Anxiety-like Behavior In Rats Research Articles

Melatonin alleviates traumatic brain injury-induced anxiety-like behaviors in rats: Roles of the protein kinase A/cAMP-response element binding signaling pathway.

Melatonin is a hormone produced by the pineal gland. Given its capabilities of neuroprotection and low neurotoxicity, melatonin could be a therapeutic strategy for traumatic brain injury (TBI). The present study was conducted to determine the neuroprotective effects of melatonin on TBI-induced anxiety and the possible molecular mechanism. Rats were randomly divided into seven groups. The rodent model of TBI was established using the weight-drop method. Melatonin was administered by intraperitoneal injection at a dose of 10 mg/kg after TBI. H89 (0.02 mg/kg), a special protein kinase A (PKA) inhibitor, or dibutyryl-cyclic adenosine monophosphate (cAMP; 0.1 mg/kg), an activator of PKA, were administered by stereotactic injection of the brain to evaluate the roles of PKA and cAMP-response element-binding protein (CREB) in melatonin-related mood regulation, respectively. At 30 days post-TBI, the changes in anxiety-like behaviors in rats were measured using the open field and elevated plus maze tests. At 24 h post-TBI, the number of activated astrocytes and neuronal apoptosis were evaluated using immunofluorescence assay. The expression levels of inflammatory cytokines (TNF-α and IL-6) in the amygdala were measured using an enzyme-linked immunosorbent assay. The expression levels of PKA, phosphorylated (p)-PKA, CREB, p-CREB, NF-κB and p-NF-κB in the amygdala were detected using western blotting. It was revealed that melatonin partially reversed TBI-induced anxiety-like behavior in rats, and decreased the number of activated astrocytes and neuronal apoptosis in the amygdala induced by TBI. H89 partially blocked the neuroprotective effects of melatonin; while dibutyryl-cAMP not only reduced the H89-induced emotional disturbance but also enhanced the protective effects of melatonin against TBI. Overall, melatonin can alleviate TBI-induced anxiety-like behaviors in rats. Moreover, the underlying mechanism may be associated with the activation of the PKA/CREB signaling pathway.

The role of peripheral transient receptor potential vanilloid 1 channels in stress-induced hyperthermia in rats subjected to an anxiogenic environment

Anxiety resulting from psychogenic stimuli elicit stress-induced hyperthermia in rats, often called “psychogenic fever”, which is part of a coordinated response to situations seen as novel or distressing. Brain transient receptor potential vanilloid 1 (TRPV1) channels modulate both thermoregulation and animal behavior; however, the role of peripheral TRPV1 channels in regulating these responses during exposure to an anxiogenic environment has not been determined. Thus, the present study aimed to investigate the involvement of abdominal TRPV1 channels in stress-induced hyperthermia and behavior in rats subjected to an unconditioned anxiety test. Desensitized rats (peripheral desensitization of TRPV1 channels with resiniferatoxin; RTX) and their respective controls were subjected to a 15-min open field (OF) test. The core body temperature (Tcore), tail skin temperature (Tskin), and rats’ movements inside the arena were recorded. The OF test induced a similar increase in Tcore in both groups throughout the exposure time; however, at the recovery period, the RTX-treated rats had a slower reduction in Tcore due to lower tail skin heat loss. Tskin decreased significantly in both groups during exposure to OF but, during recovery, the RTX-treated rats showed impaired skin vasodilation. Also, RTX-treated rats entered fewer times and spent less time in the OF center square, suggesting an anxiety-related behavior. Our findings indicate that, under stressful conditions, peripheral TRPV1 channels modulate thermoregulatory and behavioral responses. The TRPV1 desensitization induces a more prolonged hyperthermic response due to lower cutaneous heat dissipation, alongside a more evident anxiety-like behavior in rats subjected to the OF apparatus.

The effect of gallic acid on memory and anxiety-like behaviors in rats with bile duct ligation-induced hepatic encephalopathy: Role of AMPK pathway.

