Stress-induced Behavioral Alterations Research Articles

Hemokinin-1 is a mediator of chronic restraint stress-induced pain

The Tac4 gene-derived hemokinin-1 (HK-1) binds to the NK1 receptor, similarly to Substance P, and plays a role in acute stress reactions and pain transmission in mice. Here we investigated Tac4 mRNA expression in stress and pain-related regions and its involvement in chronic restraint stress-evoked behavioral changes and pain using Tac4 gene-deleted (Tac4-/-) mice compared to C57Bl/6 wildtypes (WT). Tac4 mRNA was detected by in situ hybridization RNAscope technique. Touch sensitivity was assessed by esthesiometry, cold tolerance by paw withdrawal latency from 0°C water. Anxiety was evaluated in the light–dark box (LDB) and open field test (OFT), depression-like behavior in the tail suspension test (TST). Adrenal and thymus weights were measured at the end of the experiment. We found abundant Tac4 expression in the hypothalamic–pituitary–adrenal axis, but Tac4 mRNA was also detected in the hippocampus, amygdala, somatosensory and piriform cortices in mice, and in the frontal regions and the amygdala in humans. In Tac4-/- mice of both sexes, stress-induced mechanical, but not cold hyperalgesia was significantly decreased compared to WTs. Stress-induced behavioral alterations were mild or absent in male WT animals, while significant changes of these parameters could be detected in females. Thymus weight decrease can be observed in both sexes. Higher baseline anxiety and depression-like behaviors were detected in male but not in female HK-1-deficient mice, highlighting the importance of investigating both sexes in preclinical studies. We provided the first evidence for the potent nociceptive and stress regulating effects of HK-1 in chronic restraint stress paradigm. Identification of its targets might open new perspectives for therapy of stress-induced pain.

Gestational environmental enrichment prevents chronic social stress induced anxiety- and ethanol-related behaviors in offspring

Epidemiological surveys have shown a strong relationship between maternal stress and offspring's mood disorders. Growing evidence suggested that environmental enrichment (EE) improves cognitive function in models of psychiatric and neurological disorders. However, the potential protective effects of gestational EE on social stress-elicited mood disorders in offspring have not been studied. Knowing that the undeveloped brain is more sensitive to gestational environmental stimuli, we hypothesized that initiating cognitive stimulation, during gestation, would protect against social stress-induced behavioral alterations in adulthood. Therefore, the present study aimed to investigate the effects of gestational EE on social stress-elicited anxiety- and ethanol-related behaviors in adult offspring. EE consisted of free access, of dams, to tubular devices of different shapes, colors, and sizes that were changed regularly. After birth and weaning, young adult offspring were exposed to 19 days of social stress and anxiety-like behavior was evaluated by elevated plus maze, open field, and marbles burying tests. The two-bottle choice (TBC) drinking paradigm was used to assess stress-induced ethanol intake. Results showed that gestational EE prevented social stress-elicited anxiogenic-like effects with no differences in spontaneous locomotor activity. Moreover, in the TBC paradigm, mice pre-exposed to EE consistently showed a significantly decreased consumption and preference for ethanol with no effects on tastants' intakes. Interestingly, gestational EE increased serum BDNF levels, which showed a correlation with measures of anxiety- and ethanol-related behaviors. These findings indicate that some neurodevelopmental changes associated with prenatal EE may counteract adult social stress-induced behavioral alterations through a BDNF mechanism. Therefore, we propose that gestational EE has significant protective and beneficial effects on social stress-induced cognitive impairment. It can also alleviate anxiety-like behavior and subsequent excessive alcohol consumption.

Resveratrol Attenuates Chronic Unpredictable Mild Stress-Induced Alterations in the SIRT1/PGC1α/SIRT3 Pathway and Associated Mitochondrial Dysfunction in Mice.

