proliferation and differentiation of NSCs. The study demonstrated that sertraline had no effect on NSCs proliferation but it significantly promoted NSCs to differentiate into serotoninergic neurons other than glia cells. Furthermore, we found that sertraline protected NSCs against the lipopolysaccharide-induced cellular damage. These data indicate that sertraline can promote neurogenesis and protect the viability of neural stem cells.     

Ketamine-enhanced immobility in forced swim test: a possible animal model for the negative symptoms of schizophrenia

Schizophrenia is a chronic and highly complex psychiatric disorder characterised by cognitive dysfunctions, negative and positive symptoms. The major challenge in schizophrenia research is lack of suitable animal models that mimic the core behavioural aspects and symptoms of this devastating psychiatric disorder. In this study, we used classical and atypical antipsychotic drugs to examine the predictive validity of ketamine-enhanced immobility in forced swim test (FST) as a possible animal model for the negative symptoms of schizophrenia. We also evaluated the effects of a selective serotonin reuptake inhibitor (SSRI) on the ketamine-enhanced immobility in FST. Repeated administration of a subanaesthetic dose of ketamine (30 mg kg(-1), i.p., daily for 5 days) enhanced the duration of immobility in FST 24 h after the final injection. The effect, which persisted for at least 21 days after withdrawal of the drug, was neither observed by single treatment with ketamine (30 mg kg(-1) i.p.) nor repeated treatment with amphetamine (1 and 2 mg kg(-1) i.p., daily for 5 days). The enhancing effects of ketamine (30 mg kg(-1) day(-1) i.p.) on the duration of immobility in the FST were attenuated by clozapine (1, 5 and 10 mg kg(-1) i.p.), risperidone (0.25 and 0.5 mg kg(-1) i.p.) and paroxetine (1 and 5 mg kg(-1) i.p.). Haloperidol (0.25 and 0.50 mg kg(-1) day(-1) i.p.) failed to attenuate the ketamine-enhanced immobility in the FST. The repeated ketamine administration neither affects locomotor activity nor motor coordination in rats under the same treatment conditions with the FST, suggesting that the effects of ketamine on the duration of immobility in this study was neither due to motor dysfunction nor peripheral neuromuscular blockade. Our results suggest that repeated treatment with subanaesthetic doses of ketamine enhance the duration of immobility in FST, which might be a useful animal model for the negative symptoms (particularly the depressive features) of schizophrenia.     

Microinjection of the 5-HT7 receptor antagonist SB-269970 into the rat brainstem and basal forebrain: site-dependent effects on REM sleep

The effects of SB-269970, a selective 5-HT7 receptor antagonist, on spontaneous sleep were studied in adult rats implanted for chronic sleep recordings. The 5-HT7 receptor ligand was microinjected into the horizontal limb of the diagonal band of Broca (HDB) and the laterodorsal tegmental nucleus (LDT) during the light period of the 12-h light/12-h dark cycle. For comparative purposes the compound was administered systemically and, in addition, injected directly into the dorsal raphe nucleus (DRN). Microinjection of SB-269970 into the HDB and the DRN induced a significant reduction of rapid-eye-movement sleep (REMS). Similar effects were observed after systemic administration of the 5-HT7 receptor antagonist. On the other hand, local infusion of the compound into the LDT provoked the opposite effect. It is proposed that the deactivation of GABAergic cells located in the HDB, DRN and LDT is responsible for the changes induced by SB-269970 on REM sleep values. It is suggested that the antidepressant effect of the 5-HT7 receptor antagonist could partly depend on the involvement of neuronal systems located in the DRN and the HDB.     

Amygdala Subregions Tied to SSRI and Placebo Response in Patients with Social Anxiety Disorder

