Increased Plasma Corticosterone Research Articles

Anxiety-, and depression-like behavior following short-term finasteride administration is associated with impaired synaptic plasticity and cognitive behavior in male rats

Finasteride, a 5α-Reductase inhibitor, is used to treat male pattern baldness and benign prostatic hyperplasia. Several clinical studies show that chronic finasteride treatment induces persistent depression, suicidal thoughts and cognitive impairment and these symptoms are persistent even after its withdrawal. Previous results from our lab showed that repeated administration of finasteride for six days induces depression-like behavior. However, whether short-term finasteride administration induces anxiety-like behavior and memory impairment and alters synaptic plasticity are not known, which formed the basis of this study. Finasteride was administered to 2–2.5 months old male Wistar rats for six days and subjected to behavioral evaluation, biochemical estimation and synaptic plasticity assessment. Anxiety-like behavior was evaluated in the elevated plus maze (EPM), open field test (OFT), light/dark test (LDT), and novelty suppressed feeding test (NSFT), and learning and memory using novel object recognition test (NORT) and novel object location test (NOLT) and depression-like behavior in the sucrose preference test (SPT). Synaptic plasticity in the hippocampal Schaffer collateral-CA1 was evaluated using slice field potential recordings. Plasma corticosterone levels were estimated using ELISA. Finasteride administration induced anxiety-like behavior in the EPM, OFT, LDT and NSFT, and depression-like behavior in the SPT. Further, finasteride induced hippocampal dependent spatial learning and memory impairment in the NOLT. In addition, finasteride decreased basal synaptic plasticity and long-term potentiation (LTP) in the hippocampus. A trend of increased plasma corticosterone levels was observed following repeated finasteride administration. These results indicate the potential role of corticosterone and synaptic plasticity in finasteride-induced effects and further studies will pave way for the development of novel neurosteroid-based therapeutics in neuropsychiatric diseases.

Repetitive neonatal procedural pain affects stress-induced plasma corticosterone increase in young adult females but not in male rats.

Exposure to repetitive painful procedures in the neonatal intensive care unit results in long-lasting effects, especially visible after a "second hit" in adulthood. As the nociceptive system and the hypothalamic-pituitary-adrenal (HPA) axis interact and are vulnerable in early life, repetitive painful procedures in neonates may affect later-life HPA axis reactivity. The first aim of the present study was to investigate the effects of repetitive neonatal procedural pain on plasma corticosterone levels after mild acute stress (MAS) in young adult rats. Second, the study examined if MAS acts as a "second hit" and affects mechanical sensitivity. Fifty-two rats were either needle pricked four times a day, disturbed, or left undisturbed during the first neonatal week. At 8weeks, the animals were subjected to MAS, and plasma was collected before (t0), after MAS (t20), and at recovery (t60). Corticosterone levels were analyzed using an enzyme-linked immunosorbent assay, and mechanical sensitivity was assessed with von Frey filaments. Results demonstrate that repetitive neonatal procedural pain reduces stress-induced plasma corticosterone increase after MAS only in young adult females and not in males. Furthermore, MAS does not affect mechanical sensitivity in young adult rats. Altogether, the results suggest an age- and sex-dependent effect of repetitive neonatal procedural pain on HPA axis reprogramming.

Corticosterone and immune responses to dehydration in squamate reptiles.

Many environments present some degree of seasonal water limitations; organisms that live in such environments must be adapted to survive periods without permanent water access. Often this involves the ability to tolerate dehydration, which can have adverse physiological effects and is typically considered a physiological stressor. While having many functions, the hormone corticosterone (CORT) is often released in response to stressors, yet increasing plasma CORT while dehydrated could be considered maladaptive, especially for species that experience predictable bouts of dehydration and have related coping mechanisms. Elevating CORT could reduce immunocompetence and have other negative physiological effects. Thus, such species likely have CORT and immune responses adapted to experiencing seasonal droughts. We evaluated how dehydration affects CORT and immune function in eight squamate species that naturally experience varied water limitation. We tested whether hydric state affected plasma CORT concentrations and aspects of immunocompetence (lysis, agglutination, bacterial killing ability and white blood cell counts) differently among species based on how seasonally water limited they are and whether this is constrained by phylogeny. The species represented four familial pairs, with one species of each pair inhabiting environments with frequent access to water and one naturally experiencing extended periods (>30 days) with no access to standing water. The effects of dehydration on CORT and immunity varied among species. Increases in CORT were generally not associated with reduced immunocompetence, indicating CORT and immunity might be decoupled in some species. Interspecies variations in responses to dehydration were more clearly grouped by phylogeny than by habitat type.

