Electroconvulsive stimulation results in long‐term survival of newly generated hippocampal neurons in rats

Electroconvulsive stimulation (ECS) is one of the strongest stimulators of hippocampal neurogenesis in rodents that represents a plausible mechanism for the efficacy of electroconvulsive therapy (ECT) in major depressive disorder. Using design‐based stereological cell counting, we recently documented an initial 2.6‐fold increase in neurogenesis following a clinical relevant schedule of ECS, a treatment also rescuing depression‐like behavior in rats. However, these results gave no demonstration of the longevity of newly generated neurons. The present study is a direct continuation of the previous work aiming to test the hypothesis that rats subjected to ECS in combination with chronic restraint stress (CRS) display increased formation of new hippocampal neurons, which have a potential for long‐term survival. Furthermore, using mediation analysis, we tested if an ECS‐induced increase in neurogenesis facilitates the behavioral outcome of the forced swim test (FST), an animal model of depression. The results showed that ECS in conjunction with CRS stimulates hippocampal neurogenesis, and that a significant quantity of the newly formed hippocampal neurons survives up to 12 months. The new BrdU‐positive neurons showed time‐dependent attrition of ～40% from day 1 to 3 months, with no further decline between 3 and 12 months. ECS did not affect the number of pre‐existing dentate granule neurons or the volume of the dentate granule cell layer, suggesting no damaging effect of the treatment. Finally, we found that, while ECS increases neurogenesis, this formation of new neurons was not associated to ameliorated immobility in the FST. This implies that other ECS‐induced effects than neurogenesis must be part of mediating the antidepressant action of ECS. Taken together, the results of the present study contribute to the basic understanding of the neurogenic effects of ECT, and demonstrate that ECS, neurogenesis and anti‐depressant behavior are not directly linked. © 2016 Wiley Periodicals, Inc.     

Effect of repetitive transcranial magnetic stimulation on forced swimming test

Repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive shock (ECS) have been shown to affect mood in health and disease. Evidence to date has demonstrated an antidepressant potential for rTMS and electroconvulsive therapy (ECT). The present experiment, aimed at comparing the effects of ECS and rTMS in rats, employed one test used for screening of antidepressant activity: the forced swimming test (FST). In this study, the authors investigated whether chronic rTMS influenced active behavior in the rat FST, similar to ECS. Male Wistar rats received rTMS treatment daily, for 10 days as is commonly used for ECT treatment. Control rats received sham treatment by placing the stimulation coil in a perpendicular position to the rat's head. Passing a current through earclip electrodes for 1 s induced ECS. The control animals were treated identically, but current was not applied. The FST was carried out 24 h after the last rTMS or ECS. The immobility time in the FST was not significantly affected by rTMS and ECS for 1 day. The immobility time in the FST was significantly shortened at rTMS and ECS for 10 days. Chronic treatment with rTMS, similar to chronic treatment with ECS, decreased the immobility time in the FST. These results indicate that chronic treatment with rTMS might have antidepressant effect similar to chronic treatment with ECS.     

Exposure to enriched environment restores the mRNA expression of mineralocorticoid and glucocorticoid receptors in the hippocampus and ameliorates depressive-like symptoms in chronically stressed rats

Chronic stress can cause emotional dysfunction, but exposure to an enriched environment (EE) can benefit emotional homeostasis. Recent studies have demonstrated that EE can ameliorate stress-induced depressive-like behaviors. Whether hypothalamic-pituitary-adrenal (HPA) axis activity and corticosteroid receptors are involved in these effects of EE is not known. In our current study, we examined HPA axis activity and hippocampal mineralocorticoid receptor/glucocorticoid receptor (MR/GR) mRNA levels following chronic stress in rats. Our study showed that stress reduced body weight, decreased sucrose intake and sucrose preference, and increased immobility in a forced swimming test. These effects were ameliorated by EE. Also we found that 21 days of restraint stress resulted in low HPA axis activity, and a reduction of MR mRNA and MR/GR ratio in the hippocampus of rats, which was restored by EE. Thus, our current results emphasizes the efficiency of EE in the amelioration of stress-induced decrease in the mRNA expression of MR and MR/GR ratio as well as behavioral depression, providing initial evidence for a possible mechanism by which an enriched environment can restore stress-induced deficits.     

