The total flavonoids extracted from Xiaobuxin Tang reverse the hyperactivity of hypothalamic-pituitary-adrenal axis in chronically stressed rats

Objective To investigate the effect of XBXT-2 on the activity of hypothalamic-pituitary-adrenal(HPA)axis in chronic mild stress(CMS)model of rats.Methods Using ELISA to test the serum corticosterone,adrenocorticotropic hormone(ACTH)and corticotropin-releasing hormone(CRH)level in CMS rats;Using western blot to determine hippocampal glucocorticoids receptors(GR)expression in CMS rats.Results Co-administration of XBXT-2(25,50 mg·kg-1,p.o.,28 days,the effective doses for behavioral responses)significantly decreased the serum corticosterone and ACTH level in CMS rats,while the CRH level was not markedly affected by chronic stress or drugs.Moreover,XBXT-2 significantly increased the GR expression in the hippocampus of CMS rats.The same effects were observed in the positive control drug imipramine(10 mg·kg-1,p.o.).Conclusions The decrease of serum corticosterone and ACTH level,as well as the increase of hippocampal GR expression may be the mechanisms underlying the antidepressant action of XBXT-2,which may associate with HPA axis.     

The effects of antidepressants on the hypothalamic-pituitary-adrenal axis

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis has been found in some psychiatric disorders, especially in older patients with severe depression. Altered feedback inhibition, as demonstrated by increased circulating cortisol and nonsuppresssion of cortisol following administration of dexamethasone, may be to blame. Two glucocorticoid receptors control the HPA axis, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). MR regulates normal HPA fluctuations and the GR regulates in times of stress. Long-term antidepressant treatment in humans has been shown to upregulate both GR and MR in the brain, whereas short-term treatment has been shown to downregulate GR and MR. After 6-9 weeks of treatment GR function returns to normal, and the MR stays upregulated. Chronic antidepressant treatment in rodents has been shown to reduce HPA activity, even in the absence of GR or MR upregulation. These effects of antidepressants on HPA regulation may be attributed in part to regulation of the multidrug resistance protein transporter, P-glycoprotein. Finding relationships between antidepressant action and HPA regulation leads to the conclusion that the disruption of the HPA may be more a contributing factor to depression than other biological abnormalities.     

Saikokaryukotsuboreito, a herbal medicine, prevents chronic stress-induced dysfunction of glucocorticoid negative feedback system in rat brain

Disruption of the hypothalamo-pituitary-adrenal (HPA) axis characterized by dysfunction of the glucocorticoid negative feedback system is frequently observed in human depressives and is thought to involve a reduction in glucocorticoid receptor (GR) function in the feedback sites including the brain. Recently, we found that chronic stress in rats induces similar HPA disruption that is caused by abolishment of feedback ability in the prefrontal cortex (PFC) and hippocampus, which involves decreased cytosolic GRs or increased nuclear GRs, respectively. Also, we found that saikokaryukotsuboreito (SRBT), a herbal medicine, prevents the chronic stress-induced HPA disruption. We therefore examined here the effects of this drug on the chronic stress-induced changes in GRs in the PFC and hippocampus. Chronic stress was induced in rats by water immersion and restraint (2 h/day) for 4 weeks. SRBT significantly prevented decreased cytosolic GRs in the PFC and increased nuclear GRs in the hippocampus in the chronically stressed rats. Moreover, SRBT significantly prevented the abolishment of feedback ability in both regions. These results suggest that the beneficial effects of SRBT on the GR level are involved in its ameliorating actions on the HPA disruption. This finding provides information important for the prevention and treatment of depression.     

Icariin from Epimedium brevicornum attenuates chronic mild stress-induced behavioral and neuroendocrinological alterations in male Wistar rats

Chronic mild stress (CMS) is suggested to produce abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis and hypothalamus-pituitary-thyroid (HPT) axis. Therefore, compound that attenuates the neuroendocrinological alterations may have potential as antidepressant. The behavioral and neuroendocrinological effects of icariin, a major constituent of flavonoids isolated from Epimedium brevicornum, were investigated in the CMS model of depression in male Wistar rats. CMS procedure caused an anhedonic state in rats resulted in increased corticotropin-releasing factor (CRF) concentrations in dissected brain regions and serum, decreased total triiodothyronine (tT3) in serum with no significant changes in serum adrenocorticotrophic hormone (ACTH) and thyroxine (tT4). Administration of icariin reversed CMS-induced sucrose intake reduction and CRF elevation. These results suggested that icariin possessed potent antidepressant-like activities which were at least in part mediated by improving the abnormalities in the HPA axis functions. However, we did not find a clear correlation between the HPT axis and icariin treatment in the CMS-treated rats.     