Objective:Hepatic encephalopathy (HE) is a serious neurological syndrome which is caused by acute and chronic liver diseases. In this study, the effect of gallic acid (GA) as an activator of AMP-activated protein kinase (AMPK) on memory and anxiety-like behaviors in rats with HE caused by bile duct ligation (BDL) was investigated. Materials and Methods:The rats were randomly divided into the following eight groups (n=7): sham; BDL; BDL+GA 20 mg/kg; BDL+GA 30 mg/kg; sham+dorsomorphin or compound C (CC) (as AMPK inhibitors); BDL+CC; BDL+GA 20 mg/kg+CC; and BDL+GA 30 mg/kg+CC. The rats received GA once daily by gavage for four weeks, and dorsomorphin 6.2 µg per rat was administered on a daily basis via bilateral intraventricular injection for four weeks. Behavioral tests including novel object recognition (NOR), open field and Morris water maze (MWM) were used to evaluate anxiety and memory in the rats. Results: Examining some parameters of NOR and MWM tests showed that memory performance was significantly reduced in the BDL versus the sham group, and in the BDL+CC versus the sham+CC group (p<0.05). GA intake improved memory in the GA-receiving groups compared with the BDL and BDL+CC groups (p<0.05). Examining some parameters of open field test showed that anxiety was significantly increased in the BDL versus the sham group, and the BDL+CC versus the sham+CC group (p<0.05). GA intake reduced anxiety in GA-receiving groups compared with the BDL+BDL+CC group (p<0.05). Conclusion:GA was effective in improving cognitive and anxiety-like behaviors through activating AMPK.

Odors associated with neonatal experiences with the dam have enhanced anxiolytic effects in rat

Odor stimuli are widely reported to promote relaxation and reduce anxiety in humans and rodents. However, it remains unclear if this anxiolytic efficacy can be further enhanced by association with positive experiences. Therefore, we compared the effects of a novel odor to a familiar odor previously paired with a positive experience on anxiety-like behaviors in rats. One group of Wistar-Imamichi female and male pups was exposed to an odor stimulus with their dams during postnatal days (PNDs) 8-12, whereas another control group was exposed to perfused air during the same period. Starting on PND 42, all animals were examined in the open field test (OFT) and elevated plus maze (EPM) test during exposure to scent-free air (vehicle), a novel odor, or the positive-familiar odor from postnatal exposure. In the EPM, female rats entered open arms with all 4 paws (complete entry) more frequently and spent more time on open arms during exposure to the positive-familiar odor than during exposure to air or a novel odor, whereas partial open arm entries with forepaws only were increased during exposure to both novel and positive-familiar odors compared to air. In contrast, male rats demonstrated no significant increase in open arm activity during positive-familiar odor exposure, but did show equally reduced grooming frequency during novel and familiar-positive odor exposure in the OFT. Exposure to positive-familiar odors may be an effective and safe method for anxiety reduction, especially in females.

Tangeretin Improves Anxiety-Like Behaviors in a Rat Model of Post-Traumatic Stress Disorder

Post-traumatic stress disorder often contributes to various anxiety-like behaviors. The single prolonged stress was used to induce anxiety-like behaviors of rats. In this model, using an elevated plus maze test, we observed that tangeretin treatment reversed the decrease in the number of open arms entries, the percentage of time spent in open arms with no change in the number of closed arms entries, and percentage of time spent in closed arms in rats subjected to single prolonged stress. Furthermore, in an open field test, tangeretin treatment reversed the decrease in the number of crossing and time spent in the center field with no change in the activities in the peripheral regions. Diminution in serotonin in different parts of brain of rats with post-traumatic stress disorder was reversed by tangeretin. At the molecular level, tangeretin treatment increased the expression of nuclear factor erythroid 2-related factor 2, heme oxygenase 1, and oxidoreductase-1 that was reduced in the post-traumatic stress disorder group in a dose-dependent manner. In conclusion, these studies have shown for the first time that tangeretin relieves anxiety-like behaviors in rats with post-traumatic stress disorder by activating nuclear factor erythroid 2-related factor 2 signaling pathway.

Solitary Nitric Oxide Signaling Mediates Mild Stress-Induced Anxiety and Norepinephrine Release in the Bed Nucleus of the Stria Terminalis during Protracted Ethanol Withdrawal.