Chronic restraint stress causes anxiety- and depression-like behaviors, downregulates glucocorticoid receptor expression, and attenuates glutamate release induced by brain-derived neurotrophic factor in the prefrontal cortex

Stress and the resulting increase in glucocorticoid levels have been implicated in the pathophysiology of depressive disorders. We investigated the effects of chronic restraint stress (CRS: 6hours×28days) on anxiety- and depression-like behaviors in rats and on the possible changes in glucocorticoid receptor (GR) expression as well as brain-derived neurotrophic factor (BDNF)-dependent neural function in the prefrontal cortex (PFC). We observed significant reductions in body weight gain, food intake and sucrose preference from 1week after the onset of CRS. In the 5th week of CRS, we conducted open-field (OFT), elevated plus-maze (EPM) and forced swim tests (FST). We observed a decrease in the number of entries into open arms during the EPM (anxiety-like behavior) and increased immobility during the FST (depression-like behavior). When the PFC was removed after CRS and subject to western blot analysis, the GR expression reduced compared with control, while the levels of BDNF and its receptors remained unchanged. Basal glutamate concentrations in PFC acute slice which were measured by high performance liquid chromatography were not influenced by CRS. However, BDNF-induced glutamate release was attenuated after CRS. These results suggest that reduced GR expression and altered BDNF function may be involved in chronic stress-induced anxiety- and depression-like behaviors.     

Effect of different restraint schedules on the immobility in the forced swim test: modulation by an opiate mechanism

The present research was conducted to evaluate the influence of different stress schedules on behaviors displayed during both phases of the forced swim test (FST). In addition, the involvement of an opiate mechanism in the behavioral consequences of chronic restraint was investigated. Exposure to a single, but not to chronic, restraint event induced an increase in the immobility score obtained during the 10-min initial swimming exposure (initial test) of the FST. Animals submitted to a previous regime of repeated restraint showed a significant increase in immobility during the 5-min second swimming exposure (retest period) of this behavioral task. However, naloxone (NAL) administered before each of the seven restraint events, blocked the higher immobility observed in chronically stressed rats during the retest period suggesting the involvement of an opiate mechanism. Results concerning the effect of chronic stress on the behavior displayed during the FST were discussed with reference to previous reports which have proposed that immobility performed during the retest period of the FST represents an efficient adaptive response in this inescapable aversive experience.     

重复经颅磁刺激对抑郁模型大鼠行为学及海马区糖皮质激素受体表达的影响

目的观察重复经颅磁刺激(repetitive transcranial magnetic stimulation,r TMS)对慢性应激抑郁模型大鼠的抗抑郁作用及对海马区糖皮质激素受体(glucocorticoid receptor,GR)表达的影响,探讨r TMS抗抑郁作用的可能机制。方法 75只健康成年雄性大鼠随机分为造模组(60只)和空白对照组(15只),造模组采用孤养联合慢性温和不可预见应激(chronic unpredictability stimulus,CUMS)方法制备抑郁大鼠模型,为期3周,筛选造模成功的大鼠45只随机分为r TMS组、伪r TMS组和抑郁对照组,每组15只,r TMS组和伪r TMS组分别接受10 Hz的r TMS刺激和伪刺激干预3周,抑郁对照组和空白对照组不给予干预。分别于造模前、造模后、r TMS干预后进行体重测量、蔗糖水消耗实验和强迫游泳实验评估,r TMS干预后检测大鼠海马区GR蛋白和海马GR m RNA表达水平。结果造模后,r TMS组、伪r TMS组和抑郁对照组大鼠蔗糖水消耗量较空白对照组下降,强迫游泳不动时间增加(P0.01)。r TMS干预后,r TMS组体重增长率、蔗糖水消耗量与伪r TMS组和抑郁对照组相比均较高(P0.01),强迫游泳不动时间较短(P0.01)。伪r TMS组及抑郁对照组海马区GR蛋白及其m RNA表达水平与r TMS组和空白对照组相比均较低(P0.05)。结论 r TMS能够改善CUMS抑郁模型大鼠的抑郁样行为,可能与上调海马区GR表达有关。     