Influence of chronic stress on brain corticosteroid receptors and HPA axis activity

BackgroundDisruption of the glucocorticoid negative feedback system evoked in animals by chronic stress can be induced by downregulation of glucocorticoid receptors (GRs) in several brain regions. In the present study, the dynamics of the changes in GRs, in brain structures involved in stress reactions, prefrontal cortex, hippocampus and hypothalamus was compared with the peripheral hypothalamo-pituitary-adrenocortical (HPA) axis hormones response to chronic stress.MethodsRats were exposed to 10 min restraint or restrained twice a day for 3, 7 or 14 days, and 24 h after the last stress session exposed to homotypic stress for 10 min. Control rats were not restrained. After rapid decapitation at 0, 1, 2, and 3 h after stress termination, trunk blood for plasma adrenocorticotropic hormone (ACTH) and corticosterone determinations was collected and prefrontal cortex, hippocampus and hypothalamus were excised and frozen. Plasma hormones were determined using commercially available kits and glucocorticoids and mineralocorticoids protein levels in brain structure samples were determined by western blot procedure.ResultsRestraint stress alone significantly decreased glucocorticoid receptor (GR) level in prefrontal cortex and hippocampus, and increased mineralocorticoid receptor (MR) level in hypothalamus. Prior repeated stress for 3 days significantly increased GR protein level in hippocampus and diminished that level in hypothalamus in 7 days stressed rats. Acute stress-induced strong increase in plasma ACTH and corticosterone levels decreased to control level after 1 or 2 h, respectively. Prior repeated stress for 3 days markedly diminished the fall in plasma ACTH level and repeated stress for 7 days moderately deepened this decrease. Plasma ACTH level induced by homotypic stress in rats exposed to restraint for 3, 7, and 14 days did not markedly differ from its control level, whereas plasma corticosterone response was significantly diminished. The fast decrease of stress-induced high plasma ACTH and corticosterone levels was accompanied by a parallel decline of GR level only in prefrontal cortex but not in the hippocampus or hypothalamus.ConclusionsComparison of the dynamics of changes in plasma ACTH and corticosterone level with respective alterations in GR and MR in brain structures suggests that the buffering effect of repeated stress depends on the period of habituation to stress and the brain structure involved in regulation of these stress response.     

The involvement of FK506-binding protein 51 (FKBP5) in the behavioral and neuroendocrine effects of chronic social defeat stress

Chronic stress is increasingly considered to be a main risk factor for the development of a variety of psychiatric diseases such as depression. This is further supported by an impaired negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis, which has been observed in the majority of depressed patients. The effects of glucocorticoids, the main hormonal endpoint of the HPA axis, are mediated via the glucocorticoid receptor (GR) and the mineralocorticoid receptor. The FK506-binding protein 51 (FKBP5), a co-chaperone of the Hsp90 and component of the chaperone-receptor heterocomplex, has been shown to reduce ligand sensitivity of the GR. This study aimed to investigate the function of FKBP5 as a possible mediator of the stress response system and its potential role in the development of stress-related diseases. Therefore, we assessed whether mice lacking the gene encoding FKBP5 (51KO mice) were less vulnerable to the adverse effects of three weeks of chronic social defeat stress. Mice were subsequently analyzed with regards to physiological, neuroendocrine, behavioral and mRNA expression alterations. Our results show a less vulnerable phenotype of 51KO mice with respect to physiological and neuroendocrine parameters compared to wild-type animals. 51KO mice demonstrated lower adrenal weights and basal corticosterone levels, a diminished response to a novel acute stimulus and an enhanced recovery, as well as more active stress-coping behavior. These results suggest an enhanced negative glucocorticoid feedback within the HPA axis of 51KO mice, possibly modulated by an increased sensitivity of the GR. This article is part of a Special Issue entitled 'Anxiety and Depression'.     