Reproductive experience alters the effects of diazepam and fluoxetine on anxiety-like behaviour, fear extinction, and corticosterone levels in female rats

OverviewReproductive experience (pregnancy and motherhood) leads to long-term changes in the neurobiological and hormonal features of anxiety in rats and humans. The aim of this study was to examine whether reproductive experience alters the effects of two pharmacological treatments for anxiety, a benzodiazepine (diazepam) and a selective serotonin reuptake inhibitor (fluoxetine), on animal models of anxiety.MethodsIn Experiment 1, virgin (n = 47) and age-matched mother (n = 50) rats at 1-month post-weaning were injected with diazepam (1.3 mg/kg or 1.7 mg/kg, i.p.) or vehicle, in the proestrus (high estradiol/progesterone/allopregnanolone) or metestrus (low estradiol/progesterone/allopregnanolone) phase of the estrous cycle 30 min prior to the elevated plus maze (EPM). In Experiment 2, virgin (n = 25) and mother rats (n = 20) were administered fluoxetine (10 mg/kg) or vehicle for 2 weeks prior to being tested on a Pavlovian fear conditioning and extinction protocol, and the EPM.ResultsReplicating past research, in virgin rats, the low dose of diazepam produced anxiolytic-like effects in proestrus, but only the high dose was anxiolytic-like in metestrus. In contrast, in mother rats, both doses of diazepam were anxiolytic-like irrespective of estrous phase. Fluoxetine produced anxiogenic-like effects in virgin rats during fear extinction and the EPM, but had no behavioural effects in mothers. In contrast, fluoxetine increased plasma corticosterone levels measured 30-min post-EPM in mothers, but not virgin rats.ConclusionsReproductive experience alters the dose responsivity and efficacy of common anti-anxiety medications in female rats. These findings highlight the importance of considering reproductive status in studies on anxiety and its treatment.

High-intensity interval training improves long-term memory and increases hippocampal antioxidant activity and BDNF levels in ovariectomized Wistar rats

Menopause is the period in which women cease to produce the hormone estrogen, which can trigger physiological, cognitive, and behavioral changes. In this context, alternatives are needed that can reduce the effects provided by menopause, specifically in terms of cognitive and behavioral aspects. High-intensity interval training (HIIT) is an exercise protocol that has shown the potential to improve cognition by promoting an increase in antioxidant defenses and BDNF levels. Therefore, the aim of this study was to evaluate the effects of HIIT on behavior and hippocampal neurochemistry in ovariectomized adult rats. Four groups of rats were divided into: females without ovariectomy surgery and sedentary (SHAM-SED); females with ovariectomy surgery and sedentary (OVX-SED); females without ovariectomy surgery and trained (SHAM-HIIT); females with ovariectomy surgery and trained (OVX-HIIT). After the surgical procedure and the HIIT protocol, the animals underwent anxiety (elevated plus maze and open field) and memory (novel object recognition) tests. Corticosterone was measured in blood and BDNF levels and redox status were evaluated in the hippocampus. The OVX-SED group showed low BDNF levels and antioxidant enzymes, which may be linked to the observed memory impairments. The HIIT protocol (SHAM-HIIT and OVX-HIIT groups) increased the BDNF levels and antioxidant enzymes in the hippocampus, improving the animals' memory. However, HIIT also led to increased plasma corticosterone and anxiety-like behaviors. The ovariectomy procedure induced memory impairment probably due to reductions in hippocampal BDNF levels and redox imbalance. The HIIT protocol demonstrates promising results as an alternative to improve memory in ovariectomized rats.