Ethanol withdrawal (EtOHW) alters the pattern of neurohormonal and behavioral response toward internal and external stimuli, which mediates relapse to alcohol use even after a long period of abstinence. Increased noradrenergic signaling from the nucleus tractus solitarius (NTS) to the bed nucleus of the stria terminalis (BNST) during EtOHW underlies withdrawal-induced anxiety, while nitric oxide synthase (NOS) inhibitors injected into the periaqueductal area attenuate EtOHW-induced anxiety. Therefore, this study investigated the involvement of NOS within the NTS in anxiety and increased norepinephrine (NE) release in the BNST during protracted EtOHW in rats exposed to a mild stress. Rats were intraperitoneally administered 3 g/kg/day EtOH for 21 days followed by 28 days of withdrawal, and on the 28th day of withdrawal, the rats were subjected to restraint stress for 7 minutes. The elevated plus maze test was employed to evaluate anxiety-like behavior in rats, and in vivo microdialysis was used to measure the extracellular NE level in the BNST. In elevated plus maze tests, EtOHW rats but not EtOH-naive rats exhibited anxiety-like behavior when challenged with 7-minute mild restraint stress, which was, respectively, mitigated by prior intra-NTS infusion of the nitric oxide scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO), nonselective NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME), or selective neuronal NOS (nNOS) inhibitor 7-nitroindazole (7-NI). Each of these agents also decreased the plasma corticosterone levels in EtOHW rats. In in vivo microdialysis, prior intra-NTS infusion of carboxy-PTIO, L-NAME, or 7-NI attenuated the mild stress-induced NE release in the BNST of EtOHW rats. Additionally, EtOHW rats showed increased solitary nNOS gene and protein expression. Moreover, the anxiolytic effect of intra-NTS administration of 7-NI was abolished by subsequent intra-NTS administration of sodium nitroprusside. These results suggest that elevation of solitary nitric oxide signaling derived from nNOS mediates stress-precipitated anxiety and norepinephrine release in the BNST during protracted EtOHW.

Environmental Enrichment Ameliorates Anxiety-Like Behavior in Rats without Altering Plasma Corticosterone Level

BACKGROUND: Anxiety disorder is one of the most common psychiatric problems. Prolonged stress gives rise to anxiety-like behavior in animals. Environmental interventions influence the outcome of anxiety treatment. Environmental enrichment (EE) can modulate brain’s structure and function. AIM: The objective of the study was to evaluate EE effects on anxiety-like behavior and corticosterone (CORT) level after unpredictable chronic mild stress (UCMS). METHODS: A total of 28 rats were assigned into four groups randomly: Control, UCMS, UCMS+EE, and UCMS+fluoxetine. UCMS, EE, and fluoxetine were given for 21 days. Anxiety behavior was measured on day 22nd using Elevated Plus Maze. Behavioral measurement was based on the total time spent and total entries onto open and closed arms. CORT was measured using ELISA. RESULTS: UCMS increased anxiety-like behavior as seen from reduced number of entries and time spent in open arms as well as increased number of entries and time spent in in closed arms in UCMS group than control. Rats in EE group spent more time and made more entries in the open arms than UCMS group (both p = 0.002). Anxiolytic effect of EE was stronger than fluoxetine. Plasma CORT level among groups did not differ significantly (p = 0.351). CONCLUSION: EE can ameliorate stress-induced anxiety-like behavior without affecting CORT level.

Effect of chronic sleep deprivation and sleep recovery on hippocampal CA3 neurons, spatial memory and anxiety-like behavior in rats

Sleep deprivation-induced degenerative changes in the brain lead to the impairment of memory, anxiety, and quality of life. Several studies have reported the effects of sleep deprivation on CA1 and dentate gyrus regions of the hippocampus; in contrast, there is less known about the impact of chronic sleep deprivation (CSD) and sleep recovery on CA3 neurons and behavior. Hence, the present study aimed to understand the effect of CSD and sleep recovery on hippocampal CA3 neurons and spatial memory, and anxiety-like behavior in rats. Sixty male rats (Sprague Dawley) were grouped as control, environmental control (EC), CSD, 5 days sleep recovery (CSD + 5D SR), and 21 days sleep recovery (CSD + 21D SR). CSD, CSD + 5D SR and, CSD + 21D SR group rats were sleep deprived for 21 days (18 h/day). After CSD, the CSD + 5D SR and CSD + 21D SR rats were sleep recovered for 5- and 21-days respectively. Oxidative stress, dendritic arborization of CA3 neurons, spatial memory, and anxiety-like behavior was assessed. Spatial memory, basal, and apical dendritic branching points/intersections in hippocampal CA3 neurons were reduced, and anxiety-like behavior and oxidative stress increased significantly in the CSD group compared to control (p < 0.001). The CSD + 21D SR showed a significant improvement in spatial memory, reduction in anxiety-like behavior, and oxidative stress when compared to the CSD group (p < 0.05). The basal and apical dendritic branching points/intersections in hippocampal CA3 neurons were increased after CSD + 21D SR, however, it was not significant (p > 0.05). Even though the CSD + 21D SR showed a significant improvement in all the parameters, it did not reach the control level. There was an improvement in all the parameters after CSD + 5D SR but this was not significant compared to the CSD group (p > 0.05). Overall results indicate that the CSD-induced impairment of spatial memory and anxiety-like behavior was associated with oxidative stress and reduced dendritic arborization of hippocampal CA3 neurons. The CSD + 21D SR significantly reduced the damage caused by CSD, but it was not sufficient to reach the control level.