Environmental challenges, specifically chronic stress, have long been associated with neuropsychiatric disorders, including anxiety and depression. Sirtuin-1 (SIRT1) is a NAD+-dependent deacetylase that is widely distributed in the cortex and is involved in stress responses and neuropsychiatric disorders. Nevertheless, how chronic stress modulates the SIRT1 pathway and associated signaling remains unclear. In this study, we first explored the impact of chronic unpredictable mild stress (CUMS) on the SIRT1/PGC1α/SIRT3 pathway, on GABAergic mechanisms, and on mitophagy, autophagy and apoptosis in mice. We also asked whether activation of SIRT1 by resveratrol (RSV) can attenuate CUMS-induced molecular and behavioral alterations. Two-month-old C57/BL6J mice were subjected to three weeks of CUMS and one week of RSV treatment (30mg/kg; i.p.) during the third week of CUMS. CUMS caused downregulation of the SIRT1/PGC1α/SIRT3 pathway leading to impaired mitochondrial morphology and function. CUMS also resulted in a reduction in numbers of parvalbumin-positive interneurons and increased oxidative stress leading to reduced expression of autophagy- and mitophagy-related proteins. Strikingly, activation of SIRT1 by RSV ameliorated expression of SIRT1/PGC1α/SIRT3, and also improved mitochondrial function, GABAergic mechanisms, mitophagy, autophagy and apoptosis. RSV also rescued CUMS-induced anxiety-like and depressive-like behavior in mice. Our results raise the compelling possibility that RSV treatment might be a viable therapeutic method of blocking stress-induced behavioral alterations.

Protective Effects of Zingerone Against Depression-Like Behavior and Biochemical Changes in Chronic Stressed Rats: Antioxidant Effects.

Ginger contains zingerone, an active constituent possessing antioxidant and neuroprotective properties. The present study was designed to explore the efficacy of the bioactive compound, zingerone, for treating behavioral and biochemical alterations in rats exposed to chronic restraint stress (CRS). Female Wistar rats were administered zingerone (25, 50, and 100 mg/kg p.o.) once daily for a period of 28 days while being exposed to CRS (6 h/day). Our results indicated that the stressed animals depicted depression-like behavior (reduced sucrose preference and increased immobility time) associated with increased lipid peroxidation (LPO) (cortex), decreased catalase (CAT) (hippocampus and cortex), and increased superoxide dismutase (SOD) (hippocampus and cortex). In addition, metabolic alterations were characterized by hyperglycemia and increased glycosylated hemoglobin in the CRS rats. However, no alterations were observed for learning and memory and in the levels of reduced glutathione. Repeated zingerone administration significantly reversed depression-like behavior elicited by CRS in rats. Furthermore, a significant antioxidant effect was exhibited by zingerone, as shown by decreased LPO and enhanced activity of SOD and CAT in chronically stressed rats. The findings of our study demonstrated that zingerone possesses protective actions against chronic stress-induced depressive-like behavioral, biochemical, and metabolic alterations and that its underlying mechanism may be attributed to its antioxidant properties. The results also signify its pharmacological and possible nutritional importance.

VTA-projecting cerebellar neurons mediate stress-dependent depression-like behaviors.

Although cerebellar alterations have been implicated in stress symptoms, the exact contribution of the cerebellum to stress symptoms remains to be elucidated. Here, we demonstrated the crucial role of cerebellar neurons projecting to the ventral tegmental area (VTA) in the development of chronic stress-induced behavioral alterations in mice. Chronic chemogenetic activation of inhibitory Purkinje cells in crus I suppressed c-Fos expression in the DN and an increase in immobility in the tail suspension test or forced swimming test, which were triggered by chronic stress application. The combination of adeno-associated virus-based circuit mapping and electrophysiological recording identified network connections from crus I to the VTA via the dentate nucleus (DN) of the deep cerebellar nuclei. Furthermore, chronic inhibition of specific neurons in the DN that project to the VTA prevented stressed mice from showing such depression-like behavior, whereas chronic activation of these neurons alone triggered behavioral changes that were comparable with the depression-like behaviors triggered by chronic stress application. Our results indicate that the VTA-projecting cerebellar neurons proactively regulate the development of depression-like behavior, raising the possibility that cerebellum may be an effective target for the prevention of depressive disorders in human.