Hippocampal neurochemistry is involved in the behavioural effects of neonatal maternal separation and their reversal by post-weaning environmental enrichment: a magnetic resonance study

Exposure to early life stress results in behavioural changes, and these dysfunctions may persist throughout adulthood. In this study, we investigated whether hippocampus volume and neurochemical changes were involved in the appearance of these effects in the maternal separation (MS) animal model using the noninvasive techniques of structural magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). Sprague-Dawley rats exposed to MS for 180 min from postnatal days (PND) 2-14 demonstrated decreased sucrose preference, increased immobility in the forced swimming test (FST), and impaired memory in the Morris water maze in adulthood. Environmental enrichment (EE) (PND 21-60) could ameliorate the effects of MS on sucrose preference and learning and memory but not on immobility in the FST. In addition, EE significantly increased N-acetylaspartate (NAA) of MS animals. However, we did not find an effect of MS or EE on hippocampal volume. These results indicate the involvement of hippocampal neurochemistry in the behavioural changes that result from early stressful life events and their modification by post-weaning EE. Thus changes in NAA, as a measure of neuronal integrity, appear to be a sensitive correlate of these behavioural effects.     

Effects of chronic footshock, restraint and corticotropin-releasing factor on freezing, ultrasonic vocalization and forced swim behavior in rats

The effects of chronic footshock (CFS) or chronic restraint (CRS) on the behavioral responses to acute footshock and corticotropin-releasing factor (CRF) were studied. Male rats were subjected to either footshock or restraint daily, or left undisturbed (Quiet). After 7 or 14 days treatment, they were placed in an unfamiliar footshock chamber and three footshocks administered at 20s intervals and subsequent freezing and ultrasonic vocalizations (USV's) were recorded. Context-conditioned freezing and USV's were recorded when rats were replaced in the chamber in which they had received the three footshocks. Prior CFS treatment decreased acute footshock-induced freezing and USV's, whereas it increased conditioned freezing and slightly increased conditioned USV's. CRS did not affect footshock-induced freezing, but in contrast to CFS, strongly increased USV's. Intracerebroventricular CRF (30 or 100ng) alone did not elicit freezing in either Quiet or CFS rats, nor did it have any effect on shock-induced freezing in either group. However, CRF increased conditioned freezing in Quiet, but not in CFS rats. CRF alone did not trigger USV's, but slightly increased shock-induced USV's in both Quiet and CFS rats, and significantly increased conditioned USV's in CFS rats. In the forced swim test (FST), chronic footshock did not induce consistent effects, although there was a trend to increased immobility. However, CRF increased immobility. In striking contrast to CFS, chronic restraint consistently decreased immobility. It is concluded that chronic stress has lasting effects on defensive responses. However, not all chronic stress procedures exert the same effects and thus different forms of stress may activate different neural mechanisms. The fact that CFS diminished shock-induced freezing and the effects of CRF on conditioned freezing suggests that CFS desensitizes the brain to CRF. On the other hand, the enhancement of conditioned freezing by CFS, and of conditioned USV's by CRF in CFS rats, indicates more complex effects.     

Decreased glucocorticoid receptor mRNA and dysfunction of HPA axis in rats after removal of the cholinergic innervation to hippocampus

Excess exposure to glucocorticoids can have deleterious effects on physiology and cognition. Glucocorticoids acting via receptors located in hippocampal neurons contribute to negative feedback after stress by terminating the further release of glucocorticoids. The current study investigated the effects of selective immunolesions of septo-hippocampal cholinergic neurons on hippocampal corticosterone receptor mRNA and on hypothalamic-pituitary-adrenal (HPA) activity. As evaluated by in situ hybridization, hippocampal glucocorticoid receptor (GR) mRNA, but not mineralocorticoid receptor (MR) mRNA, was significantly decreased in lesioned rats compared to controls. In a companion study, the peak corticosterone response to one hour of restraint stress did not differ between lesion and control groups but the post-stress decline of corticosterone was more protracted in the lesioned rats. These findings are discussed in terms of their possible relevance to ageing as age-related degeneration of the basal forebrain cholinergic system may contribute to the commonly observed dysfunction of the HPA axis in older animals.     