The amygdala is a key structure in the pathophysiology of anxiety disorders, and a putative target for anxiolytic treatments. Selective serotonin reuptake inhibitors (SSRIs) and placebo seem to induce anxiolytic effects by attenuating amygdala responsiveness. However, conflicting amygdala findings have also been reported. Moreover, the neural profile of responders and nonresponders is insufficiently characterized and it remains unknown whether SSRIs and placebo engage common or distinct amygdala subregions or different modulatory cortical areas. We examined similarities and differences in the neural response to SSRIs and placebo in patients with social anxiety disorder (SAD). Positron emission tomography (PET) with oxygen-15-labeled water was used to assess regional cerebral blood flow (rCBF) in 72 patients with SAD during an anxiogenic public speaking task, before and after 6–8 weeks of treatment under double-blind conditions. Response rate was determined by the Clinical Global Impression-Improvement scale. Conjunction analysis revealed a common rCBF-attenuation from pre- to post-treatment in responders to SSRIs and placebo in the left basomedial/basolateral and right ventrolateral amygdala. This rCBF pattern correlated with behavioral measures of reduced anxiety and differentiated responders from nonresponders. However, nonanxiolytic treatment effects were also observed in the amygdala. All subgroups, including nonresponders, showed deactivation of the left lateral part of the amygdala. No rCBF differences were found between SSRI responders and placebo responders. This study provides new insights into the brain dynamics underlying anxiety relief by demonstrating common amygdala targets for pharmacologically and psychologically induced anxiety reduction, and by showing that the amygdala is functionally heterogeneous in anxiolysis.     

Antidepressant-like effects of curcumin on serotonergic receptor-coupled AC-cAMP pathway in chronic unpredictable mild stress of rats

Serotonergic receptors take their physiologic effects by affecting adenylyl cyclase (AC) catalytic activity and cyclic adenosine monophosphate (cAMP) concentration. AC-cAMP second messenger pathway has been recently suggested to play an important role in depression. Therefore, the compound that regulates the signal pathway may have potential as antidepressant. Curcumin is the main component of Curcuma longa L, a well-known indigenous herb with comprehensive bioactivities. In the present study, we investigated the effects of chronic unpredictable mild stress (CUMS) and curcumin on behaviours and serotonergic receptor-coupled AC-cAMP signal pathway in rats. Curcumin produced beneficial effects on the stressed rats by effectively improving CUMS-induced low sucrose consumption and reducing serum corticosterone levels in rats. Moreover, curcumin enhanced AC activity and cAMP levels in platelet and various brain regions, and up-regulated mRNA expressions of AC subtypes AC 2, AC 8 and cAMP response element binding protein (CREB) in the hippocampus, cortex and hypothalamus of the CUMS rats. Curcumin also attenuated CUMS-induced reductions of 5-hydroxytryptamine (5-HT) levels and high expressions of central 5-HT_1A/1B/7 receptors in rats. These results suggested that the potent antidepressant property of curcumin might be attributed to its improvement of AC-cAMP pathway as well as CREB via suppressing central 5-HT_1A/1B/7 receptors in the CUMS rats. Our findings provided a basis for examining the interaction of serotonergic receptors and AC-cAMP pathway in depression and curcumin treatment.     

阿戈美拉汀治疗首发抑郁障碍效果和安全性的Meta分析

目的系统评价阿戈美拉汀治疗首发抑郁障碍患者的效果和安全性,以期为抑郁障碍的药物治疗提供参考。方法检索PubMed、Web of Science、中国学术期刊全文数据库(CNKI)、维普数据库(VIP)、万方数据库中关于阿戈美拉汀治疗首发抑郁障碍患者的临床随机对照研究,提取阿戈美拉汀与SSRIs/SNRIs类抗抑郁药物在治疗首发抑郁障碍的效果和安全性的数据,采用RevMan 5. 3进行Meta分析。结果共纳入12篇文章,其中中文10篇,英文2篇。Meta分析结果显示,治疗后阿戈美拉汀组与对照组HAMD-17评分差异有统计学意义(SMD=-1. 31,95%CI:-1. 55～-1. 07,Z=10. 77,P0. 01)。由于研究间异质性较大(I2=83%,P0. 01),根据对照组所采用抗抑郁药种类进行亚组分析,分别以氟西汀(SMD=-1. 22,95%CI:-1. 66～-0. 77,Z=5. 30,P0. 01)、度洛西汀(SMD=-0. 88,95%CI:-1. 26～-0. 50,Z=4. 49,P0. 01)为对照的研究治疗后HAMD-17评分与阿戈美拉汀组差异均有统计学意义。关于副作用的Meta分析显示,阿戈美拉汀组与对照组之间差异有统计学意义(RR=0. 63,95%CI:0. 49～0. 80,Z=3. 73,P0. 01)。结论阿戈美拉汀治疗首发抑郁障碍的疗效优于SSRIs/SNRIs类抗抑郁药物或与其疗效相当,副作用小于SSRIs/SNRIs类抗抑郁药物。     

Cotinine enhances the extinction of contextual fear memory and reduces anxiety after fear conditioning