Combined effects of royal jelly and environmental enrichment against stress-induced cognitive and behavioral alterations in male rats: behavioral and molecular studies

ABSTRACT Background Exposure to chronic stress has detrimental effects on cognitive and emotional processing. Also, the neuroprotective influences of environmental enrichment (EE) and royal jelly (RJ) have been indicated in previous studies. Aims To our knowledge, to date, there are no studies about the synergistic effects of EE and RJ on cognitive changes induced by stress. Therefore, this study aimed to investigate the protective effects of RJ, and EE on anxiety-like behaviors, cognitive functions, and expression of hippocampal and also prefrontal cortex (PFC) brain-derived neurotrophic factor (BDNF) levels in stressed rats. Methods By using restraint and cold temperature, rats were exposed to stressful situations and then subjected to treatment with RJ or/ and EE for 14 days. Stress induction was done 14 days before treatments by placing the rats in the restrainer under 4°C. Following the interventions, anxiety-like behaviors, novel object recognition memory (NORM), inhibitive avoidance performance, hippocampal, and PFC BDNF expression were examined. The plasma corticosterone level of all groups was also evaluated. Results Results showed increased plasma corticosterone levels, stress-induced deficits in the NORM and IA tests, and increased anxiety-like behaviors. EE and RJ improved these deficits with a decline in serum corticosterone and also increased BDNF levels in the hippocampus and PFC in stressed ones. Conclusion The EE and the RJ prevented the detrimental effects of stress on anxiety-like behaviors and memory processes. These treatments can protect susceptible brain areas against chronic stress via improvement in behavioral and cognitive impairments through mediating BDNF expression.

Ameliorative effect of trigonelline in restraint stress-induced behavioral alterations in mice

Ameliorative effect of trigonelline in restraint stress-induced behavioral alterations in mice

Protective Effects of Morin Hydrate on Acute Stress-Induced Behavioral and Biochemical Alterations in Mice.

Introduction:As stress affects the brain both physiologically and chemically, researchers try to find novel anti-stress compounds with beneficial therapeutic effects. In this regard, the effect of stress and its modulation by Morin hydrate was studied using different acute models in mice.Methods:The models employed were anoxic tolerance, swimming endurance, and acute restraint test. Morin hydrate or the vehicle was administered 30 minutes prior to each stress exposure while in the acute restraint test; the animals were pretreated for 7 days with Morin hydrate, vehicle, imipramine, or diazepam before stress exposure. The measured parameters were the onset of convulsion and immobility time in the anoxic tolerance and swimming endurance test, respectively, while in the acute restraint test, the animals were assessed for stress-induced anxiety using the elevated plus maze and depression using the forced swim test. Thereafter blood was withdrawn from the retro-orbital plexus and plasma separated, the brain was also isolated, homogenized, centrifuged, and the supernatant was obtained for biochemical estimation.Results:Morin hydrate (5, 10, 20 mg/kg) produced a significant reduction in immobility time in the swimming endurance test, while significantly increased the anoxic stress tolerance time. Acute restraint stress caused a significant decrease in reduced glutathione levels (which was reversed by Morin hydrate) and increased the level of malondialdehyde, a thiobarbituric acid reactive substance which is an index of oxidative stress and nitrite. These effects were attenuated by Morin hydrate. Also, pretreatment with Morin hydrate attenuates acute restraint stress-associated anxiety and depression, reversed the hyperglycemia evoked by the stressful exposure and normalized serum cholesterol levels.Conclusion:These findings suggest that Morin hydrate exhibits anti-stress effects and may be useful in the relief of stress.

Enhancing Endocannabinoid Neurotransmission Augments The Efficacy of Extinction Training and Ameliorates Traumatic Stress-Induced Behavioral Alterations in Rats.

