Social vs. environmental stress models of depression from a behavioural and neurochemical approach

Major depression is a mental disorder often preceded by exposure to chronic stress or stressful life events. Recently, animal models based on social conflict such as chronic social defeat stress (CSDS) are proposed to be more relevant to stress-induced human psychopathology compared to environmental models like the chronic mild stress (CMS). However, while CMS reproduces specifically core depressive symptoms such as anhedonia and helplessness, CSDS studies rely on the analysis of stress-induced social avoidance, addressing different neuropsychiatric disorders. Here, we study comparatively the two models from a behavioural and neurochemical approach and their possible relevance to human depression. Mice (C57BL/6) were exposed to CMS or CSDS for six weeks and ten days. Anhedonia was periodically evaluated. A battery of test applied during the fourth week after the stress procedure included motor activity, memory, anxiety, social interaction and helplessness. Subsequently, we examined glutamate, GABA, 5-HT and dopamine levels in the prefrontal cortex, hippocampus and brainstem. CMS induced a clear depressive-like profile including anhedonia, helplessness and memory impairment. CSDS induced anhedonia, hyperactivity, anxiety and social avoidance, signs also common to anxiety and posttraumatic stress disorders. While both models disrupted the excitatory inhibitory balance in the prefrontal cortex, CMS altered importantly this balance in the brainstem. Moreover, CSDS decreased dopamine in the prefrontal cortex and brainstem. We suggests that while depressive-like behaviours might be associated to altered aminoacid neurotransmission in cortical and brain stem areas, CSDS induced anxiety behaviours might be linked to specific alteration of dopaminergic pathways involved in rewarding processes.     

Zileuton ameliorates depressive-like behaviors,hippocampal neuroinflammation,apoptosis and synapse dysfunction in mice exposed to chronic mild stress

Our previous study has found that zileuton, a selective 5-lipoxygenase (5LO) inhibitor, abrogated lipopolysaccharide-induced depressive-like behaviors and hippocampal neuroinflammation. Herein, we further extended our curiosity to investigate effects of zileuton on stress-induced depressive-like behaviors. Our data indicated that zileuton significantly ameliorated depressive-like behaviors in mice subjected to chronic mild stress (CMS), as shown in the tail suspension test, forced swimming test and novelty-suppressed feeding test. The further studies indicated that zileuton suppressed hippocampal neuroinflammation, evidenced by lower levels of TNF-α, IL-1β and nuclear NF-κB p65 as well as decreased number of Iba1-positive cells. It also significantly ameliorated hippocampal apoptosis, indicated by deceased number of TUNEL-positive cells, deceased ratio of cleaved caspase-3/procaspase-3 and increased ratio of Bcl-2/Bax. More importantly, zileuton increased the level of synaptic proteins PSD-95 and SYN and the number of NeuN⁺/BrdU⁺ cells in the hippocampus. Over all, zileuton alleviated CMS-induced depressive-like behaviors, neuroinflammatory and apoptotic responses, abnormalities of synapse and neurogenesis in the hippocampus, suggesting that it might has beneficial effects on depression.     

Chronic social defeat stress model: behavioral features, antidepressant action, and interaction with biological risk factors

Rationale

Chronic social defeat stress (CSDS) has been proposed as a model of depression. However, most CSDS studies rely only on the analysis of stress-induced social avoidance. Moreover, the predictive validity of the model has been poorly analyzed, let alone its interaction with biological risk factors.

Objectives

Here, we explore the validity of CSDS as a depression model. Further, the effect of decreased vesicular glutamate transporter 1 (VGLUT1), as a potential factor enhancing a depressive-like phenotype, was studied.

Methods

Mice were exposed to CSDS (10?days) followed by saline, venlafaxine, fluoxetine, or tianeptine treatment (30?days). The battery of behaviors included motor activity, memory, anxiety, social interaction, helplessness, and anhedonic-like behavior. Moreover, the behavioral effect of CSDS in VGLUT1 heterozygous (VGLUT1+/?) mice was studied, as well as the regulation of VGLUT1 mRNA.

Results

CSDS induced anhedonia, helplessness, hyperactivity, anxiety, social avoidance, and freezing, as well as downregulation of VGLUT1 mRNA in the amygdala. Repeated venlafaxine showed antidepressant-like activity and both venlafaxine and tianeptine behaved as effective anxiolytics. CSDS-induced social avoidance was reverted by tianeptine. Fluoxetine failed to revert most of the behavioral alterations. VGLUT1+/? mice showed an enhanced vulnerability to stress-induced social avoidance.