Oral CBD-rich hemp extract modulates sterile inflammation in female and male rats.

Introduction: Cannabidiol (CBD) extract from the cannabis plant has biomedical and nutraceutical potential. Unlike tetrahydrocannabinol (THC), CBD products produce few psychoactive effects and pose little risk for abuse. There is emerging preclinical and clinical evidence that CBD is stress modulatory and may have anti-inflammatory properties. People across the United States legally ingest CBD-rich hemp extracts to manage mental and physical health problems, including stress and inflammation. Preclinical studies have revealed potential mechanisms for these effects; however, the impact of this prior work is diminished because many studies: 1) tested synthetic CBD rather than CBD-rich hemp extracts containing terpenes and/or other cannabinoids thought to enhance therapeutic benefits; 2) administered CBD via injection into the peritoneal cavity or the brain instead of oral ingestion; and 3) failed to examine potential sex differences. To address these gaps in the literature, the following study tested the hypothesis that the voluntary oral ingestion of CBD-rich hemp extract will attenuate the impact of stressor exposure on plasma and tissue inflammatory and stress proteins in females and males. Methods: Adult male and female Sprague Dawley rats (10-15/group) were randomly assigned to be given cereal coated with either vehicle (coconut oil) or CBD-rich hemp extract (L-M0717, CBDrx/Functional Remedies, 20.0mg/kg). After 7days, rats were exposed to a well-established acute model of stress (100, 1.5mA, 5-s, intermittent tail shocks, 90min total duration) or remained in home cages as non-stressed controls. Results: Stressor exposure induced a robust stress response, i.e., increased plasma corticosterone and blood glucose, and decreased spleen weight (a surrogate measure of sympathetic nervous system activation). Overall, stress-induced increases in inflammatory and stress proteins were lower in females than males, and oral CBD-rich hemp extract constrained these responses in adipose tissue (AT) and mesenteric lymph nodes (MLN). Consistent with previous reports, females had higher levels of stress-evoked corticosterone compared to males, which may have contributed to the constrained inflammatory response measured in females. Discussion: Results from this study suggest that features of the acute stress response are impacted by oral ingestion of CBD-rich hemp extract in female and male rats, and the pattern of changes may be sex and tissue dependent.

Continuous Monochromatic Blue Light Exacerbates High-Fat Diet-Induced Kidney Injury via Corticosterone-Mediated Oxidative Stress.

Excessive illumination is one of the most severe environmental factors that impacts the organism. There is growing evidence that obesity significantly contributes to the onset of chronic kidney disease. However, the effect of continuous light on the kidney and which color can produce an apparent phenomenon remains elusive. In this study, C57BL/6 mice given either a normal diet (LD-WN) or a high-fat diet (LD-WF) were subjected to a light cycle of 12 h of illumination followed by 12 h of darkness for 12 weeks. Meanwhile, 48 high-fat diet mice were given a 24 h monochromatic light exposure of varying colors (white, LL-WF; blue, LL-BF; green, LL-GF) for 12 weeks. As expected, the LD-WF mice showed significant obesity, kidney injury, and renal dysfunction compared with the LD-WN group. LL-BF mice had worse kidney injury than LD-WF mice, including higher Kim-1 and Lcn2. The kidney of the LL-BF group showed marked glomerular and tubular injury, with decreased levels of Nephrin, Podocin, Cd2ap, and α-Actinin-4 compared to LD-WF. LL-BF also reduced the antioxidant capacity, including GSH-Px, CAT, and T-AOC, increased the production of MDA, and inhibited the activation of the NRF2/HO-1 signaling pathway. Furthermore, LL-BF upregulated the mRNA levels of the pro-inflammatory factors Tnf-α, Il-6, and Mcp-1, decreasing the inhibitory inflammatory Il-4 expression. We observed increased plasma corticosterone (CORT), renal glucocorticoid receptors (GR) expression, Hsp90, Hsp70, and P23 mRNA levels. These findings suggested that LL-BF increased CORT secretion and affected glucocorticoid receptors (GR) in comparison to the LD-WF group. Moreover, in vitro research demonstrated that CORT treatment increased oxidative stress and inflammation, which was counteracted by adding a GR inhibitor. Thus, the sustained blue light worsened kidney damage, possibly by inducing elevated CORT and increasing oxidative stress and inflammation via GR.