Attenuating corticosterone levels on the day of memory assessment prevents chronic stress-induced impairments in spatial memory

This study investigated whether chronic stress-induced spatial memory deficits were caused by changes in the hypothalamic-pituitary-adrenal axis, such as corticosterone (CORT) elevations on the day of memory assessment, rather than the consequence of structural changes in the hippocampus. Male Sprague-Dawley rats were restrained for 6 h/day/21 days, and spatial memory was assessed on the Y-maze on day 22. Ninety minutes before training, rats received a subcutaneous injection of vehicle or metyrapone, a CORT synthesis inhibitor, and then spatial memory was determined 4-h later. The highest dose of metyrapone (75 mg/kg, s.c.) was most effective at preventing stress-induced spatial memory deficits. Chronic stress increased total CORT levels following Y-maze exposure, while acute metyrapone treatment dose-dependently attenuated total and free (unbound) CORT levels in both stress and control conditions. Blood samples taken from a separate subset of chronically stressed rats showed that baseline CORT levels were similar across the restraint period. Finally, chronic stress down-regulated glucocorticoid, but not mineralocorticoid, receptor mRNA expression within the hippocampus (dentate gyrus, CA1, CA2, CA3). These findings suggest that chronic stress-induced spatial memory deficits may be mediated by hypothalamic-pituitary-adrenal axis dysregulation. Specifically, CORT elevations and reductions in hippocampal glucocorticoid receptor expression, at the time of behavioural assessment may be involved, as opposed to a direct effect that is solely dependent upon hippocampal structural changes. These results have significance for treating cognitive decline in conditions associated with elevated glucocorticoids that include subpopulations in ageing, depression, Cushing's disease and Alzheimer's disease.     

Effects of serotonin depletion on the hippocampal GR/MR and BDNF expression during the stress adaptation

Increased serotonin (5-hydroxytryptamine, 5-HT) release in the hippocampus induced by repeated stress is thought to be critical for the neuroadaptation that alleviates the adverse effects of stressors on emotion and behavior. A failure in this process may be one of the primary neuropathological mechanisms underlying the development of stress-related disorders. The para-chloroamphetamine (p-PCA) was used to deplete 5-HT in the rat prior to repeated restraint stress (6h/day for 10 days), and determined the consequences of 5-HT depletion on stress-induced alterations of animal behaviors, hippocampal corticosteroid receptor immunoreactivity and the brain-derived neurotrophic factor (BDNF) mRNA expression. Behavioral tests indicate that the stressed rats with 5-HT depletion showed pronounced anxiety, reduced reward sensitivity and enhanced learned-helplessness. In addition, they also developed learning impairments in Morris water maze tests. These results suggest that hippocampal 5-HT depletion compromised adaptation to chronic stress. Furthermore, repeated stress caused a lesser degree of glucocorticoid receptor increase and down-regulation of BDNF mRNA. The study suggest that 5-HT deficiency in the adult hippocampus may impair stress adaptation by suppressing hippocampal GR and BDNF expression.     

7,8-Dihydroxyflavone,a Tropomyosin-Kinase Related Receptor B Agonist,Produces Fast-Onset Antidepressant-Like Effects in Rats Exposed to Chronic Mild Stress

ObjectiveBrain-derived neurotrophic factor (BDNF) and its specific receptor, tropomyosin-related kinase (TrkB), play important roles in treating depression. In this experiment, we examined whether 7,8-dihydroxyflavone, a novel potent TrkB agonist, could reverse the behavioral and biochemical abnormalities induced by the chronic mild stress (CMS) paradigm in rats.MethodsSD rats were exposed to a battery of stressors for 56 days. 7,8-dihydroxyflavone (5 and 20 mg/kg) were administered intraperitoneally during the last 28 days of the CMS paradigm. Rats were tested in sucrose consumption test (SCT), forced-swimming test (FST) and elevated T-maze (ETM). Serum corticosterone levels and hippocampal BDNF levels of the rats were measured.ResultsFour-week CMS on the rats induced their depression-like behavior in SCT. The CMS-reduced sucrose consumption was reversed starting from 7 days after the 7,8-dihydroxyflavone (20 mg/kg) treatment and remained across the subsequent treatment regime. 7,8-dihydroxyflavone, when given at 5 mg/kg for 3 weeks, reduced the immobility time in the FST in the CMS-subjected rats. Additionally, the 4-week treatment with 7,8-dihydroxyflavone (20 mg/kg) attenuated the CMS-induced increase in anxiety-like behavior in the ETM. For the CMS-subjected rats, 7,8-dihydroxyflavone treatment dose-dependently reduced their serum corticosterone levels but increased their hippocampal BDNF levels only at 5 mg/kg.Conclusion7,8-dihydroxyflavone was beneficial for both depression and anxiety-like behaviors, and may exert fast-onset antidepressant effects. This provides a new insight into the pharmacological management of depression.     

