Anxiety In Elevated Plus-maze Research Articles

Promiscuous or Dirty drug with Multifunctional Druggability nature of Curcumin (Curcuma longa Linn.); Repurposing in propranolol withdrawal-induced OCD related Anxiety: A promising drug discovery besides One-Drug-One-Receptor approach via in silico in vivo studies

Background: Curcumin (Curcuma longa) and propranolol display a plethora of pharmacological activity linked with multifunctional druggable nature designated as a promiscuous or dirty drug (magic shotguns) that hit 'on-target as well as 'off-target' (anti-target). Multifactorial origins, with complex neuronal networks and broad-spectrum symptomatology, operates most CNS disorders. Anxiety is one of the comorbidities in the psychogenic spectrum of obsessive-compulsive disorder (OCD). The present study of OCD has been based on its multifunctionality and diverse drug potential, tailoring together the morbidity and comorbidity patterns of OCD. Very few multimodal drugs did trial in this regard, which has multifunctional druggability, except selective serotonin reuptake inhibitors (SSRIs) that work via the one-drug-one-receptor-one-disease approach; however, with inter-individual variability, unwanted side effects and limited multifunctionality with the druggable targets. SSRI success rates in OCD and its related disorder are minimal, especially in the adversity of comorbidity pattern. Objective: The principal objective of the current research was to testify the multifunctional druggable plethora of curcumin via repurposing of its dirty drug nature to reverse the obsessed anxiety of propranolol withdrawal-induce mice, besides the "one drug one receptor" approach or magic bullet. Methods: The present study evaluated OCD related anxiety-like behavior after different periods of abstinence (24 h, 7 and 21 days) from repeated propranolol (10 mg/kg) administration in mice. In addition, we also examined the action of curcumin (EERCL-50 mg/kg) and fluoxetine (20 mg/kg) for the attenuation or reversal of OCD related anxiety-like behavior after seven days to 24 hours propranolol withdrawal. The initial stage of the hypothesis toward the target of curcumin was identified via in-silico using SwissADME drug-likeness study, followed by in-vivo studies using Swiss albino mice. Evaluation for the same did use elevated plus maze (EPM), marble-burying behaviour (MBB) and motor activity (MA) test as a model. Further, did also investigate the antioxidant activity. Result: The result revealed a decrease in all parameters 24 hours and 14 days after exposure to propranolol, indicating anxious behaviour. The administration of curcumin and fluoxetine after 24 hrs of abstinence reduced animal anxiety in EPM; after the abstinence periods, the drug reduced the MA in the MBB. Curcumin reversed the anxiogenic effect induced by propranolol in EPM. The value of p<0.05 was considered statistically significant. Conclusion: Results revealed that propranolol might, to a large extent, impart to withdrawal-induced obsessed anxiety, and curcumin could effectively treat propranolol dependent obsessed mice. Further, curcumin anti-compulsive competency substantially showed promising success besides one drug-one receptor-one disease approach or magic bullet.

Lateral Hypothalamus Corticotropin-releasing Hormone Receptor-1 Inhibition and Modulating Stress-induced Anxiety Behavior.