The effect of early handling on anxiety-like behaviors of rats exposed to valproic acid pre-and post-natally

IntroductionAutism spectrum disorder (ASD) is a complex, behaviorally defined disorder of the immature brain as a result of genetic and environmental risk factors, such as prenatal exposure to valproic acid (VPA). This syndrome is known for its high prevalence. On the other hand, postnatal manipulations have been shown to affect brain development, cortical neuroscience, and pituitary-adrenal activity. In early handling (EH) procedure, pups are removed from their mother on a daily basis from birth to lactation, are physically touched, and exposed to the (a) new environment. In the present study, the effect of EH on anxiety-like behaviors in rats exposed pre- and post-natally to valproic acid was investigated. MethodsPregnant Wistar rats were randomly separated into six groups which are prenatal saline, Prenatal VPA, Prenatal VPA + EH and postnatal saline, Postnatal VPA, Postnatal VPA + EH. VPA administration was performed either on ED12.5 (600 mg/kg, i.p.) or PD 2–4 (400 mg/kg, s.c.). In the groups receiving EH, pups underwent physical handling from PD 1 to 21. On postnatal day 21 all offspring were weaned and the behavioral tests were performed on 30 and 31 days of age. Elevated plus maze and open field tests were used to investigate anxiety-like behaviors. ResultsThe results revealed that intraperitoneal injection of valrpoic acid (600 mg.kg) during pregnancy significantly reduced OAT% in males (p < 0.01) and females in a non-significant manner (p > 0.05). In comparison, rearing counts of prenatal VPA groups significantly increased in female sex (p < 0.05) in the EPM test. Following postnatal VPA administration (400 mg/kg), decrease in the time spent in central zone occurred in female rats in the open filed (p < 0.05), as well as a significant increase in the number of grooming of the male sex (p < 0.05). Applying Early Handling to male and female Wistar rats receiving prenatal VPA significantly reversed the OAT% fall (p < 0.05). EH in postnatally VPA exposed animals significantly decreased the OAT% and OAE% criteria, while increasing the locomotor activity of the female sex (p < 0.05). Compared with the postnatal VPA group, no significant change was reported in the EPM performance of postnatal VPA + EH group in neither of sexes (p > 0.05). ConclusionThe findings of this study suggest that injections of valproic acid during pregnancy lead to anxiety-like behaviors in male offspring, which EH can improve (attenuate) to some extent. VPA injections on the second to the fourth day of infancy did not have a profound effect on anxiety level. Further behavioral studies need to be performed using other devices to investigate anxiety-like behaviors and to determine the mechanisms involved in these behaviors.

Neuroprotective and acetylcholinesterase inhibitory activity of plumbagin in ICV-LPS induced behavioral deficits in rats