Conclusion

We suggest that CSDS is not a pure model of depression. Indeed, it addresses relevant aspects of anxiety-related disorders. Firstly, CSDS-induced anhedonia and social avoidance are not associated in this model. Moreover, CSDS might be affecting brain areas mainly involved in the processing of social behavior, such as the amygdala, where the glutamatergic mechanism could play a key role.     

Low-Level Stress Induces Production of Neuroprotective Factors in Wild-Type but Not BDNF+/- Mice: Interleukin-10 and Kynurenic Acid

Background:

Brain-derived neurotrophic factor (BDNF) deficiency confers vulnerability to stress, but the mechanisms are unclear. BDNF^+/- mice exhibit behavioral, physiological, and neurochemical changes following low-level stress that are hallmarks of major depression. After immune challenge, neuroinflammation-induced changes in tryptophan metabolism along the kynurenine pathway mediate depressive-like behaviors.

Methods:

We hypothesized that BDNF^+/- mice would be more susceptible to stress-induced neuroinflammation and kynurenine metabolism, so BDNF^+/- or wild-type littermate mice were subject to repeated unpredictable mild stress. Proinflammatory cytokine expression and kynurenine metabolites were measured.

Results:

Unpredictable mild stress did not induce neuroinflammation. However, only wild-type mice produced the neuroprotective factors interleukin-10 and kynurenic acid in response to repeated unpredictable mild stress. In BDNF^+/- mice, kynurenine was metabolized preferentially to the neurotoxic intermediate 3-hydroxykynurenine following repeated unpredictable mild stress.

Conclusions:

Our data suggest that BDNF may modulate kynurenine pathway metabolism during stress and provide a novel molecular mechanism of vulnerability and resilience to the development of stress-precipitated psychiatric disorders.     

Increased Cdk5/p35 activity in the dentate gyrus mediates depressive-like behaviour in rats

Depression is one of the most pervasive and debilitating psychiatric diseases, and the molecular mechanisms underlying the pathophysiology of depression have not been elucidated. Cyclin-dependent kinase 5 (Cdk5) has been implicated in synaptic plasticity underlying learning, memory, and neuropsychiatric disorders. However, whether Cdk5 participates in the development of depressive diseases has not been examined. Using the chronic mild stress (CMS) procedure, we examined the effects of Cdk5/p35 activity in the hippocampus on depressive-like behaviour in rats. We found that CMS increased Cdk5 activity in the hippocampus, accompanied by translocation of neuronal-specific activator p35 from the cytosol to the membrane in the dentate gyrus (DG) subregion. Inhibition of Cdk5 in DG but not in the cornu ammonis 1 (CA1) or CA3 hippocampal subregions inhibited the development of depressive-like symptoms. Overexpression of p35 in DG blocked the antidepressant-like effect of venlafaxine in the CMS model. Moreover, the antidepressants venlafaxine and mirtazapine, but not the antipsychotic aripiprazole, reduced Cdk5 activity through the redistribution of p35 from the membrane to the cytosol in DG. Our results showed that the development of depressive-like behaviour is associated with increased Cdk5 activity in the hippocampus and that the Cdk5/p35 complex plays a key role in the regulation of depressive-like behaviour and antidepressant actions.     

Implication of 5-HT7 receptor in prefrontal circuit assembly and detrimental emotional effects of SSRIs during development