Effects of Glutamine, Curcumin and Fish Bioactive Peptides Alone or in Combination on Intestinal Permeability in a Chronic-Restraint Stress Model.

Irritable bowel syndrome (IBS), a multifactorial intestinal disorder, is often associated with a disruption in intestinal permeability as well as an increased expression of pro-inflammatory markers. The aim of this study was to first test the impact of treatment with glutamine (Gln), a food supplement containing natural curcumin extracts and polyunsaturated n-3 fatty acids (Cur); bioactive peptides from a fish protein hydrolysate (Ga); and a probiotic mixture containing Bacillus coagulans, Lactobacillus acidophilus, Lactobacillus gasseri and Lactobacillus helveticus. These compounds were tested alone on a stress-based IBS model, the chronic-restraint stress model (CRS). The combination of Gln, Cur and Ga (GCG) was also tested. Eight-week-old C57Bl/6 male mice were exposed to restraint stress for two hours every day for four days and received different compounds every day one week before and during the CRS procedure. Plasma corticosterone levels were measured as a marker of stress, and colonic permeability was evaluated ex vivo in Ussing chambers. Changes in the gene expression of tight junction proteins (occludin, claudin-1 and ZO 1) and inflammatory cytokines (IL1β, TNFα, CXCL1 and IL10) were assessed using RT-qPCR. The CRS model led to an increase in plasma corticosterone and an increase in colonic permeability compared with unstressed animals. No change in plasma corticosterone concentrations was observed in response to CRS with the different treatments (Gln, Cur, Ga or GCG). Stressed animals treated with Gln, Cur and Ga alone and in combination showed a decrease in colonic permeability when compared to the CRS group, while the probiotic mixture resulted in an opposite response. The Ga treatment induced an increase in the expression of the anti-inflammatory cytokine IL-10, and the GCG treatment was able to decrease the expression of CXCL1, suggesting the synergistic effect of the combined mixture. In conclusion, this study demonstrated that a combined administration of glutamine, a food supplement containing curcumin and polyunsaturated n-3 fatty acids, and bioactive peptides from a fish hydrolysate was able to reduce colonic hyperpermeability and reduce the inflammatory marker CXCL1 in a stress-based model of IBS and could be of interest to patients suffering from IBS.

Effect of the glucocorticoid receptor antagonist PT150 on acquisition and escalation of fentanyl self-administration following early-life stress.

There is comorbidity between posttraumatic stress disorder (PTSD) and opioid use disorder (OUD), perhaps because PTSD-like stressful experiences early in life alter the hypothalamic-pituitary-adrenal stress axis to increase the risk for OUD. The present study determined if the glucocorticoid receptor antagonist PT150 reduces the escalation of fentanyl intake in rats exposed to a "two-hit" model of early-life stress (isolation rearing and acute stress). Male and female rats were raised during adolescence in either isolated or social housing and then were given either a single acute stress (restraint and cold-water swim) or control treatment in young adulthood. Rats were then treated daily with PT150 (50 mg/kg, oral) or placebo and were tested for acquisition of fentanyl self-administration in 1-hr sessions, followed by escalation across 6-hr sessions. Regardless of PT150 treatment or sex, acquisition of fentanyl self-administration in 1-hr sessions was greater in isolate-housed rats compared to social-housed rats; the acute stress manipulation did not have an effect on self-administration even though it transiently increased plasma corticosterone levels. During the 6-hr sessions, escalation of fentanyl was observed across all treatment groups; however, there was a significant PT150 Treatment × Sex interaction. While males self-administered more than females overall, PT150 decreased intake in males and increased intake in females, thus negating the sex difference. Although PT150 may serve as an effective treatment for reducing the risk of OUD following early-life stress in males, further work is needed to determine the mechanism underlying the differential effects of PT150 in males and females. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Periodic hypoxia, intermittent pain, and caffeine in male and female neonatal rats: corticosterone, insulin resistance, and hepatic gene expression.