Prenatal stress and subsequent exposure to chronic mild stress in rats; interdependent effects on emotional behavior and the serotonergic system

Exposure to prenatal stress (PS) can predispose individuals to the development of psychopathology later in life. We examined the effects of unpredictable chronic mild stress (CMS) exposure during adolescence on a background of PS in male and female Sprague-Dawley rats. PS induced more anxiety-like behavior in the elevated zero maze in both sexes, an effect that was normalized by subsequent exposure to CMS. Moreover, PS was associated with increased depression-like behavior in the forced swim test in males only. Conversely, sucrose intake was increased in PS males, whilst being decreased in females when consecutively exposed to PS and CMS. Hypothalamo–pituitary–adrenal (HPA) axis reactivity was affected in males only, with higher stress-induced plasma corticosterone levels after PS. Markedly, CMS normalized the effects of PS on elevated zero maze behavior as well as basal and stress-induced plasma corticosterone secretion. At the neurochemical level, both PS and CMS induced various sex-specific alterations in serotonin (5-HT) and tryptophan hydroxylase 2 (TPH2) immunoreactivity in the dorsal raphe nucleus, hippocampus and prefrontal cortex with, in line with the behavioral observations, more profound effects in male offspring. In conclusion, these findings show that prenatal maternal stress in Sprague-Dawley rats induces various anxiety- and depression-related behavioral and neuroendocrine changes, as well as alterations in central 5-HT and TPH2 function, predominantly in male offspring. Moreover, CMS exposure partially normalized the effects of previous PS experience, suggesting that the outcome of developmental stress exposure largely depends on the environmental conditions later in life and vice versa.     

Effect of prior stress on interleukin-1β and HPA axis responses to acute stress

Interleukin-1β (IL-1β) level is modulated during multiple stress reactions both in brain structures involved in hypothalamic-pituitary-adrenal (HPA) axis regulation and peripheral systems. Multiple distinct stressors induce different IL-1β and HPA axis responses. The purpose of the present study was to determine if the effect of prior repeated restraint stress on IL-1β levels in prefrontal cortex, hippocampus, hypothalamus and plasma may have an impact on alterations induced in HPA axis responses. Experiments were performed on male Wistar rats which were exposed to 10 min restraint stress twice a day for 3 days. Twenty four hours after the last stress period rats were restrained for 10 min and decapitated at 0, 1, 2 or 3 h after cessation of stress. Control rats were injected ip with saline and some of experimental groups with IL-1β receptor antagonist (IL-1ra). After rapid decapitation, trunk blood was collected and prefrontal cortex, hippocampus and hypothalamus were excised and frozen. Interleukin-1β, adrenocorticotropic hormone (ACTH) and corticosterone (CORT) levels were determined in plasma using commercially available kits and IL-1β levels in brain structures samples were analyzed by western blot procedure. Repeated restraint for 3 days alone did not alter resting plasma levels of IL-1β, and moderately augmented plasma ACTH and CORT levels and IL-1β content in brain structures 24 h after the last restraint. IL-1β antagonist abolished the increase in plasma levels of IL-1β, ACTH and CORT as well as IL-1β in brain structures in response to repeated stress and also reduced these changes induced by 10 min stress. This suggests the selectivity of IL-1β receptors in central and peripheral mechanisms modulating the stress-induced HPA axis responses. These results indicate that repeated stress markedly increases IL-1β production in brain structures involved in HPA axis regulation. The present results support the role of brain and peripheral IL-1β in adaptation of HPA response during prolonged stress.     

Prenatal stress decreases glycogen synthase kinase-3 phosphorylation in the rat frontal cortex

It has been postulated that hyperactive glycogen synthase kinase-3 (GSK-3) is an important factor in the pathogenesis of depression, and that this enzyme also contributes to the mechanism of antidepressant drug action. In the present study, we investigated the effect of prenatal stress (an animal model of depression) and long-term treatment with antidepressant drugs on the concentration of GSK-3β and its main regulating protein kinase B (PKB, Akt). The concentration of GSK-3β, its inactive form (phospho-Ser9-GSK-3β), and the amounts of active (phospho-Akt) and total Akt were determined in the hippocampus and frontal cortex in rats. In order to verify our animal model of depression, immobility time in the forced swim test (Porsolt test) was also determined.We found that prenatally stressed rats display a high level of immobility in the Porsolt test and chronic treatment with imipramine, fluoxetine, mirtazapine and tianeptine normalize this change. Western blot analysis demonstrated that GSK-3β levels were significantly elevated in the frontal cortex, but not in the hippocampus, of prenatally stressed rats. The concentration of its non-active form (phospho-Ser9-GSK-3β) was decreased only in the former brain structure. No changes were found in the amounts of active (phospho-Akt) and total Akt in both studied brain structures. Chronic treatment with antidepressant drugs diminished stress-induced alterations in GSK-3β and phospho-GSK-3β levels in the frontal cortex, but had no effect on the concentration of these enzymes in the hippocampus. Moreover, levels of Akt and phospho-Akt in all experimental groups remained unchanged. Since our animal model of depression is connected with hyperactivity of the HPA axis, our results suggest that GSK-3β is an important intracellular target for maladaptive glucocorticoid action on frontal cortex neurons and in antidepressant drug effects. Furthermore, the influence of stress and antidepressant drugs on GSK-3β does not appear to impact the kinase activity of Akt.     