• ICV-LPS treated rats exhibited memory deficits and anxiety-like behavior in rats. • The neuroprotective effect of plumbagin mediated through mitigation of oxidative stress and inflammation. • In-silico study revealed binding affinity of plumbagin on acetylcholinesterase site. • Plumbagin could be considered as promising therapeutic agent in the neuroprotection against behavioral disorders. Plumbagin (5‑hydroxy-2-methyl-1,4-naphthoquinone), a phytoconstituent has been shown to exhibit potent antioxidant and anti-inflammatory effects. In the present investigation, we explored the neuroprotective effects of plumbagin against intracerebroventricular (ICV) lipopolysaccharide (LPS)-induced behavioral deficits. We found that ICV administration of LPS (5 μg/5μl in each ICV injection) bilaterally in the hippocampus caused significant reduction in learning and memory abilities of rats. Moreover, ICV-LPS treated rats displayed anxiety-like behavior evident by open field test and elevated plus maze test. Biochemical analysis in the hippocampus revealed oxidative-nitrosative stress, mitochondrial complexes (I, II, and III) impairment and cholinergic dysfunction in ICV-LPS rats. However, pre- and post-treatment with plumbagin (10 and 20 mg/kg) dose-dependently attenuated ICV-LPS induced oxidative stress (reduction of MDA and nitrite with GSH elevation), mitochondrial impairment, and cholinergic dysfunction (reduction of AChE) in the hippocampus. The pro-inflammatory cytokine (IL-1β) was also found to be increased in the ICV-LPS treated group which was markedly reduced by the treatment of Plumbagin-20 mg/kg. Further, i n-silico analysis revealed that the calculated dock score (-5.116 kcal/mol) and predicted binding energy (-45.800 kcal/mol) supports the binding of plumbagin in the binding site of AChE. All these findings support the neuroprotective effect of plumbagin against ICV-LPS induced behavioral and neurochemical deficits in rats. Thus, plumbagin may be considered an intriguing pharmacological intervention for the management of behavioral dysfunction.

Anxiolytic effect of chronic intake of supplemental magnesium chloride in rat

Evidence suggest that magnesium dietary supplementation has several health benefits including lowering blood pressure, reducing insulin resistance, and improving symptoms of depression, anxiety, and migraine. Here, we aimed to study the effect of chronic magnesium supplementation on anxiety-like behavior in rats by supplementing with magnesium their drinking water for 30 days. Anxiety-like behavior was induced by subcutaneous injection of veratrin 30 min before performing elevated plus maze and open field tests to measure anxiety levels and locomotion, respectively. We quantify the concentration of magnesium in plasma and cerebrospinal fluid. We used diazepam to compare the efficacy of magnesium supplementation as an anxiolytic agent. Our results show that rats supplemented with magnesium had a statistically significant decrease in anxiety levels with not effects on locomotion and a statistically significant increase in concentration of magnesium in plasma and cerebrospinal fluid. However, the anxiolytic effect of magnesium supplementation washes-out in 12 days. We discuss the advantages of using supplemental magnesium as anxiolytic.

Protective effects of tetramethylpyrazine on dysfunction of the locus coeruleus in rats exposed to single prolonged stress by anti-ER stress mechanism.

Post-traumatic stress disorder (PTSD) is a serious stress-related neuropsychiatric disorder caused by major traumatic events. Abnormal activity of the locus coeruleus (LC)-noradrenergic system is related to the development of PTSD-like symptoms. Our previous studies have indicated that endoplasmic reticulum (ER) stress induced neuronal apoptosis of LC in rats with PTSD. The purpose of this study was to further investigate the role of ER stress pathways in LC neuronal dysfunction and elucidate the effect of the bioactive component tetramethylpyrazine (TMP) against ER stress response. We used an acute exposure to single prolonged stress (SPS) to model PTSD in rats. There were higher norepinephrine (NE) levels in the brain, increased tyrosine hydroxylase expression in LC, and enhanced anxiety-like behaviors in rats exposed to SPS, which were observed by enzyme-linked immunosorbent assay, western blot analysis and elevated plus maze test, respectively. In addition, the three major pathways of ER stress were activated by SPS exposure, which may be involved in the dysregulation of the LC-noradrenergic system of rats with PTSD. Furthermore, we found that TMP administration significantly suppressed the increased responsiveness of LC-noradrenergic system, effectively reduced the anxiety response of SPS rats, and selectively attenuated the activation of pro-apoptotic ER stress pathways. The results suggest that TMP was efficient in improving the LC-NE dysfunction induced by excessive ER stress. TMP exhibited a significant neuroprotective effect and potential therapeutics on PTSD-like symptoms.