Altered development of prefrontal cortex (PFC) circuits can have long-term consequences on adult emotional behavior. Changes in serotonin homeostasis during critical periods produced by genetic or pharmacological inactivation of the serotonin transporter (SERT, or Slc6a4), have been involved in such developmental effects. In mice, selective serotonin reuptake inhibitors (SSRIs), administered during postnatal development cause exuberant synaptic connectivity of the PFC to brainstem dorsal raphe nucleus (DRN) circuits, and increase adult risk for developing anxiety and depressive symptoms. SERT is transiently expressed in the glutamate neurons of the mouse PFC, that project to the DRN. Here, we find that 5-HTR7 is transiently co-expressed with SERT by PFC neurons, and it plays a key role in the maturation of PFC-to-DRN synaptic circuits during early postnatal life. 5-HTR7-KO mice show reduced PFC-to-DRN synaptic density (as measured by array-tomography and VGLUT1/synapsin immunocytochemistry). Conversely, 5-HTR7 over-expression in the developing PFC increased PFC-to-DRN synaptic density. Long-term consequences on depressive-like and anxiogenic behaviors were observed in adults. 5-HTR7 over-expression in the developing PFC, results in depressive-like symptoms in adulthood. Importantly, the long-term depressive-like and anxiogenic effects of SSRIs (postnatal administration of fluoxetine from P2 to P14) were not observed in 5-HTR7-KO mice, and were prevented by co-administration of the selective inhibitor of 5-HTR7, SB269970. This study identifies a new role 5-HTR7 in the postnatal maturation of prefrontal descending circuits. Furthermore, it shows that 5-HTR7 in the PFC is crucially required for the detrimental emotional effects caused by SSRI exposure during early postnatal life.Subject terms: Synaptic development, Depression     

囊泡谷氨酸转运体与神经系统疾病

囊泡谷氨酸转运体(vesicular glutamate transporters,VGLUTs)能特异地装载谷氨酸进入突触囊泡并促进释放,它包括3个成员,其中VGLUT1和VGLUT2是谷氨酸能神经元和它们轴突末端高度特异的标志,同时VGLUT1标志着皮质-皮质投射,VGLUT2标志着丘脑-皮层投射。而VGLUT3则会出现在胆碱能中间神经元、5-羟色胺能神经元、海马和皮层中GABA能中间神经元中。VGLUTs的异常会导致兴奋性神经递质谷氨酸的异常,从而诱发多种神经系统疾病。该文综述了VGLUTs的功能障碍与阿尔采末病(Alzheimer’sdisease,AD)、帕金森病(Parkinson’s disease,PD)、精神分裂症、抑郁症、癫痫、耳聋发病的关系的研究进展,为这些疾病的防治提供新的线索。     

In utero exposure to benzo[a]pyrene increases adiposity and causes hepatic steatosis in female mice,and glutathione deficiency is protective

Polycyclic aromatic hydrocarbons (PAHs), including benzo[a]pyrene (BaP), are ubiquitous environmental pollutants found in tobacco smoke, air pollution, and grilled foods. Reactive metabolites and reactive oxygen species generated during PAH metabolism are detoxified by reactions involving glutathione (GSH). Early life exposures to tobacco smoke and air pollution have been linked to increased risk of obesity and metabolic syndrome. We investigated the independent and interactive effects of prenatal exposure to BaP and GSH deficiency due to deletion of the modifier subunit of glutamate cysteine ligase (Gclm), the rate-limiting enzyme in GSH synthesis, on adiposity and hepatic steatosis in adult female F1 offspring. We mated Gclm^+/− dams with Gclm^+/− males and treated the pregnant dams with 0, 2, or 10 mg/kg/day BaP in sesame oil by oral gavage daily from gestational day 7 through 16. We analyzed metabolic endpoints in female Gclm^−/− and Gclm^+/+ littermate F1 offspring. Prenatal BaP exposure significantly increased visceral adipose tissue weight, weight gain between 3 weeks and 7.5 months of age, hepatic lipid content measured by oil red O staining, and hepatic fatty acid beta-oxidation gene expression in Gclm^+/+, but not in Gclm^−/−, female offspring. Hepatic expression of lipid biosynthesis and antioxidant genes were decreased and increased, respectively, in Gclm^−/− mice. Our results suggest that reported effects of pre- and peri-natal air pollution and tobacco smoke exposure on obesity may be mediated in part by PAHs. GSH deficiency is protective against the metabolic effects of prenatal BaP exposure.     