Exposure to a traumatic event may result in the development of post-traumatic stress disorder (PTSD). Endocannabinoids are crucial modulators of the stress response, interfere with excessive retrieval and facilitate the extinction of traumatic memories. Exposure therapy, combined with pharmacotherapy, represents a promising tool for PTSD treatment. We investigated whether pharmacological manipulations of the endocannabinoid system during extinction learning ameliorates the behavioral changes induced by trauma exposure. Rats were exposed to inescapable footshocks paired with social isolation, a risk factor for PTSD. One week after trauma, rats were subjected to three spaced extinction sessions, mimicking human exposure therapy. The anandamide hydrolysis inhibitor URB597, the 2-arachidonoylglycerol hydrolysis inhibitor JZL184 or the cannabinoid agonist WIN55,212-2 were administered before or after the extinction sessions. Rats were tested for extinction retention 16 or 36 days after trauma and 24-h later for social interaction. Extinction training alone reduced fear of the trauma-associated context but did not restore normal social interaction. Traumatized animals not exposed to extinction sessions exhibited reductions in hippocampal anandamide content with respect to home-cage controls. Noteworthy, all drugs exerted beneficial effects, but URB597 (0.1 mg/kg) induced the best improvements by enhancing extinction consolidation and restoring normal social behavior in traumatized rats through indirect activation of CB1 receptors. The ameliorating effects remained stable long after treatment and trauma exposure. Our findings suggest that drugs potentiating endocannabinoid neurotransmission may represent promising tools when combined to exposure-based psychotherapies in the treatment of PTSD.

Rutin alleviates chronic unpredictable stress-induced behavioral alterations and hippocampal damage in mice.

Chronic stress results in neurological complications like depression, cognitive dysfunction, and anxiety disorders. In our previous study, we observed that Urtica dioica leaf extract attenuated chronic stress-induced complications. Further, we observed that Urtica dioica contained a great amount of the flavonoid rutin in it. Hence, we aimed to evaluate the effect of rutin on 21days chronic unpredictable stress (CUS) mouse model. CUS led to a decline in locomotion & muscle coordination abilities, cognitive deficits, anxiety, and depression. These neurobehavioral outcomes were associated with neurodegeneration in the CA3 region of the hippocampus as found by H&E staining. Rutin efficiently rescued the CUS-induced behavioral deficits by reducing depression, anxiety, improving cognition, and locomotor & muscle coordination skills. Further, rutin treatment protected the CUS-induced hippocampal neuronal loss. This study establishes the neuroprotective effect of rutin in chronic stress.

Bifidobacterium CECT 7765 modulates early stress-induced immune, neuroendocrine and behavioral alterations in mice

Emerging evidence suggests that there is a window of opportunity within the early developmental period, when microbiota-based interventions could play a major role in modulating the gut-brain axis and, thereby, in preventing mood disorders. This study aims at evaluating the effects and mode of action of Bifidobacterium pseudocatenulatum CECT 7765 in a murine model of chronic stress induced by maternal separation (MS). C57Bl/6J male breast-fed pups were divided into four groups, which were subjected or not to MS and supplemented with placebo or B. pseudocatenulatum CECT7765 until postnatal period (P) 21 and followed-up until P41. Behavioral tests were performed and neuroendocrine parameters were analyzed including corticosterone, cytokine/chemokine concentrations and neurotransmitters. Microbiota was also analyzed in stools by 16S rRNA gene sequencing. B. pseudocatenulatum CECT 7765 administration attenuated some aspects of the excessive MS-induced stress response of the hypothalamic–pituitary–adrenal (HPA) axis, particularly corticosterone production at baseline and in response to subsequent acute stress in adulthood. B. pseudocatenulatum CECT 7765 also down-regulated MS-induced intestinal inflammation (reducing interferon gamma [IFN-γ]) and intestinal hypercatecholaminergic activity (reducing dopamine [DA] and adrenaline [A] concentrations) at P21. These effects have a long-term impact on the central nervous system (CNS) of adult mice since MS mice fed B. pseudocatenulatum CECT 7765 showed lower anxiety levels than placebo-fed MS mice, as well as normal neurotransmitter levels in the hypothalamus. The anti-inflammatory effect of B. pseudocatenulatum CECT 7765 seemed to be related to an improvement in glucocorticoid sensitivity in mesenteric lymph node immunocompetent cells at P21. The administration of B. pseudocatenulatum CECT 7765 to MS animals also reversed intestinal dysbiosis affecting the proportions of ten Operational Taxonomic Units (OTUs) at P21, which could partly explain the restoration of immune, neuroendocrine and behavioral alterations caused by stress in early and later life. In summary, we show that B. pseudocatenulatum CECT 7765 is able to beneficially modulate the consequences of chronic stress on the HPA response produced by MS during infancy with long-lasting effects in adulthood, via modulation of the intestinal neurotransmitter and cytokine network with short and long-term consequences in brain biochemistry and behavior.