Bacteroides uniformis CECT 7771 Modulates the Brain Reward Response to Reduce Binge Eating and Anxiety-Like Behavior in Rat

Food addiction (FA) is characterized by behavioral and neurochemical changes linked to loss of food intake control. Gut microbiota may influence appetite and food intake via endocrine and neural routes. The gut microbiota is known to impact homeostatic energy mechanisms, but its role in regulating the reward system is less certain. We show that the administration of Bacteroides uniformis CECT 7771 (B. uniformis) in a rat FA model impacts on the brain reward response, ameliorating binge eating and decreasing anxiety-like behavior. These effects are mediated, at least in part, by changes in the levels of dopamine, serotonin, and noradrenaline in the nucleus accumbens and in the expression of dopamine D1 and D2 receptors in the prefrontal cortex and intestine. B. uniformis reverses the fasting-induced microbiota changes and increases the abundance of species linked to healthy metabolotypes. Our data indicate that microbiota-based interventions might help to control compulsive overeating by modulating the reward response.

Atractylenolide III reduces depressive- and anxiogenic-like behaviors in rat depression models

Atractylenolide III, a major component of the atractylodes macrocephala Koidz, derived from the rhizoma atractylodes, has been reported to produce various pharmacological effects including anti-aging, anti-inflammation, anti-tumor, and other effects. Growing evidence suggests that proinflammatory cytokines, such as interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-α, are increased in depressed patients. The present study was aimed at investigating the antidepressant- and anxiolytic-like effects of atractylenolide III in lipopolysaccharide (LPS) challenge and chronic unpredictable mild stress (CUMS) rat model. We found that 30 mg/kg of atractylenolide III administered by oral gavage for 14 days, significantly reduced the immobility time in a forced swimming test (FST), but did not alter the number of crossings in an open field test (OFT), respectively. The results indicated that atractylenolide III has an antidepressant-like effect without affecting locomotor activity. We then used the LPS-induced depression model to assess the effects of atractylenolide III on behaviors in FST, sucrose preference test (SPT), and novelty-suppressed feeding test (NSFT). Interestingly, in addition to the antidepressant-like effects, 30 mg/kg of atractylenolide III also produced an anxiolytic-like effect. To further identify the antidepressant- and anxiolytic-like effects of atractylenolide III, we used the CUMS model with 28 consecutive days of the atractylenolide III treatment, followed by the SPT, FST, and NSFT. Atractylenolide III prevented CUMS-induced depressive- and anxiety-like behaviors in rats. To illustrate the underlying possible mechanisms of action of atractylenolide III, we measured the proinflammatory cytokines levels. The results showed that atractylenolide III decreased the proinflammatory cytokines levels in the hippocampus of CUMS exposed rats. In summary, our findings demonstrated that atractylenolide III produces antidepressant- and anxiolytic-like effects in rats, and these effects appear to be mediated by inhibition of hippocampal neuronal inflammation.

Chronic oxytocin-driven alternative splicing of Crfr2α induces anxiety

The neuropeptide oxytocin (OXT) has generated considerable interest as potential treatment for psychiatric disorders, including anxiety and autism spectrum disorders. However, the behavioral and molecular consequences associated with chronic OXT treatment and chronic receptor (OXTR) activation have scarcely been studied, despite the potential therapeutic long-term use of intranasal OXT. Here, we reveal that chronic OXT treatment over two weeks increased anxiety-like behavior in rats, with higher sensitivity in females, contrasting the well-known anxiolytic effect of acute OXT. The increase in anxiety was transient and waned 5 days after the infusion has ended. The behavioral effects of chronic OXT were paralleled by activation of an intracellular signaling pathway, which ultimately led to alternative splicing of hypothalamic corticotropin-releasing factor receptor 2α (Crfr2α), an important modulator of anxiety. In detail, chronic OXT shifted the splicing ratio from the anxiolytic membrane-bound (mCRFR2α) form of CRFR2α towards the soluble CRFR2α (sCRFR2α) form. Experimental induction of alternative splicing mimicked the anxiogenic effects of chronic OXT, while sCRFR2α-knock down reduced anxiety-related behavior of male rats. Furthermore, chronic OXT treatment triggered the release of sCRFR2α into the cerebrospinal fluid with sCRFR2α levels positively correlating with anxiety-like behavior. In summary, we revealed that the shifted splicing ratio towards expression of the anxiogenic sCRFR2α underlies the adverse effects of chronic OXT treatment on anxiety.

Protective effect of metformin against ovariectomy induced depressive- and anxiety-like behaviours in rats: role of oxidative stress.