Effect of repeated restraint on homotypic stress-induced nitric oxide synthases expression in brain structures regulating HPA axis

BackgroundRestraint stress (RS) markedly increases interleukin 1-β (IL-1β) generation in brain structures involved in hypothalamic-pituitary adrenocortical (HPA) axis regulation. The IL-1β-induced transient stimulation of HPA axis activity was parallel in time and magnitude to respective changes in regulation of HPA activity. In the present experiment the expression of neuron al and inducible nitric oxide synthase (nNOS and iNOS) were investigated in prefrontal cortex, hippocampus and hypothalamus in response to acute restraint stress in control and prior repeatedly restrained rats.MethodsExperiments were performed on male Wistar rats which were exposed to 10 min restraint stress or restrained twice a day for 3 days, and 24 h after the last stress period exposed to homotypic stress for 10 min. After rapid decapitation at 0,1,2 and 3 h after cessation of stress, trunk blood was collected and prefrontal cortex, hippocampus and hypothalamus were excised and frozen. Interleukin-1β, adrenocorticotropic hormone (ACTH) and corticosterone (CORT) levels were determined in plasma using commercially available kits and neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) in brain structure samples were analyzed by western blot procedure.ResultsPrior repeated restraint stress enhanced the acute restraint stress induced increase in IL-1β levels in all three structures examined. Restraint stress for 10 min moderately decreased nNOS level in prefrontal cortex in control rats, augmented this level in hippocampus and markedly increased nNOS level in hypothalamus. Restraint itself significantly decreased iNOS level in prefrontal cortex, while it enhanced iNOS level in hippocampus and hypothalamus. Prior restraint stress for 3 days enhanced the nNOS level in prefrontal cortex and hippocampus and did not substantially affect nNOS levels response in hypothalamus. Repeated restraint stress considerably augmented the iNOS levels in both prefrontal cortex, hippocampus and hypothalamus induced by followed homotypic stress.ConclusionThese results indicate that during restraint stress nNOS regulate formation of low amount of NO and the high-output generation of NO is effected by inducible isoform of nitric oxide synthase. Prior repeated stress significantly enhances the homotypic stress-induced nNOS and iNOS responses.     

Ethanolic extracts from Curcuma longa attenuates behavioral, immune, and neuroendocrine alterations in a rat chronic mild stress model

The ethanolic extracts from the rhizome of Curcuma longa L. (turmeric), possesses a wide variety of biological activities related to the treatment and prevention of affective disorders. To study their antidepressant effects, the impacts of chronic mild stress (CMS) and of the subsequent administration of ethanolic extracts of C. longa were investigated. Male Sprague-Dawley rats subjected to the CMS procedure demonstrated increased serum interleukin-6 and tumor necrosis factor-alpha levels, as well as a reduction of natural killer cell activity in splenocytes. In addition, CMS-treated rats exhibited elevated corticotropin-releasing factor in serum and medulla oblongata and cortisol levels in serum, with no significant change in serum adrenocorticotropin hormone levels. The preferential behavior of reduction in sucrose intake was also observed. These findings indicate that the alterations in immune and hypothalamic-pituitary-adrenal (HPA) axis systems could participate in the behavioral response to the CMS procedure in animals. Administration of ethanolic extracts of C. longa largely reversed the above effects. These results demonstrate the antidepressant-like activity of ethanolic extracts of C. longa in the rat CMS model of depression, at least in part by improving the abnormalities in immune and the HPA axis functions.     

The psychoneuroimmunology of depression

Chronic stress, by initiating changes in the hypothalamic‐pituitary‐adrenal (HPA) axis and the immune system, acts as a trigger for anxiety and depression. There is experimental and clinical evidence that the rise in the concentration of pro‐inflammatory cytokines and glucocorticoids, which occurs in a chronically stressful situation and also in depression, contribute to the behavioural changes associated with depression. A defect in serotonergic function is associated with these hormonal and immune changes. Neurodegenerative changes in the hippocampus, prefrontal cortex and amygdalae are the frequent outcome of the changes in the HPA axis and the immune system. Such changes may provide evidence for the link between chronic depression and dementia in later life. Copyright © 2009 John Wiley & Sons, Ltd.     