Higher susceptibility of somatostatin 4 receptor gene-deleted mice to chronic stress-induced behavioral and neuroendocrine alterations

The somatostatin 4 receptor (sst4) is widely expressed in stress-related brain areas (e.g. hippocampus, amygdala) and regulates the emotional behavior in acute situations. Since its importance in chronic stress-induced complex pathophysiological alterations is unknown, we investigated the involvement of sst4 in the responsiveness to chronic variable stress (CVS). Sstr4 gene-deficient (Sstr4−/−) mice and their wildtype counterparts (Sstr4+/+) were used to examine the behavioral and neuroendocrine alterations as well as chronic neuronal activity (FosB expression) changes in response to CVS. In Sstr4+/+ mice, there was no behavioral response to the applied CVS paradigm. In contrast, immobility time in the tail suspension test increased after the CVS in the knockouts. In the forced swim test, Sstr4−/− animals showed increased baseline immobility and then it decreased after the CVS. Light–dark box and open field test behaviors and sucrose preference did not respond to the stress in the knockouts. Adrenal weights increased and thymus weights decreased in both Sstr4+/+ and Sstr4−/− mice demonstrating the effect of chronic stress. The relative adrenal weight of stressed knockouts increased to a greater extent, while relative thymus and body weights decreased only in the Sstr4−/− mice. Basal plasma corticosterone concentrations did not change after the CVS in either genotype. FosB immunopositivity in the central and basolateral amygdaloid nuclei was enhanced in stressed knockouts, but not in wild types. This is the first evidence that sst4 activation is involved in the behavioral and neuroendocrine alterations induced by chronic stress with a crucial role of plastic changes in the amygdala.

Effects of Chronic Stress on Alcohol Reward- and Anxiety-Related Behavior in High- and Low-Alcohol Preferring Mice.

Stress exposure (SE) during adolescence is associated with an increased risk for the development of alcohol use disorders (AUDs). Past research has shown that SE during adolescence increases voluntary alcohol consumption in mice during adulthood; however, little is known about the positive or negative motivational aspects of this relationship. High-alcohol preferring (HAP2) and low-alcohol preferring (LAP2) male mice were exposed to stress during adolescence, stress during adulthood, or no stress. After a 30-day interim, subjects were exposed to alcohol-induced place and footshock-induced fear conditioning procedures to measure stress-induced behavioral alterations during adulthood. SE during adolescence did not increase the magnitude of alcohol-induced conditioned place preference (CPP), as hypothesized, but increased the magnitude of conditioned fear, as measured by fear-potentiated startle (FPS), in HAP2 subjects only. Regardless of stress treatment group, LAP2 subjects showed greater alcohol-induced CPP expression than HAP2 mice. HAP2 mice also showed greater FPS than LAP2 mice, as previously shown. These results in mice, taken together with past research, suggest that mice exposed to stress during adolescence do not increase alcohol consumption during adulthood because of a greater sensitivity to the rewarding effects of alcohol, as measured via place conditioning. These results in mice also suggest that humans exposed to stress during adolescence may be more susceptible to developing anxiety during adulthood. The findings may be particularly relevant for humans with a familial history of AUDs.