Posttraumatic stress disorder (PTSD) is an anxiety disorder triggered by traumatic events. Symptoms include anxiety, depression and deficits in fear memory extinction (FE). PTSD patients show a higher prevalence of cigarette smoking than the general population. The present study investigated the effects of cotinine, a tobacco-derived compound, over anxiety and contextual fear memory after fear conditioning (FC) in mice, a model for inducing PTSD-like symptoms. Two-month-old C57BL/6J mice were separated into three experimental groups. These groups were used to investigate the effect of pretreatment with cotinine on contextual fear memory and posttreatment on extinction and stability or retrievability of the fear memory. Also, changes induced by cotinine on the expression of extracellular signal-regulated kinase (ERK)1/2 were assessed after extinction in the hippocampus. An increase in anxiety and corticosterone levels were found after fear conditioning. Cotinine did not affect corticosterone levels but enhanced the extinction of contextual fear, decreased anxiety and the stability and/or retrievability of contextual fear memory. Cotinine-treated mice showed higher levels of the active forms of ERK1/2 than vehicle-treated mice after FC. This evidence suggests that cotinine is a potential new pharmacological treatment to reduce symptoms in individuals with PTSD.     

Alterations of the amplitude of low-frequency fluctuations in treatment-resistant and treatment-response depression: A resting-state fMRI study

Background

Patients with treatment-resistant depression (TRD) and those with treatment-response depression (TSD) respond to antidepressants differently and previous studies have commonly reported different brain networks in resistant and nonresistant patients. Using the amplitude of low-frequency fluctuations (ALFF) approach, we explored ALFF values of the brain regions in TRD and TSD patients at resting state to test the hypothesis of the different brain networks in TRD and TSD patients.

Methods

Eighteen TRD patients, 17 TSD patients and 17 gender-, age-, and education-matched healthy subjects participated in the resting-state fMRI scans.

Results

There are widespread differences in ALFF values among TRD patients, TSD patients and healthy subjects throughout the cerebellum, the visual recognition circuit (middle temporal gyrus, middle/inferior occipital gyrus and fusiform), the hate circuit (putamen), the default circuit (ACC and medial frontal gyrus) and the risk/action circuit (inferior frontal gyrus). The differences in brain circuits between the TRD and TSD patients are mainly in the cerebellum, the visual recognition circuit and the default circuit.

Conclusions

The affected brain circuits of TRD patients might be partly different from those of TSD patients.     

Involvement of endocannabinoids in antidepressant and anti-compulsive effect of fluoxetine in mice

Endocannabinoid analogues exhibit antidepressant and anti-compulsive like effects similar to that of serotonin selective reuptake inhibitors (SSRIs) indicating a parallelism between the effects of serotonin and endocannabinoids. Therefore, the present study was designed to investigate the role of endocannabinoids in the antidepressant and anti-compulsive like effect of fluoxetine using mice model of forced swim test (FST) and marble-burying behavior (MBB). The results revealed that intracerebroventricular injections of endocannabinoid analogues, anandamide, a CB₁ agonist (AEA: 1-20 μg/mouse); AM404, an anandamide transport inhibitor (0.1-10 μg/mouse); and URB597, a fatty acid amide hydrolase inhibitor (0.05-10 μg/mouse) produced antidepressant-like effect dose-dependently, whereas influenced the MBB in a biphasic manner (produced a U-shaped dose-response curve). Fluoxetine (2.5-20 mg/kg, i.p.) dose dependently decreased the immobility time as well as burying behavior. Co-administration of sub-effective dose of fluoxetine (2.5 mg/kg, i.p.) potentiated the effect of sub-effective dose of AEA (0.5 μg/mouse, i.c.v.), AM404 (0.05 μg/mouse, i.c.v) or URB597 (0.01 μg/mouse, i.c.v) in both the paradigms. Interestingly, pretreatment with AM251, a CB₁ antagonist, blocked the effect of fluoxetine in FST and MBB at a dose (1 μg/mouse, i.c.v) that per se had no effect on either parameter. Similar effects were obtained with endocannabinoid analogues in AM251 pretreated mice. However, AM251 increased the burying behavior in MBB at a highest dose tested (5 μg/mouse). None of the treatments had any influence on locomotor activity. Thus, the study indicates an interaction between endocannabinoid and serotonergic system in regulation of depressive and compulsive-like behavior.