Cdk5/p35参与了慢性应激诱导的大鼠抑郁样行为

背景:对抑郁症发生机制的研究表明,抑郁症患者表现为海马以及其他脑边缘结构的体积减少和细胞丢失,抗抑郁剂可显著促进抑郁模型动物海马神经元发生,提示神经可塑性机制涉及了抑郁症的发生过程。周期素依赖性蛋白激酶-5(Cdk5)及其活性调节蛋白p35是保持成熟神经系统内边缘系统,尤其是海马中神经元具有潜在可塑性的关键激酶。Cdk5在中枢神经系统发育过程中起着至关重要的作用,主要与神经元迁移、轴突生长和神经递质释放有关,还参与细胞骨架形成、轴突导向、膜转运、突触功能和多巴胺信号转导等多种神经功能调控。然而,在某些病理性因素作用下,Cdk5激酶活性异常升高会引起神经元的过度死亡,导致一些神经退行性疾病的发生。Cdk5在调节神经元的生存方面发挥着重要的作用,那么在抑郁症损伤的海马神经元中,Cdk5是否也参与了神经元的生存过程,从而介导了抑郁症的发生尚未见到报道。目的:本研究将基于抑郁症神经可塑性的研究基础,探讨Cdk5/p35在抑郁症模型大鼠抑郁样行为中的作用,以期进一步阐明抑郁症发生的神经生物学机制,并为临床发现新的治疗抑郁症的有效手段奠定理论基础。方法:采用连续21d的慢性不可预见性的中等强度应激抑郁模型(CMS),以动物的体重变化、蔗糖水偏爱(sucrosep reference)和自发活动能力为指标,考察抑郁模型动物行为学变化;通过测定Cdk5特定底物-组蛋白H1被磷酸化的程度检测大鼠海马部位Cdk5激酶活性,用Westernblot的方法检测p35蛋白的表达;同时在应激过程中,采用微量注射的方法,分别在海马齿状回(DG),CA1及CA3亚区给予Cdk5激酶抑制剂(butyrolactone),观察抑制不同脑区Cdk5激酶对抑郁症模型动物体重,糖水偏爱、自发活动性等抑郁样行为的影响。此外,在慢性应激的同时,连续给予抗抑郁药venlafaxine和mirtazapine,考察抗抑郁剂的治疗作用对海马p35蛋白表达水平的影响。结果:慢性应激大鼠海马部位Cdk5激酶活性显著升高;Western blot结果表明应激大鼠海马DG区胞膜组分p35蛋白的表达水平明显上调,而胞浆p35蛋白表达水平显著降低;相关性分析结果表明海马Cdk5激酶活性与胞膜p35蛋白的表达水平呈明显正相关,而与胞浆p35蛋白的表达水平呈明显负相关;大鼠体重增加值,糖水偏爱与海马胞膜p35蛋白的表达水平呈显著负相关。上述结果表明海马Cdk5激酶活性升高参与了慢性应激诱导的大鼠抑郁样行为。行为学检测结果表明,海马DG区微注射Cdk5激酶抑制剂butyrolactone(50,100ng)可显著逆转慢性应激引起的大鼠抑郁样行为,而在CA1和CA3区微注射butyrolactone(100ng)则对大鼠的抑郁样行为没有明显影响,说明抑制Cdk5激酶活性改善大鼠抑郁样行为具有脑区特异性。在慢性应激实验中发现连续给予抗抑郁药venlafaxine(40mg·kg-1)和mirtazapine(20mg·kg-1)可明显降低DG区胞膜p35蛋白的表达水平,促进p35蛋白由胞膜转运至胞浆,而抗精神病药aripiprazole(5mg.kg-1)对慢性应激引起的DG区胞膜p35蛋白表达增加没有明显影响,说明降低胞膜p35蛋白的表达水平,抑制Cdk5激酶活性是抗抑郁药物特异性的。结论:本研究通过一系列实验证实了Cdk5/p35在慢性应激大鼠抑郁样行为中的作用,抑制Cdk5活性可有效逆转动物的抑郁样行为,抗抑郁剂在发挥治疗作用的同时可抑制Cdk5激酶的异常激活。因此,本研究结果为抑郁症的神经生物学机制研究和临床抗抑郁治疗药物研究开发提供了新的思路。     

Changes in glutamate decarboxylase enzyme activity and tau-protein phosphorylation in the hippocampus of old rats exposed to chronic mild stress: reversal with the neuronal nitric oxide synthase inhibitor 7-nitroindazole