The effects of stress during early postnatal periods on behavior and hippocampal neuroplasticity markers in adult male mice

Infancy is a critical period for brain development. Emerging evidence indicates that stress experienced during that period can have long-term programming effects on the brain and behavior. However, whether different time periods represent different vulnerabilities to the programming of different neurobehavioral domains is not yet known. Disrupted maternal care is known to interfere with neurodevelopmental processes and may lead to the manifestation of behavioral abnormalities in adulthood. Mouse dams confronted with insufficient bedding/nesting material have been shown to provide fragmented maternal care to their offspring. Here, we compared the impact of this model of early-life stress (ELS) during different developmental periods comprising either postnatal days (PNDs) 2–9 (ELS-early) or PND 10–17 (ELS-late) on behavior and hippocampal cell adhesion molecules in male mice in adulthood. ELS-early treatment caused a permanent reduction in bodyweight, whereas this reduction only occurred transiently during juvenility in ELS-late mice. Anxiety was only affected in ELS-late mice, while cognition and sociability were equally impaired in both ELS-treated groups. We analyzed hippocampal gene expression of the γ2 subunit of the GABAa receptor (Gabrg2) and of genes encoding cell adhesion molecules. Gabrg2 expression was increased in the ventral hippocampus in ELS-late-treated animals and was correlated with anxiety-like behavior in the open-field (OF) test. ELS-early-treated animals exhibited an increase in nectin-1 expression in the dorsal hippocampus, and this increase was associated with the social deficits seen in these animals. Our findings highlight the relevance of developmental age on stress-induced long-term behavioral alterations. They also suggest potential links between early stress-induced alterations in hippocampal Gabrg2 expression and the developmental programming of anxiety and between changes in hippocampal nectin-1 expression and stress-induced social impairments.

GABAergic modulation with classical benzodiazepines prevent stress-induced neuro-immune dysregulation and behavioral alterations

ObjectivePsychosocial stress is associated with altered immunity, anxiety, and depression. Repeated social defeat (RSD), a model of social stress, triggers egress of inflammatory myeloid progenitor cells (MPCs; CD11b+/Ly6Chi) that traffic to the brain, promoting anxiety-like behavior. In parallel, RSD enhances neuroinflammatory signaling and long-lasting social avoidant behavior. Lorazepam and clonazepam are routinely prescribed anxiolytics that act by enhancing GABAergic activity in the brain. Besides binding to the central benzodiazepine binding site (CBBS) in the central nervous system (CNS), lorazepam binds to the translocator protein (TSPO) with high affinity causing immunomodulation. Clonazepam targets the CBBS and has low affinity for the TSPO. Here the aims were to determine if lorazepam and clonazepam would: (1) prevent stress-induced peripheral and central inflammatory responses, and (2) block anxiety and social avoidance behavior in mice subjected to RSD. MethodsC57/BL6 mice were divided into experimental groups, and treated with either lorazepam (0.10mg/kg), clonazepam (0.25mg/kg) or vehicle (0.9% NaCl). Behavioral data and tissues were collected the morning after the last cycle of RSD. ResultsLorazepam and clonazepam were effective in attenuating mRNA expression of CRH in the hypothalamus and corticosterone in plasma in mice subjected to RSD. Both drugs blocked stress-induced levels of IL-6 in plasma. Lorazepam and clonazepam had different effects on stress-induced enhancement of myelopoiesis and inhibited trafficking of monocytes and granulocytes in circulation. Furthermore, lorazepam, but not clonazepam, inhibited splenomegaly and the production of pro-inflammatory cytokines in the spleen following RSD. Additionally, lorazepam and clonazepam, blocked stress-induced accumulation of macrophages (CD11b+/CD45high) in the CNS. In a similar manner, both lorazepam and clonazepam prevented neuroinflammatory signaling and reversed anxiety-like and depressive-like behavior in mice exposed to RSD. ConclusionThese data support the notion that lorazepam and clonazepam, aside from exerting anxiolytic and antidepressant effects, may have therapeutic potential as neuroimmunomodulators during psychosocial stress. The reversal of RSD-induced behavioral outcomes may be due to the enhancement of GABAergic neurotransmission, or some other off-target effect. The peripheral actions of lorazepam, but not clonazepam, seem to be mediated by TSPO activation.