Cognitive impairment associated to HPA axis hyperactivity after maternal separation in rats

Exposure to early stressful adverse life events may increase vulnerability to psychopathology in adult life. There are important memory disturbances in stress-related psychiatric disorders. Therefore, there is much interest in understanding the mechanisms responsible for interactions between stress and cognition. Male Wistar rats that experienced 3-h daily separations from the dam during the first 3 weeks of life (maternal separation, MS) showed in adulthood a depressive-like behaviour in the forced swimming test, increased hypothalamic-pituitary-adrenal (HPA) axis responsiveness to stressors and elevated CRF mRNA in the paraventricular nucleus of the hypothalamus (PVN). In the hippocampus of MS rats, there was a lower glucocorticoid receptor density. MS produced significant learning impairments both in the Morris water maze and in the novel object recognition test (NORT). The glucocorticoid receptor antagonist mifepristone and the beta-adrenoceptor antagonist propranolol were able to completely reverse the increased immobility time in the forced swimming test and the memory deficits in the NORT observed in MS rats. Our data support the hypothesis that elevated secretion of glucocorticoids may be associated to behavioural and cognitive deficits in MS rats. The stress hyperresponsiveness observed in MS rats could be attributed, at least in part, to an impaired feedback sensitivity mediated by hippocampal glucocorticoid receptors. It can also be suggested the possible involvement of the noradrenergic system in cognitive impairments mediated by glucocorticoids in the MS model.     

Endogenous opioids upregulate brain-derived neurotrophic factor mRNA through delta- and micro-opioid receptors independent of antidepressant-like effects

Systemic administration of delta-opioid receptor (DOR) agonists decreases immobility in the forced swim test (FST) and increases brain-derived neurotrophic factor (BDNF) mRNA expression in rats, indicating that DOR agonists may have antidepressant-like effects. The aim of this study was to investigate the effects of central administration of endogenous opioid peptides on behavior in the FST and on brain BDNF mRNA expression in rats. Effects of endogenous opioids were compared with those produced by intracerebroventricular administration of a selective non-peptidic DOR agonist (+)BW373U86. Antidepressant-like effects were measured by decreased immobility in the FST. BDNF mRNA expression was determined by in situ hybridization. Centrally administered (+)BW373U86 decreased immobility and increased BDNF mRNA expression in the frontal cortex through a DOR-mediated mechanism, because these effects were blocked by the DOR antagonist naltrindole, but not by the micro-opioid receptor (MOR) antagonist naltrexone (NTX) or the kappa-opioid receptor antagonist nor-binaltorphimine. Of all the endogenous opioids tested, only leu- and met-enkephalin produced behavioral effects like those of (+)BW373U86 in the FST. Unlike (+)BW373U86, the enkephalins upregulated BDNF mRNA expression in the hippocampus through DOR- and MOR-mediated mechanisms. beta-Endorphin, endomorphin-1 and endomorphin-2 significantly increased BDNF mRNA levels in the frontal cortex, hippocampus and amygdala without reducing immobility; and most of these effects were reversed by NTX. This study is the first to provide evidence that endogenous opioids can upregulate BDNF mRNA expression through the DOR and MOR, and that leu- and met-enkephalin have similar pharmacological profiles to synthetic DOR agonists in producing antidepressant-like effects.     