Effects of chronic stress are not completely understood. They may underlie depression and dementia. This study assessed the association between chronic stress, glutamate levels, tau-protein phosphorylation, and nitric-oxide in old rats exposed to chronic mild stress (CMS). Old (> 15 months) male Wistar rats were exposed to CMS. Comparison groups included old and young control rats, young CMS-exposed, and old CMS-exposed rats treated with the neuronal nitric-oxide synthase (nNOS) enzyme inhibitor, 7-nitroindazole (20 mg/kg/day i.p.). Hippocampal glutamate levels and glutamate decarboxylase (GAD) activity were determined and tau protein phosphorylation was assessed. Age was a significant (p = 0.025) source of variation in glutamate level [811.71 ± 218.1, 665.9 ± 124.9 µmol/g tissue protein (M ± SD) in young and old control rats, respectively]. Old rats exposed to CMS were characterized by an increased risk to develop anhedonia. There was significant (p = 0.035) decrease in GAD enzyme activity (− 60.06%) and increased tau protein hyperphosphorylation in old rats exposed to CMS compared to control. Administration of 7-nitroindazole to CMS-exposed old rats significantly (p = 0.002) increased GAD activity, decreased glutamate levels (7.19 ± 3.19 vs. 763.9 ± 91 µmol/g tissue protein; p = 0.0005), and decreased phosphorylation of tau proteins compared to CMS exposed rats.     

An activated renin-angiotensin system maintains normal blood pressure in aryl hydrocarbon receptor heterozygous mice but not in null mice

It has been postulated that fetal vascular abnormalities in aryl hydrocarbon receptor null (ahr^−/−) mice may alter cardiovascular homeostasis in adulthood. We tested the hypothesis that blood pressure regulation in adult heterozygous mice (ahr^+/−) would be normal, compared to ahr^−/− mice, since no vascular abnormalities have been reported in the heterozygote animals. Mean arterial blood pressure (MAP) was measured using radiotelemetry prior to and during treatment with inhibitors of the autonomic nervous system, nitric oxide synthase (NOS), angiotensin converting enzyme (ACE), or endothelin-1 A receptor (ET_A). Also, indices of renin-angiotensin system (RAS) activation were measured. ahr^+/− and ahr^−/− mice were normotensive and hypotensive, respectively, compared to wild-type (ahr^+/+) littermates. Responses of all genotypes to autonomic nervous system inhibition were normal. ahr^+/− mice responded normally to NOS inhibition, while the responses of ahr^−/− mice were significantly blunted. In contrast, ahr^+/− mice were significantly more responsive to inhibition of ACE, an ET_A antagonist, or both, while ahr^−/− mice were significantly less responsive to ACE inhibition and more responsive to an ET_A antagonist. ahr^+/− mice also exhibited significant increases in plasma renin and ACE activity, plasma sodium, and urine osmolality, indicative of RAS activation. Thus, normotension in ahr^+/− mice appears to be maintained by increased RAS and ET-1 signaling, while hypotension in ahr^−/− mice may result from decreased RAS signaling. In conclusion, despite the lack of overt fetal vascular abnormalities in ahr^+/− mice, the loss of a single ahr allele has a significant effect on blood pressure regulation.     

Targeting glial physiology and glutamate cycling in the treatment of depression

Accumulating evidence indicates that dysfunction in amino acid neurotransmission contributes to the pathophysiology of depression. Consequently, the modulation of amino acid neurotransmission represents a new strategy for antidepressant development. While glutamate receptor ligands are known to have antidepressant effects, mechanisms regulating glutamate cycling and metabolism may be viable drug targets as well. In particular, excitatory amino acid transporters (EAATs) that are embedded in glial processes constitute the primary means of clearing extrasynaptic glutamate. Therefore, the decreased glial number observed in preclinical stress models, and in postmortem tissue from depressed patients provides intriguing, yet indirect evidence for a role of disrupted glutamate homeostasis in the pathophysiology of depression. More direct evidence for this hypothesis comes from studies using magnetic resonance spectroscopy (MRS), a technique that non-invasively measures in vivo concentrations of glutamate and other amino acids under different experimental conditions. Furthermore, when combined with the infusion of ¹³C-labeled metabolic precursors, MRS can measure flux through discrete metabolic pathways. This approach has recently shown that glial amino acid metabolism is reduced by chronic stress, an effect that provides a link between environmental stress and the decreased EAAT activity observed under conditions of increased oxidative stress in the brain. Furthermore, administration of riluzole, a drug that enhances glutamate uptake through EAATs, reversed this stress-induced change in glial metabolism. Because riluzole has antidepressant effects in both animal models and human subjects, it may represent the prototype for a novel class of antidepressants with the modulation of glial physiology as a primary mechanism of action.     