Neuroprotective mechanism of losartan and its interaction with nimesulide against chronic fatigue stress.

Potential role of angiotensin-II and cyclooxygenase have been suggested in the pathophysiology of chronic fatigue stress. The present study has been designed to evaluate the neuroprotective effect of losartan and its interaction with nimesulide against chronic fatigue stress and related complications in mice. In the present study, male Laca mice (20-30 g) were subjected to running wheel activity test session (RWATS) for 6 min daily for 21 days. Losartan, nimesulide and their combinations were administered daily for 21 days, 45 min before being subjected to RWATS. Various behavioral and biochemical and neuroinflammatory mediators were assessed subsequently. 21 days RWATS treatment significantly decreased number of wheel rotations/6 min indicating fatigue stress like behaviors as compared to naive group. 21 days treatment with losartan (10 and 20 mg/kg, ip), nimesulide (5 and 10 mg/kg, po) and their combinations significantly improved behavior [increased number of wheel rotations, reversal of post-exercise fatigue, locomotor activity, antianxiety-like behavior (number of entries, latency to enter and time spent in mirror chamber), and memory performance (transfer latency in plus-maze performance task)], biochemical parameters (reduced serum corticosterone, brain lipid peroxidation, nitrite concentration, acetylcholinesterase activity, restored reduced glutathione levels and catalase activity) as compared to RWATS control. Besides, TNF-α, CRP levels were significantly attenuated by these drugs and their combinations as compared to control. The present study highlights the role of cyclooxygenase modulation in the neuroprotective effect of losartan against chronic fatigue stress-induced behavioral, biochemical and cellular alterations in mice.

Investigations in foot shock stress of variable intensity in mice: Adaptation and role of angiotensin II

The present study investigated the stress adaptation and role of angiotensin in response to repeated exposures of electric foot shocks of varying intensity. Mice were subjected to moderate (0.5mA) or severe (1.5mA) electric foot shocks for 1h for 5 days. Stress-induced behavioral changes were assessed by actophotometer, hole board, open field and social interaction tests. The serum corticosterone levels were measured as an index of HPA axis. Telmisartan (a selective AT1 receptor blocker) was employed as a pharmacological tool. A single exposure of moderate and severe stress produced behavioral deficits and increased the corticosterone levels. The restoration of these alterations was observed in response to repeated exposures of moderate stress, while no adaptation was observed in severe foot shock stress. A single administration of telmisartan (5mg/kg) exacerbated the moderate stress-induced decrease in behavioral activity and increase in corticosterone levels on the first day of stress exposure, suggesting the anti-stress role of angiotensin. In contrast, telmisartan normalized severe stress-induced behavioral and biochemical alterations suggesting the stress inducing actions of angiotensin. Furthermore, treatment with telmisartan abolished the stress adaptive response following repeated exposures of moderate stress suggesting that angiotensin has an adaptive role. It is concluded that there is a differential adaptive response in foot shock stress depending upon the severity of stress. Angiotensin II may act as an anti-stress agent and helps to promote the adaptation during medium stress, whereas it may promote stress response during severe stress.

Rapid Antidepressant Action and Restoration of Excitatory Synaptic Strength After Chronic Stress by Negative Modulators of Alpha5-Containing GABAA Receptors.