拟青霉代谢物提取物对慢性应激抑郁模型大鼠皮质激素受体mRNA表达的影响

目的研究拟青霉代谢物提取物(BCPT)对慢性不可预见性应激(CUS)抑郁模型大鼠海马和皮质中盐皮质激素受体(MR)、糖皮质激素受体(GR)mRNA表达的影响。方法采用CUS法建立大鼠抑郁模型,用逆转录-聚合酶链反应方法分别检测CUS模型大鼠海马和皮质中MR、GR mRNA的表达。结果BCPT可上调CUS模型大鼠皮质和海马中MR、GR mRNA的表达,降低MR/GR mRNA值。结论BCPT的抗抑郁作用可能与上述结果有关。     

Possible mechanism of the antidepressant effect of 3,6'-disinapoyl sucrose from Polygala tenuifolia Willd

Objective The present study was designed to observe the effects of 3,6′‐disinapoyl sucrose (DISS), an active oligosaccharide ester component obtained from the roots of Polygala tenuifolia Willd., on behavioral and biochemical aspects of depression induced by chronic mild stress (CMS) in rats. It is the first exploration of the possible association between DISS's antidepressant‐like effects and biochemical markers of depression, and involved measuring monoamine oxidase (MAO) activity, cortisol levels, superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels. Methods Rats were exposed to stressor once daily for consecutive 5 weeks. DISS and a positive control drug, fluoxetine, were administered via gastric intubation to once daily for consecutive 3 weeks from the third week. Key findings The results showed that rats subjected to CMS exhibit a reduction in sucrose intake. Conversely, brain MAO‐A and MAO‐B activity, plasma cortisol levels, and MDA levels were increased, while SOD activity was decreased following CMS exposures. DISS significantly inhibited MAO‐A and MAO‐B activity and blocked plasma elevated cortisol level, an indicator of the hypothalamic–pituitary–adrenal (HPA) axis. In addition, DISS increases SOD activity, inhibits lipid peroxidation, and lessens production of MDA. Conclusion These results suggest that DISS may possess potent and rapid antidepressant properties, which are mediated via MAO, the HPA axis and oxidative systems. These antidepressant actions make DISS a potentially valuable drug for the treatment of depression.     

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.     

Cannabinoids Ameliorate Impairments Induced by Chronic Stress to Synaptic Plasticity and Short-Term Memory

Repeated stress is one of the environmental factors that precipitates and exacerbates mental illnesses like depression and anxiety as well as cognitive impairments. We have previously shown that cannabinoids can prevent the effects of acute stress on learning and memory. Here we aimed to find whether chronic cannabinoid treatment would alleviate the long-term effects of exposure to chronic restraint stress on memory and plasticity as well as on behavioral and neuroendocrine measures of anxiety and depression. Late adolescent rats were exposed to chronic restraint stress for 2 weeks followed each day by systemic treatment with vehicle or with the CB1/2 receptor agonist WIN55,212-2 (1.2 mg/kg). Thirty days after the last exposure to stress, rats demonstrated impaired long-term potentiation (LTP) in the ventral subiculum-nucleus accumbens (NAc) pathway, impaired performance in the prefrontal cortex (PFC)-dependent object-recognition task and the hippocampal-dependent spatial version of this task, increased anxiety levels, and significantly reduced expression of glucocorticoid receptors (GRs) in the amygdala, hippocampus, PFC, and NAc. Chronic WIN55,212-2 administration prevented the stress-induced impairment in LTP levels and in the spatial task, with no effect on stress-induced alterations in unconditioned anxiety levels or GR levels. The CB1 antagonist AM251 (0.3 mg/kg) prevented the ameliorating effects of WIN55,212-2 on LTP and short-term memory. Hence, the beneficial effects of WIN55,212-2 on memory and plasticity are mediated by CB1 receptors and are not mediated by alterations in GR levels in the brain areas tested. Our findings suggest that cannabinoid receptor activation could represent a novel approach to the treatment of cognitive deficits that accompany a variety of stress-related neuropsychiatric disorders.     