Depression-resistant endophenotype in mice overexpressing cannabinoid CB2 receptors

Background and purpose:

The present study evaluated the role of CB₂ receptors in the regulation of depressive-like behaviours. Transgenic mice overexpressing the CB₂ receptor (CB2xP) were challenged with different types of acute and chronic experimental paradigms to evaluate their response in terms of depressive-like behaviours.

Experimental approach:

Tail suspension test (TST), novelty-suppressed feeding test (NSFT) and unpredictable chronic mild stress tests (CMS) were carried out in CB2xP mice. Furthermore, acute and chronic antidepressant-like effects of the CB₂ receptor-antagonist AM630 were evaluated by means of the forced swimming test (FST) and CMS, respectively, in wild-type (WT) and CB2xP mice. CB₂ gene expression, brain-derived neurotrophic factor (BDNF) gene and protein expressions were studied in mice exposed to CMS by real-time PCR and immunohistochemistry, respectively.

Key results:

Overexpression of CB₂ receptors resulted in decreased depressive-like behaviours in the TST and NSFT. CMS failed to alter the TST and sucrose consumption in CB2xP mice. In addition, no changes in BDNF gene and protein expression were observed in stressed CB2xP mice. Interestingly, acute administration of AM630 (1 and 3 mg·kg⁻¹, i.p.) exerted antidepressant-like effects on the FST in WT, but not in CB2xP mice. Chronic administration of AM630 for 4 weeks (1 mg·kg⁻¹; twice daily, i.p.) blocked the effects of CMS on TST, sucrose intake, CB₂ receptor gene, BDNF gene and protein expression in WT mice.

Conclusion and implications:

Taken together, these results suggest that increased CB₂ receptor expression significantly reduced depressive-related behaviours and that the CB₂ receptor could be a new potential therapeutic target for depressive-related disorders.     

Chronic mild stress induces behavioral and physiological changes,and may alter serotonin 1A receptor function,in male and cycling female rats

Rationale Interactions among stress, serotonin 1A (5-HT_1A) receptors, and the hypothalamic–pituitary–adrenocortical (HPA) system have been proposed to influence the development of depression in humans. The investigation of depression-relevant behaviors and physiological responses to environmental stressors in animal models of depression may provide valuable insight regarding these mechanisms.Objectives The purpose of these experiments was to investigate the interactions among central 5-HT_1A receptors, endocrine function, and behavior in an animal model of depression, chronic mild stress (CMS).Methods The current study examined behavioral responses to a pleasurable stimulus (sucrose), estrous cycle length (in female rats), and plasma hormone levels following systemic administration of a selective 5-HT_1A receptor agonist [(+)8-hydroxy-N,N-dipropyl-2-aminotetralin hydrobromide (8-OH-DPAT); 40 g/kg, s.c.; administered 15 min prior to sacrifice], in male and female rats exposed to 4 weeks of CMS.Results Four weeks of CMS produced a reduction in the intake of 1% sucrose (anhedonia), as well as attenuated adrenocorticotropic hormone (ACTH) responses to 8-OH-DPAT in both male and female rats (22 and 18% lower than the control groups, respectively). Corticosterone and oxytocin responses to 8-OH-DPAT were not altered by exposure to CMS. In female rats, CMS induced a lengthening of the estrous cycle by 40%.Conclusions CMS produces minor HPA disruptions along with behavioral disruptions. Alterations in 5-HT_1A receptor function in specific populations of neurons in the central nervous system may be associated with the CMS model. The current findings contribute to our understanding of the relations that stress and neuroendocrine function have to depressive disorders.     

Monoacylglycerol Lipase Inhibition Blocks Chronic Stress-Induced Depressive-Like Behaviors via Activation of mTOR Signaling