Genetic selection for coping style predicts stressor susceptibility

Genetically selected aggressive (SAL) and nonaggressive (LAL) male wild house-mice which show distinctly different coping styles, also display a differential regulation of the hypothalamic-pituitary-adrenal axis after exposure to an acute stressor. To test the hypothesis that coping style predicts stressor susceptibility, the present study examined line differences in response to a chronic stressor. Chronic psychosocial stress was evoked using two paradigms. In the first paradigm, a SAL or LAL male was living in sensory contact (except tactile contact) with a dominant SAL male for 25 days (sensory contact stress). In the second paradigm, a SAL or LAL male was, in addition to the first paradigm, defeated by a SAL male for 21 consecutive days (defeat stress). The sensory contact stressor induced in LAL mice chronic body weight loss and increased plasma adrenocorticotropic hormone levels compared to SAL mice and increased corticosterone levels, thymus involution and lower hippocampal mineralocorticoid receptor (MR) : glucocorticoid receptor (GR) ratio compared to LAL controls. The defeat stressor increased corticosterone secretion and caused adrenal hypertrophy and thymus involution in both mouse lines. Defeated LAL mice showed long-lasting body weight loss and higher corticosterone concentrations than SAL mice and lower hippocampal MR : GR ratio and decreased immobility behaviour in the forced swimming test than LAL controls. Hypothalamic corticotropin-releasing hormone mRNA expression was higher in defeated SAL than in controls. The present data show that both stress paradigms induced line-dependent physiological and neuroendocrine changes, but that the sensory contact stressor produced chronic stress symptoms in LAL mice only. This latter stress paradigm therefore seems promising to analyse the role of genetic factors in the individual differences in stress-related psychopathology.     

强迫性游泳压力对大鼠单胺水平和神经退行性变化没有影响(英文)

目的本文旨在研究强迫性游泳试验中的不动时间(压力的行为性指示)与海马中单胺水平(抑郁指标)、血浆中肾上腺素水平(循环系统中的压力指标)以及神经退行性变化(fluoro-jade C染色法检测)的关系。方法给予雄性Sprague-Dawley大鼠急性、亚慢性(7天)或慢性(14天)强迫游泳的压力,并在强迫游泳试验中记录大鼠的不动时间。试验结束后,用高效液相色谱电化学检测法测定大鼠海马中去甲肾上腺素、5-羟色胺和多巴胺以及血浆中肾上腺素的水平,并对大鼠脑片进行fluoro-jade C染色。结果急性、亚慢性和慢性压力的大鼠均显示出较长的不动时间,分别为(214±5)s,(220±4)s和(231±7)s,表明这些大鼠都处在压力状态下。然而,与非压力状态下的对照组大鼠相比,急性和亚慢性压力下的大鼠海马中单胺类分子的水平并没有显著降低,并且血浆中肾上腺素的水平也没有显著升高。此外,慢性压力大鼠的脑片呈现出fluoro-jade C染色阴性。结论强迫性游泳试验中的不动时间与抑郁和压力并不相关,提示此法可能不能准确地指示压力水平。     

细脚拟青霉提取物对抗大小鼠抑郁的作用

研究发现细脚拟青霉提取物（BCPT）在体外对单胺氧化酶A具有一定的抑制作用,这表明其可能具有一定的抗抑郁作用。在这项研究中,目的是探讨BCPT对慢性应激（CUS）模型大鼠和小鼠行为学的影响。方法采用慢性应激大鼠随机暴露在21天的未知应激中,大鼠的奖赏反应采用24小时的糖水消耗量去检测,应激大鼠海马5-HT, 5-HIAA,DA,DOPAC和 NE含量采用高效液相色谱电化学检测器检测,盐皮质激素受体（MR）的表达和糖皮质激素受体（GR）的表达采用反向转录聚合酶链反应（RT - PCR）检测;小鼠行为学实验采用利血平、5 -色氨酸处理的小鼠模型和小鼠强迫游泳实验。结果表明,BCPT增加应激大鼠糖摄入量,缩短小鼠强迫游泳不动时间,改善了眼睑下垂及运动不能和增加5 -色氨酸引起的小鼠甩头症状,增强应激大鼠海马GR mRNA 和MR mRNA表达,降低MR/ GR的比例,提高DA,NE和5 - HT的水平,降低5-HIAA和DOPAC的含量。结论：因此BCPT具有潜在的抗抑郁样作用,其中改善海马神经递质和MR和GR mRNA的表达水平可能是其抗抑郁作用的重要机制。     