Hippocampal cytogenesis correlates to escitalopram-mediated recovery in a chronic mild stress rat model of depression.

From clinical studies it is known that recurrent depressive episodes associate with a reduced hippocampal volume. Conversely, preclinical studies have shown that chronic antidepressant treatment increases hippocampal neurogenesis. Consequently, it has been suggested that a deficit in hippocampal neurogenesis is implicated in the pathophysiology of depression. To study a potential correlation between recovery and hippocampal cytogenesis, we established the chronic mild stress (CMS) rat model of depression. When rats are subjected to CMS, several depressive symptoms develop, including the major symptom anhedonia. Rats were exposed to stress for 2 weeks and subsequently to stress in combination with antidepressant treatment for 4 consecutive weeks. The behavioral deficit measured in anhedonic animals is a reduced intake of a sucrose solution. Prior to perfusion animals were injected with bromodeoxyuridine (BrdU), a marker of proliferating cells. Brains were sectioned horizontally and newborn cells positive for BrdU were counted in the dentate gyrus and tracked in a dorsoventral direction.CMS significantly decreased sucrose consumption and cytogenesis in the ventral part of the hippocampal formation. During exposure to the antidepressant escitalopram, given as intraperitoneally dosages of either 5 or 10 mg/kg/day, animals distributed in a bimodal fashion into a group, which recovered (increase in sucrose consumption), and a subgroup, which refracted treatment (no increase in sucrose consumption). Chronic treatment with escitalopram reversed the CMS-induced decrease in cytogenesis in the dentate gyrus of the ventral hippocampal formation, but in recovered animals only. Our data show a correlation between recovery from anhedonia, as measured by cessation of behavioral deficits in the CMS model, and an increase in cytogenesis in the dentate gyrus of the ventral hippocampal formation.     

一种白僵菌代谢产物BCEF0083对慢性应激抑郁大鼠下丘脑、垂体精氨酸加压素含量及海马GR mRNA表达的影响

目的：研究一种白僵菌代谢产物(BCEF0083)对实验性慢性应激抑郁大鼠下丘脑、垂体精氨酸加压素(AVP)含量及海马糖皮质激素受体mRNA(GRmRNA)表达的影响。方法：采用慢性不可预见性应激法造成大鼠抑郁模型，用放射免疫分析法测定抑郁模型大鼠下丘脑、垂体AVP含量，采用逆转录-聚合酶链反应(RT-PCR)法测定海马GR mRNA表达。 结果：BCEF0083可降低慢性应激抑郁大鼠下丘脑、垂体AVP含量，上调海马GR mRNA表达。结论：BCEF0083的抗抑郁作用可能与其降低慢性应激大鼠下丘脑、垂体AVP含量及上调海马GR mRNA表达有关。     

Neurogenesis-Independent Antidepressant-Like Effects on Behavior and Stress Axis Response of a Dual Orexin Receptor Antagonist in a Rodent Model of Depression

Growing evidence indicates that an increase of orexin (or hypocretin) signaling is involved in the pathophysiology of major depression, but little is known regarding the causal link between the orexinergic system and depressive-like states. Here we blocked orexin receptors in mice subjected to unpredictable chronic mild stress (UCMS) to investigate putative antidepressant-like effects of this treatment, as well as the underlying mechanisms. BALB/c mice were exposed to 9 weeks of UCMS and from the third week onward treated daily with fluoxetine (20 mg/kg per day, per os) or with the dual orexin receptor antagonist almorexant (100 mg/kg per day, per os). The effects of UCMS regimen and pharmacological treatments were assessed by physical measures and behavioral testing. The dexamethasone suppression test was performed to examine the integrity of the negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis, and immunohistochemical markers were used to assess cell proliferation (Ki-67), immature newborn neurons (doublecortin), and mature newborn neurons (5-bromo-2′-deoxyuridine/NeuN) in the dorsal and ventral parts of the hippocampus. Our results show that 7 weeks of fluoxetine or almorexant treatments counteract the UCMS-induced physical and behavioral alterations. Both treatments prevented the HPA axis dysregulation caused by UCMS, but only fluoxetine reversed the UCMS-induced decrease of hippocampal cell proliferation and neurogenesis, while chronic almorexant treatment decreased cell proliferation and neurogenesis specifically in the ventral hippocampus. Taken together, this is the first evidence that pharmacological blockade of the orexinergic system induces a robust antidepressant-like effect and the restoration of stress-related HPA axis defect independently from a neurogenic action.