Preterm infants experience multiple stressors including periodic neonatal hypoxia, maternal/caregiver separation, and acute pain from clinical procedures. Although neonatal hypoxia or interventional pain are associated with sexually dimorphic effects that may last into adulthood, the interaction of these common preterm stressors and caffeine pretreatment remains unknown. We hypothesize that an interaction of acute neonatal hypoxia, isolation, and pain modeling the experience of the preterm infant will augment the acute stress response and that caffeine routinely given to preterm infants will alter this response. Male and female rat pups were isolated and exposed to six cycles of periodic hypoxia (10% O2) or normoxia (room air control) and/or intermittent pain by administering needle pricks (or touch control) to the paw on postnatal (PD) days 1-4. An additional set of rat pups was pretreated with caffeine citrate (80 mg/kg ip) and studied on PD1. Plasma corticosterone, fasting glucose, and insulin were measured to calculate homeostatic model assessment for insulin resistance (HOMA-IR) (index of insulin resistance). Glucocorticoid-, insulin-, and caffeine-sensitive gene mRNAs were analyzed in the PD1 liver and hypothalamus to evaluate downstream markers of glucocorticoid action. Acute pain with periodic hypoxia led to a large increase in plasma corticosterone, which was attenuated by pretreatment with caffeine. Pain with periodic hypoxia led to a 10-fold increase in hepatic Per1 mRNA expression in males, which was attenuated with caffeine. The augmentation of corticosterone and HOMA-IR at PD1 after periodic hypoxia with pain suggests early intervention to attenuate the stress response may mitigate the programming effects of neonatal stress.

Handling and restraint induce a significant increase in plasma corticosterone in Hispaniolan Amazon parrots (Amazona ventralis).

To measure baseline plasma corticosterone levels in Hispaniolan Amazon parrots (Amazona ventralis) and assess the effects of handling and restraint on corticosterone levels over 1 hour, reflective of what parrots might experience during veterinary care. 10 male and 12 female Hispaniolan Amazon parrots. Each parrot was removed from its cage and wrapped in a towel for restraint similar to that performed in a clinical setting. An initial baseline blood sample was collected in < 3 minutes upon entrance into the parrot room, after which blood samples were taken every 15 minutes for 1 hour (a total of 5 blood samples). An enzyme-linked immunoassay was validated for Hispaniolan Amazon parrots and used to determine concentrations of plasma corticosterone. On average, parrots showed a significant increase in corticosterone between baseline samples and all subsequent postrestraint time points (average baseline corticosterone ± SD: 0.51 ± 0.65 ng/mL). Females, on average, displayed significantly higher corticosterone levels than males after 30, 45, and 60 minutes of restraint (P = .016, P = .0099, and P = .015, respectively). Birds with feather-destructive behavior did not have significantly higher corticosterone levels than birds without the condition (P = .38). Understanding the physiological stress response in companion psittacine birds during routine handling will allow clinicians to better evaluate how this may affect the patient's condition and diagnostic test results. Assessing how corticosterone correlates to behavioral conditions such as feather-destructive behavior will provide clinicians with the potential to develop treatment options.

Genes Associated with Increased Stress Sensitivity in Hypertensive ISIAH Rats

Inherited stress-induced arterial hypertension (ISIAH) rats are characterized by increased stress reactivity of the hypothalamic-pituitary-adrenal and sympathoadrenal systems. The genetic basis of increased susceptibility to stress was studied in hypertensive ISIAH rats. Adrenal transcriptomes were sequenced in hypertensive ISIAH and normotensive WAG rats, and nine differentially expressed genes (DEGs) were found in the X-chromosome locus that was previously associated with mild emotional stress-induced increases in blood pressure and plasma corticosterone and an increased adrenal weight in ISIAH rats. An analysis of the functions performed by DEG-encoded proteins suggested the Sms (spermine synthase) gene to be the most likely candidate gene in the X-chromosome locus associated with an elevated stress susceptibility in ISIAH rats.