Influence of malathion on acetylcholinesterase activity in rats submitted to a forced swimming test

The organophosphorus insecticides, including malathion, are used indiscriminately in large amounts, causing environmental pollution and risk to human health. Classically, this toxicity is attributed mainly to the accumulation of acetylcholine (ACh), due to inhibition of acetylcholinesterase (AChE), and consequently overstimulation of the nicotinic and muscarinic receptors. The present study investigated the effects of acute and chronic malathion administration in immobility time in the forced swimming test (FST), open-field test and AChE activity in neural tissue of rats. Malathion was administered intraperitoneally once a day for one day (acute) or for 28 days (chronic) (in both protocols malathion was administered at 25, 50, 100 and 150 mg/kg). No significant effect was seen in immobility time in the FST after acute malathion treatment. The chronic malathion treatment induced an increase in the time of immobility in the FST. Both treatments do not interfere in locomotor activity evaluated in a novel environment. The inhibition of AChE activity was significant in the hippocampus (25, 50, 100 and 150 mg/kg), cortex (100 and 150 mg/kg) and striatum (150 mg/kg) after chronic treatment, but not significantly after acute treatment. These data suggest a possible interaction between increased immobility time in the FST and activation of cholinergic receptors by accumulated ACh subsequent to AChE inhibition.     

Ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex

Ketamine exerts fast acting, robust, and lasting antidepressant effects in a sub-anesthetic dose, however, the underlying mechanisms are still not fully elucidated. Recent studies have suggested that ketamine's antidepressant effects are probably attributed to the activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The present study aimed to observe the effects of AMPA receptor modulators on mammalian target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF) expression during the procedure of ketamine exerting antidepressant effects. Therefore, we pretreated rats with NBQX, an AMPA receptor antagonist, or CX546, an AMPA receptor agonist, and subsequently observed the immobility time during the forced swimming test (FST) and the hippocampal and prefrontal cortical levels of mTOR and BDNF. The results showed ketamine decreased the immobility time of rats during the FST and increased the hippocampal and prefrontal cortical mTOR and BDNF. NBQX pretreatment significantly increased the immobility time and decreased the levels of mTOR and BDNF when compared with vehicle 1 (DMSO) pretreatment. CX546 pretreatment significantly decreased the immobility time and increased the levels of mTOR and BDNF when compared with vehicle 2 (DMSO + ethanol) pretreatment. Our results suggest ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex.     

The positive allosteric modulator at mGlu2 receptors,LY487379, reverses the effects of chronic stress‐induced behavioral maladaptation and synaptic dysfunction in the adulthood

Chronic stress induces maladaptive neural responses in several brain areas including hippocampus. It has been demonstrated that chronic stress exposure induced a downregulation of the putative presynaptic type 2 metabotropic glutamate (mGlu2) receptors, which would reduce the negative feedback role exerted by these receptors. The reduced availability of these receptors would enhance glutamate overflow in the hippocampus, supporting the hypothesis that hippocampal glutamatergic neurotransmission plays a key etiopathological determinant in stress‐induced neuropsychiatric disorders. Since modulation of glutamatergic neurotransmission has been shown to represent an interesting pharmacological tool to treat psychiatric disorders, in the present study we have investigated the effects of the mGlu2 receptor positive allosteric modulator (PAM) LY487379. The rational bases of our study were: (a) chronic restraint stress (CRS) application in C57/BALB6 mouse induced a loss of resilience at the behavioral, biochemical, and electrophysiological level; (b) a superimposed familiar stressor (restraint) but not unfamiliar (i.e., forced swim stress) completely reversed the effects of CRS. Using the CRS model, in the present study we have investigated the effects of LY487379, an mGlu2 PAM, as well as a superimposed familiar stressor (acute restraint stress—ARS), on the immobility time at the tail suspension test and electrophysiological profile of glutamatergic transmission in the dentate gyrus (DG).