Several studies have shown that low estrogen levels can lead to an increase in the incidence of depression and anxiety during menopause. The hippocampus and prefrontal cortex are parts of the brain involved in depressive- and anxiety-like behaviors. Recent studies have revealed that metformin has neuroprotective effects mainly due to its antioxidant properties. The aim of the present study was to examine the therapeutic potential of metformin in depressive- and anxiety-like behavior as well as oxidative stress in the prefrontal cortex and hippocampus of ovariectomized rats. Young female Wistar Albino rats were distributed into four groups (n:8): control, metformin-administered control, ovariectomized and metformin administered ovariectomized groups. Metformin (25 mg/kg) was administered daily by oral gavage for 2 weeks. Forced swimming test and open field test were performed to evaluate depression- and anxiety-like behaviors, respectively. Following the treatment with metformin, the tissues of the hippocampus and prefrontal cortex were isolated for the measurement of malondialdehyde, reduced glutathione and ascorbic acid contents. Ovariectomy resulted in depressive- and anxiety-like behaviors, and besides, increased content of malondialdehyde in both prefrontal cortex and hippocampus. The levels of ascorbic acid and glutathione were found to be reduced in ovariectomized rats. Metformin treatment significantly decreased depressive behaviour and malondialdehyde content in the prefrontal cortex. Reducing oxidative stress of the prefrontal cortex was suggested as a possible mechanism implicated in the beneficial effects of metformin on ovariectomy-induced depressive-like behaviour. We believe that the therapeutic efficiency of metformin needs to be tested for potential clinical use in surgical menopause or gonadal hormone deficiency women with depression.

Electroacupuncture Attenuates Neuropathic Pain and Comorbid Negative Behavior: The Involvement of the Dopamine System in the Amygdala

Neuropathic pain (NeuP) is an important clinical problem accompanying negative mood symptoms. Neuroinflammation in the amygdala is critically involved in NeuP, and the dopamine (DA) system acts as an important endogenous anti-inflammatory pathway. Electroacupuncture (EA) can improve the clinical outcomes in NeuP, but the underlying mechanisms have not been fully elucidated. This study was designed to assess the effectiveness of EA on pain and pain-related depressive-like and anxiety-like behaviors and explore the role of the DA system in the effects of EA. Male Sprague-Dawley rats were subjected to the chronic constrictive injury (CCI) model to induce NeuP. EA treatment was carried out for 30 min once every other day for 3 weeks. The results showed that CCI caused mechanical hyperalgesia and depressive and anxiety-like behaviors in rats and neuroinflammation in the amygdala, such as an increased protein level of TNFα and IL-1β and activation of astrocytes. EA treatment significantly improved mechanical allodynia and the emotional dysfunction induced by CCI. The effects of EA were accompanied by markedly decreased expression of TNFα, IL-1β, and glial fibrillary acid protein (GFAP) in the amygdala. Moreover, EA treatment reversed CCI-induced down-regulation of DA concentration, tyrosine hydroxylase (TH) expression, and DRD1 and DRD2 receptors. These results suggest that EA-ameliorated NeuP may possibly be associated with the DA system to inhibit the neuroinflammation in the amygdala.

Sauchinone Blocks Ethanol Withdrawal-Induced Anxiety but Spares Locomotor Sensitization: Involvement of Nitric Oxide in the Bed Nucleus of the Stria Terminalis.