Social adversity during juvenile age but not adulthood increases susceptibility to an immune challenge later in life

Adverse experiences in early life can increase mental vulnerability to immune challenges experienced later in life, which may induce the development of stress-related psychopathologies. Here, we investigated whether the combined effect of both events is higher if the first adverse experience occurs when the brain is still in development. Therefore, male Wistar rats were exposed to repeated social defeat (RSD, first hit) during juvenile age or adulthood and to an immune challenge consisting of a single injection of lipopolysaccharide (LPS, second hit) in adulthood. Control animals were not exposed to RSD, but only to the LPS challenge. Translocator protein density, a marker for reactive microglia, microglia cell density and plasma corticosterone levels were measured using in vivo [11C]PBR28 positron emission tomography, iba1 immunostaining, and corticosterone ELISA, respectively. Anhedonia, social behavior and anxiety were measured with the sucrose preference, social interaction, and open field tests, respectively. Rats exposed to RSD during juvenile age exhibited enhanced anhedonia and social interaction dysfunction after an immune challenge in adulthood. This enhanced susceptibility was not observed in rats exposed to RSD during adulthood. In addition, exposure to RSD synergistically increased microglia cell density and glial reactivity to the LPS challenge. This increase in microglia cell density and reactivity to the LPS challenge was more pronounced in rats exposed to RSD during juvenile age than in adulthood. Exposure to RSD alone in juvenile age or adulthood induced similar short-term anhedonia, a long-lasting increase in plasma corticosterone and microglial activity, but no change in anxiety and social behavior. Our findings indicate that exposure to social stress during juvenile age, but not adulthood, primes the immune system and increases the sensitivity to an immune challenge experienced later in life. This suggests that juvenile social stress can have more deleterious effects in the long term than similar stress in adulthood.

Genes Associated with Increased Stress Sensitivity in Hypertensive ISIAH Rats

Inherited stress-induced arterial hypertension (ISIAH) rats are characterized by increased stress reactivity of the hypothalamic-pituitary-adrenal and sympathoadrenal systems. The genetic basis of increased susceptibility to stress was studied in hypertensive ISIAH rats. Adrenal transcriptomes were sequenced in hypertensive ISIAH and normotensive WAG rats, and nine differentially expressed genes (DEGs) were found in the X-chromosome locus that was previously associated with mild emotional stress-induced increases in blood pressure and plasma corticosterone and an increased adrenal weight in ISIAH rats. An analysis of the functions performed by DEG-encoded proteins suggested the Sms (spermine synthase) gene to be the most likely candidate gene in the X-chromosome locus associated with an elevated stress susceptibility in ISIAH rats.

Site-Specific knockdown of microglia in the locus coeruleus regulates hypervigilant responses to social stress in female rats

BackgroundWomen are at increased risk for psychosocial stress-related anxiety disorders, yet mechanisms regulating this risk are unknown. Psychosocial stressors activate microglia, and the resulting neuroimmune responses that females exhibit heightened sensitivity to may serve as an etiological factor in their elevated risk. However, studies examining the role of microglia during stress in females are lacking. MethodsMicroglia were manipulated in the stress-sensitive locus coeruleus (LC) of female rats in the context of social stress in two ways. First, intra-LC lipopolysaccharide (LPS; 0 or 3 μg/side, n = 5–6/group), a potent TLR4 agonist and microglial activator, was administered. One hour later, rats were exposed to control or an aggressive social defeat encounter between two males (WS, 15-min). In a separate study, females were treated with intra-LC or intra-central amygdala mannosylated liposomes containing clodronate (m-CLD; 0 or 25 μg/side, n = 13–14/group), a compound toxic to microglia. WS-evoked burying, cardiovascular responses, and sucrose preference were measured. Brain and plasma cytokines were quantified, and cardiovascular telemetry assessed autonomic balance. ResultsIntra-LC LPS augmented the WS-induced burying response and increased plasma corticosterone and interleukin-1β (IL-1β). Further, the efficacy and selectivity of microinjected m-CLD was fully characterized. In the context of WS, intra-LC m-CLD attenuated the hypervigilant burying response during WS as well as the accumulation of intra-LC IL-1β. Intra-central amygdala m-CLD had no effect on WS-evoked behavior. ConclusionsThese studies highlight an innovative method for depleting microglia in a brain region specific manner and indicate that microglia in the LC differentially regulate hypervigilant WS-evoked behavioral and autonomic responses.