Selective serotonin reuptake inhibitors (SSRIs) are the primary pharmacological treatment for depression, but SSRIs are effective in only half of the patients and typically take several weeks to relieve symptoms. The NMDA receptor antagonist ketamine exerts a rapid antidepressant action, but has troubling side effects. We hypothesized that negative allosteric modulators of GABAA receptors would exert similar effects on brain activity as ketamine, but would not exert as many side effects if targeted only to GABAA receptors containing α5 subunits, which are enriched in the hippocampus and prefrontal cortex. Here, we show that the α5-selective negative modulator L-655,708 reversed the alterations in hedonic behavior in the sucrose preference and social interaction tests produced by two different chronic stress paradigms in rats within 24 h of systemic administration. Similar effects were observed with another α5-selective negative modulator, MRK-016. L-655,708 had no effect on hedonic or open-field behavior in unstressed animals. Within 24 h, L-655,708 injection also restored the strength of pathologically weakened excitatory synaptic transmission at the stress-sensitive temporoammonic-CA1 synapse, measured electrophysiologically, and increased levels of the GluA1 subunit of the AMPA receptor, measured with western blotting. We suggest that the ability of L-655,708 to restore excitatory synaptic strength rapidly may underlie its ability to restore stress-induced behavioral alterations rapidly, supporting evidence that dysfunction of multiple excitatory synapses in cortico-mesolimbic reward pathways contributes, in part, to the genesis of depression. Negative allosteric modulators of α5 subunit-containing GABAA receptors represent a promising novel class of fast-acting and clinically viable antidepressant compounds.

Pretreatment with curcumin attenuates anxiety while strengthens memory performance after one short stress experience in male rats.

It is observed that memories are more strengthened in a stressful condition. Studies have also demonstrated an association between stressful events and the onset of depression and anxiety. Considering the nootropic, anxiolytic and antidepressant-like properties of curcumin in various experimental approaches, we appraised the beneficial effects of this herb on acute immobilization stress-induced behavioral and neurochemical alterations. Rats in test group were administrated with curcumin (200mg/kg/day), dissolved in neutral oil, for 1 week. Both control and curcumin-treated rats were divided into unstressed and stressed groups. Rats in the stressed group were subjected to immobilization stress for 2h. After stress, the animals were subjected to behavioral tests. Immobilization stress induced an anxiogenic behavior in rats subjected to elevated plus maze test (EPM). Locomotor activity was also significantly increased following the acute immobilization stress. Pre-administration of curcumin prevented the stress-induced behavioral deficits. Highest memory performance was observed in stressed rats that were pre-treated with curcumin in Morris water maze (MWM). Brain malondialdehyde (MDA) levels, catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), and acetylcholinesterase (AChE) activities were also estimated. Present study suggests a role of antioxidant enzymes in the attenuation of acute stress induced anxiety by curcumin. The findings therefore suggest that supplementation of curcumin may be beneficial in the treatment of acute stress induced anxiety and enhancement of memory function.

Investigating the stress attenuating potential of furosemide in immobilization and electric foot-shock stress models in mice

The present study was designed to investigate the antistress effect of furosemide (sodium potassium chloride co-transporter inhibitor) in immobilization and foot-shock stress-induced behavioral alterations in the mice. Acute stress was induced in Swiss albino mice either by applying electric foot shocks of 0.6-mA intensity of 1-s duration with 30-s inter-shock interval for 1h or immobilizing for 150min. The acute stress-induced behavioral changes were assessed by using actophotometer, hole board, open-field, and social interaction tests. Biochemically, the corticosterone levels were estimated in the serum as a biomarker of hypothalamus-pituitary-adrenal (HPA) axis. Acute stress resulted in the development of behavioral alterations and elevation of the corticosterone levels. Intraperitoneal administration of furosemide (25 and 50mg/kg) significantly attenuated immobilization and foot-shock stress-induced behavioral changes along with normalization of the corticosterone levels. It may be concluded that furosemide produces beneficial effects in reestablishing the behavioral and biochemical alterations in immobilization and foot-shock-induced acute stress in mice.