The endocannabinoid (eCB) system regulates mood, emotion, and stress coping, and dysregulation of the eCB system is critically involved in pathophysiology of depression. The eCB ligand 2-arachidonoylglycerol (2-AG) is inactivated by monoacylglycerol lipase (MAGL). Using chronic unpredictable mild stress (CUS) as a mouse model of depression, we examined how 2-AG signaling in the hippocampus was altered in depressive-like states and how this alteration contributed to depressive-like behavior. We report that CUS led to impairment of depolarization-induced suppression of inhibition (DSI) in mouse hippocampal CA1 pyramidal neurons, and this deficiency in 2-AG-mediated retrograde synaptic depression was rescued by MAGL inhibitor JZL184. CUS induced depressive-like behaviors and decreased mammalian target of rapamycin (mTOR) activation in the hippocampus, and these biochemical and behavioral abnormalities were ameliorated by chronic JZL184 treatments. The effects of JZL184 were mediated by cannabinoid CB₁ receptors. Genetic deletion of mTOR with adeno-associated viral (AAV) vector carrying the Cre recombinase in the hippocampus of mTORf/f mice recapitulated depressive-like behaviors induced by CUS and abrogated the antidepressant-like effects of chronic JZL184 treatments. Our results suggest that CUS decreases eCB-mTOR signaling in the hippocampus, leading to depressive-like behaviors, whereas MAGL inhibitor JZL184 produces antidepressant-like effects through enhancement of eCB-mTOR signaling.     

Synthesis and in vitro pharmacology of substituted quinoline-2,4-dicarboxylic acids as inhibitors of vesicular glutamate transport

The vesicular glutamate transport (VGLUT) system selectively mediates the uptake of L-glutamate into synaptic vesicles. Uptake is linked to an H+-ATPase that provides coupling among ATP hydrolysis, an electrochemical proton gradient, and glutamate transport. Substituted quinoline-2,4-dicarboxylic acids (QDCs), prepared by condensation of dimethyl ketoglutaconate (DKG) with substituted anilines and subsequent hydrolysis, were investigated as potential VGLUT inhibitors in synaptic vesicles. A brief panel of substituted QDCs was previously reported (Carrigan et al. Bioorg. Med. Chem. Lett. 1999, 9, 2607-2612)(1) and showed that certain substituents led to more potent competitive inhibitors of VGLUT. Using these compounds as leads, an expanded series of QDC analogues were prepared either by condensation of DKG with novel anilines or via aryl-coupling (Suzuki or Heck) to dimethyl 6-bromoquinolinedicarboxylate. From the panel of almost 50 substituted QDCs tested as inhibitors of the VGLUT system, the 6-PhCH=CH-QDC (K(i) = 167 microM), 6-PhCH2CH2-QDC (K(i) = 143 microM), 6-(4'-phenylstyryl)-QDC (K(i) = 64 microM), and 6-biphenyl-4-yl-QDC (K(i) = 41 microM) were found to be the most potent blockers. A preliminary assessment of the key elements needed for binding to the VGLUT protein based on the structure-activity relationships for the panel of substituted QDCs is discussed herein. The substituted QDCs represent the first synthetically derived VGLUT inhibitors and are promising templates for the development of selective transporter inhibitors.     

Long-lasting behavioral effects and recognition memory deficit induced by chronic mild stress in mice: effect of antidepressant treatment

RATIONALE: Many studies support the validity of the chronic mild stress (CMS) model of depression in rodents. However, most of them focus on analysis of reactivity to rewards during the CMS and/or depressive-like behavior shortly after stress. In this study, we investigate acute and long-term effects of CMS and antidepressant treatment on depressive, anxiety-like behavior and learning. MATERIALS AND METHODS: Mice (C57BL/6) were exposed to CMS for 6 weeks and anhedonia was evaluated by weekly monitoring of sucrose intake. Paroxetine (10 mg kg(-1)day(-1) i.p.) or saline were administered the last 3 weeks of CMS and continued for 2 weeks thereafter. Behavioral tests were performed over the last week of CMS (acute effects) and 1 month later (long-term effects). RESULTS: Mice exposed to CMS displayed both acute and long-term decreased sucrose intake, increased immobility in the forced swimming test (FST) and impaired memory in the novel object recognition test. It is interesting to note that a correlation was found between the cognitive deficits and the helpless behavior in the FST induced by CMS. During the CMS procedure, paroxetine treatment reverted partially recognition memory impairment but failed to prevent the increased immobility in the FST. Moreover, it decreased on its own sucrose intake. Importantly, the long-term effects of CMS were partially prevented by chronic paroxetine. CONCLUSIONS: CMS leads to a long-term altered behavioral profile that could be partially reverted by chronic antidepressant treatment. This study brings novel features regarding the long-term effects of CMS and on the predictive validity of this depression animal model.