Effect of abrupt and gradual calorie restriction regimens on biochemical and behavioral markers in obese mice model.

Background: Although Calorie Restriction (CR) is primarily considered in obesity management, behavioral studies of CR and its methodology of implementation are not well-defined. Objective: The study aimed to determine the efficacy of the extensively researched method of CR-abrupt calorie restriction (ACR) and a newly proposed gradual calorie restriction (GCR) in terms of body weight, behavioral and biochemical parameters in the obese animal model-C57BL/6J mice. Design: Male obese mice were subjected to GCR regimen for 14 weeks which was compared and evaluated for anxiety-like behavior and stress levels with ACR. Plasma corticosterone was measured before initiation of CR and every three weeks following GCR and ACR, whereas plasma insulin was measured twice-after obesity induction and post 14 weeks of CR. The behavioral assessments were conducted before inducing CR and every three weeks following ACR and GCR. Results: A significant anxiety-like behavior and an increase in plasma corticosterone were observed in mice on GCR during the critical initial six weeks of CR (p < 0.05). Both groups showed a decrease in plasma glucose levels; however, the GCR group showed a significant reduction (p < 0.01). There was a significant decrease in social interaction in both groups with an increase in the latency period and a decrease in time spent with the stranger animal during the social interaction test (p < 0.05). Conclusion: The mice on GCR regimen demonstrated lesser anxiety-like behavior and low plasma corticosterone levels compared to those on ACR. This gives us a new avenue in CR research to evaluate the methodologies of implementing CR.

Sleep restriction during opioid abstinence affects the hypothalamic-pituitary-adrenal (HPA) axis in male and female rats

Hypothalamic-pituitary-adrenal (HPA) axis dynamics are disrupted by opioids and may be involved in substance abuse; this persists during withdrawal and abstinence and is associated with co-morbid sleep disruption leading to vulnerability to relapse. We hypothesized that chronic sleep restriction (SR) alters the HPA axis diurnal rhythm and the sexually dimorphic response to acute stressor during opioid abstinence. We developed a rat model to evaluate the effect of persistent sleep loss during opioid abstinence on HPA axis dynamics in male and female rats. Plasma ACTH and corticosterone were measured diurnally and in response to acute restraint stress in rats Before (control) compared to During subsequent opioid abstinence without or with SR. Abstinence, regardless of sleep state, led to an increase in plasma ACTH and corticosterone in the morning in males. There was a tendency for higher PM plasma ACTH during abstinence in SR males (p = 0.076). ACTH and corticosterone responses to restraint were reduced in male SR rats whereas there was a failure to achieve the post-restraint nadir in female SR rats. There was no effect of the treatments or interventions on adrenal weight normalized to body weight. SR resulted in a dramatic increase in hypothalamic PVN AVP mRNA and plasma copeptin in male but not female rats. This corresponded to the attenuation of the HPA axis stress response in SR males during opioid abstinence. We have identified a potentially unique, sexually dimorphic role for magnocellular vasopressin in the control of the HPA axis during opioid abstinence and sleep restriction.

Gestational arsenic exposure induces anxiety-like behaviors in F1 female mice by dysregulation of neurological and immunological markers.