Both the positive (manifested by locomotor sensitization) and negative (withdrawal symptoms) reinforcing effects of ethanol (EtOH) involve central nitric oxide (NO) signaling. Sauchinone (a bioactive lignan in Saururus chinensis) has been shown to improve methamphetamine-induced behavioral and neurochemical changes via the NO signaling pathway. Thus, this study evaluated the effects of sauchinone on locomotor sensitization and anxiety during EtOH withdrawal (EtOHW). Male adult Sprague-Dawley rats were treated with 1.5 g/kg/day of EtOH (20%, vol/vol) via intraperitoneal injection for 28 days, followed by a 3-day withdrawal. During withdrawal, the rats were given intragastric sauchinone (2.5, 7.5, or 25 mg/kg/day) once a day. EtOH locomotor sensitization was determined by challenging EtOHW rats with 0.75 g/kg EtOH, while EtOHW-induced anxiety was assessed using the elevated plus maze (EPM). None of the three doses of sauchinone affected EtOH locomotor sensitization. However, in the EPM, treatment of EtOHW rats with sauchinone at 7.5 or 25 mg/kg/day increased both the number of entries into and the time spent in the open arms. Moreover, the two doses of sauchinone inhibited the oversecretion of plasma corticosterone during EtOHW. In the bed nucleus of the stria terminalis (BNST), EtOHW increased NO production, enhanced gene and protein expression of both inducible nitric oxide synthase (iNOS) and neuronal NOS (nNOS), and also elevated protein levels of corticotropin-releasing factor, which were all inhibited by 25 mg/kg/day sauchinone. In an in vitro experiment, sauchinone (3, 10, and 30 μM) inhibited H2O2-stimulated nNOS protein expression in neuronal PC12 cells. Finally, intra-BNST infusion of sodium nitroprusside, a NO donor, after sauchinone (25 mg/kg/day) administration, abolished its expected anxiolytic effect. Taken together, these results indicate that sauchinone attenuates anxiety-like behavior in rats during EtOHW but spares EtOH locomotor sensitization, and the anxiolytic effect is mediated via the NO signaling pathway in the BNST.

Transcriptomic signature of early life stress in male rat prefrontal cortex

Early life stress (ELS) is associated with adverse mental health outcomes including anxiety, depression and addiction-like behaviours. While ELS is known to affect the developing brain, leading to increased stress responsiveness and increased glucocorticoid levels, the molecular mechanisms underlying the detrimental effects of ELS remain incompletely characterised.Rodent models have been instrumental in beginning to uncover the molecular and cellular underpinnings of ELS. Limited nesting (LN), an ELS behavioural paradigm with significant improvements over maternal separation, mimics human maternal neglect.We have previously shown that LN leads to an increase in one of the behavioural measures of anxiety like-behaviours in rats (percent of entries in the EPM open arm). Here we assessed gene expression changes induced by ELS in rat prefrontal cortex by RNA-sequencing. We show that LN leads primarily to transcriptional repression and identify a molecular signature of LN in rat PFC that is observed across ELS protocols and replicable across rodent species (mouse and rat).

Ethoprophos induces rats' brain injury and neurobehavioral impairment via transcriptional activation of glial fibrillary acidic protein and tubulin-associated unit even at the threshold inhibition of acetylcholinesterase: A 90-days study

Ethoprophos, a common organophosphate nematicide, has adverse effects on the nervous system. However, the specific mechanism of its neurotoxicity is unclear. Here, we have studied the possible involvement of brain glial fibrillary acidic protein and tubulin-associated unit in the neurotoxicity mechanism of ethoprophos, even at the threshold inhibition of acetylcholinesterase. The adult male rats were divided into four groups ( n = 8/group), including the control and exposed groups that were orally received ethoprophos at the low (0.56 mg/kg), median (1.12 mg/kg), and high doses (2.24 mg/kg) for 90 days. Sub-chronic exposure to ethoprophos exhibited a significant decline in the brain activity and mRNA gene expression of acetylcholinesterase, while the levels of dopamine and serotonin were markedly increased at the medium and high doses ( p < 0.01). Ethoprophos increased the anxiety-like behavior in rats subjected to the open field quiz and induced many histopathological alterations in the brain. Furthermore, ethoprophos markedly ( p < 0.05) increased malondialdehyde and nitric oxide levels, while the glutathione content, together with the activities of glutathione peroxidase, glutathione-S-transferase, superoxide dismutase, and catalase were decreased in a dose-dependent manner. Additionally, there was a dose-dependent up-regulation in the mRNA gene expression of brain glial fibrillary acidic protein and tubulin-associated unit in the ethoprophos-exposed rats ( p < 0.05). The obtained data deliver the initial demonstration about the involvement of this up-regulation in the neurotoxicity mechanism of ethoprophos and may use as a biomarker for organophosphate-induced neurodegeneration. • Ethoprophos is a commonly used organophosphate nematicide. • Sub-chronic exposure to ethoprophos elicited oxidative injury in the rat's brain. • Ethoprophos declined the brain activity and mRNA gene expression of AChE. • Ethoprophos increased the catecholamine levels and induced neurobehavioral disorder. • Ethoprophos up-regulated GFAP and TAU mRNA levels at the AChE threshold inhibition.