Arsenic is a harmful heavy metal and a well-known developmental neurotoxicant. Previously, we have reported that gestational arsenic exposure resulted in impaired social behaviors in F1 and F2 male mice. However, little is known about the developmental arsenic exposure on anxiety-like behavior. This study aimed to detect the effect of gestational arsenic exposure on anxiety-like behavior and related gene expressions in 74-week-old F1 female mice. Pregnant C3H/HeN mice (F0) were given drinking water containing 85 ppm sodium arsenite (NaAsO2) from gestational day 8 to 18. The control mice were given tap water only. At 74-week-old, open field test was performed, then anxiety and apoptosis-related factors were determined by real_time RT_PCR and immunohistochemical analyses. The arsenite-exposed F1 female mice showed decreased center entry and center time in open field test. In addition, the number of grooming and fecal pallet was significantly increased in the arsenite-exposed F1 female mice compared to the control. Downregulation of brain-derived neurotrophic factor (BDNF), serotonin receptor (5HT1A) and upregulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), interleukin 1 β (IL-1β), cyclooxygenase 2 (COX2), caspase-3, Bcl2-associated X protein (Bax) were detected in the prefrontal cortex in the arsenite-exposed F1 female mice. Microglial marker ionized calcium-binding adapter molecule 1 (Iba1)-positive cells were increased in the arsenite-exposed F1 female mice. Moreover, a significantly increased plasma corticosterone level was observed in the arsenic-exposed F1 female mice. This study suggested that gestational arsenic exposure induced anxiety-like behavior accompanied with dysregulation of neurological and immunological markers, neuroinflammatory responses, neuronal apoptosis, and decreased neurogenesis in the prefrontal cortex of F1 female mice.

Free-L-Cysteine improves corticosterone-induced behavioral deficits, oxidative stress and neurotransmission in rats.

L-Cysteine (L-Cys) is a semi-essential amino acid. It serves as a substrate for enzyme cystathionine-β-synthase in the central nervous system (CNS). L-Cys showed various antioxidant characteristics. Though, studies on the effect of free L-Cys administration to evaluate the CNS functioning is very limited. Therefore, we assessed the effects of L-Cys on corticosterone (CORT) induced oxidative stress, behavioral deficits and memory impairment in male rats. L-Cys (150mg/kg/ml) administered to vehicle and CORT (20mg/kg/ml) treated rats orally for 28days. Behavioral activities were conducted after treatment period. Subsequently, rats were sacrificed, blood and brain were removed. Hippocampus was isolated from brain and then hippocampus and plasma were collected for oxidative, biochemical and neurochemical analysis. Results showed that repeated treatment of L-Cys produced antidepressant, anxiolytic and memory-improving effects which may be ascribed to the enhanced antioxidant profile, normalized cholinergic, serotonergic neurotransmission in brain (hippocampus) following CORT administration. Increased plasma CORT by CORT administration was also normalized by L-Cys. The current study concluded that administration of free L-Cys improved the behavioral, biochemical, neurochemical and redox status of CNS. Hence, L-Cys could be protective therapeutic modulator against stress induced neurological ailments.

Handling method affects measures of anxiety, but not chronic stress in mice

Studies in mice have shown that less aversive handling methods (e.g. tunnel or cup handling) can reduce behavioural measures of anxiety in comparison to picking mice up by their tail. Despite such evidence, tail handling continues to be used routinely. Besides resistance to change accustomed procedures, this may also be due to the fact that current evidence in support of less aversive handling is mostly restricted to effects of extensive daily handling, which may not apply to routine husbandry practices. The aim of our study was to assess whether, and to what extent, different handling methods during routine husbandry induce differences in behavioural and physiological measures of stress in laboratory mice. To put the effects of handling method in perspective with chronic stress, we compared handling methods to a validated paradigm of unpredictable chronic mild stress (UCMS). We housed mice of two strains (Balb/c and C57BL/6) and both sexes either under standard laboratory conditions (CTRL) or under UCMS. Half of the animals from each housing condition were tail handled and half were tunnel handled twice per week, once during a cage change and once for a routine health check. We found strain dependent effects of handling method on behavioural measures of anxiety: tunnel handled Balb/c mice interacted with the handler more than tail handled conspecifics, and tunnel handled CTRL mice showed increased open arm exploration in the elevated plus-maze. Mice undergoing UCMS showed increased plasma corticosterone levels and reduced sucrose preference. However, we found no effect of handling method on these stress-associated measures. Our results therefore indicate that routine tail handling can affect behavioural measures of anxiety, but may not be a significant source of chronic husbandry stress. Our results also highlight strain dependent responses to handling methods.