Stress is a reaction to unwanted events disturbing body homeostasis and its pathways and target areas. Stress affects the brain through the lateral hypothalamic area (LHA), the orexinergic system that mediates the effect of corticotropin-releasing hormone (CRH) through CRH Receptor Type 1 (CRHr1). Therefore, this study explores the outcome of stress exposure on anxiety development and the involvement of the LHA through LHA-CRHr1. Male Wistar rats (220-250 g) implanted with a cannula on either side of the LHA received acute or chronic stress. Subsequently, exploratory behavior was examined using the Open Field (OF), and anxiety was tested by Elevated Plus Maze (EPM). Before sacrifice, the cerebrospinal fluid (CSF) and the blood were sampled. Nissl stain was performed on fixed brain tissues. Acute stress reduced exploration in of and increased anxiety in EPM. LHA-CRHr1 inhibition reversed the variables to increase the exploration and decrease anxiety. In contrast, chronic stress did not show any effect on anxiety-related behaviors. Chronic stress decreased the cell population in the LHA, which was prevented by the CRHr1 inhibition. However, the CRHr1 inhibition could not reverse the chronic stress-induced increase in the CSF orexin level. Furthermore, plasma corticosterone levels increased through acute or chronic stress, impeded by the inhibition of CRHr1. Our results recognize LHA-CRHr1 as a capable candidate that modulates acute stress-induced anxiety development and chronic stress-induced changes in the cellular population of the region. Acute stress, increased immobility of the rat in open field and elevated plus maze.Chronic stress, increased orexin production while decreasing neuronal survival.The anxiety and immobility were not developed in presence of CRHr1.CRHr1 blocking reversed the chronic stress changes in corticosterone and orexin. Lateral Hypothalamus (LH) is a region involved in sleep and appetite regulation and recently known to play role in stress pathophysiology. The stress mediating function of the LH is performed through Corticotropin Releasing Hormone Receptor type-1 (CRHr1). This study explored the role of LH- CRHr1 in anxiety development and orexin production. Acute and chronic stress affected the behavior and molecular changes, differently. The acute stress increased the anxiety condition, while the chronic stress could only change the molecular criteria. Although we assumed that the inability of the chronic stress to develop anxiety may be attributable to habituation, the chronic stress could increase the plasma corticosterone and orexin level. All of the stress mal-changes in behavior and molecular level prevented by antagonising CRHr1 in the LH, indicating a gating function of LH-CRHr1 for stress development.

Chronic Exposure to Morphine Leads to a Reduced Affective Pain Response in the Presence of Hyperalgesia in an Animal Model of Empathy.

BackgroundEmpathy is the capability to represent the mental and emotional states of other subjects. Previous studies have demonstrated a possible correlation between morphine addiction and altered empathy response in morphine-addicted subjects. This study was performed to evaluate the effect of chronic morphine exposure as an animal model of morphine addiction on empathic changes in affective and sensory pain.MethodsAdult male Wistar rats (3 months old) were used for the current study. Animals were grouped in cages of two (n = 8 for each group) and one animal was selected as the pain observer group. Pain observer animals received either saline or morphine (10 mg/kg, twice daily for 8 days). At ninth day, formalin [50 µg, 5%, subcutaneous (SC)] was injected into the hindpaw of the cagemate and placed inside the cage. Elevated plus maze (EPM) and open field test (OFT) were recruited to evaluate anxiety; hot plate and tail flick tests were used to assay sensory pain. Conditioned place aversion (CPA) was also measured as indicator of affective pain component.FindingsChronic morphine exposure led to a reduced level of anxiety in EPM and OFT assays. An opioid-induced hyperalgesia was observed in the sensory pain assays, while there was a reduced affective pain in the CPA paradigm in morphine-treated animals.ConclusionIt might be plausible that chronic morphine exposure might alter empathy for pain through affective and not sensory pain pathways.

Neonatal handling prevents anxiety-like symptoms in rats exposed to chronic mild stress: Behavioral and oxidative parameters

This study investigated the influence of neonatal handling on behavioral and biochemical consequences of chronic mild stress (CMS) in adulthood. Male rat pups were submitted to daily tactile stimulation (TS) or maternal separation (MS), from postnatal day 1 (PND1) to postnatal day 21 (PND21), for 10 min/day. In adulthood, half the number of animals were exposed to CMS for 3 weeks and submitted to behavioral testing, including sucrose preference (SP), elevated plus maze (EPM), and defensive burying tasks (DBTs), followed by biochemical assessments. CMS reduced SP, increased anxiety in EPM and DBT, and increased adrenal weight. In addition, CMS decreased plasma vitamin C (VIT C) levels and increased protein carbonyl (PC) levels, catalase (CAT) activity in hippocampus and cortex, and superoxide dismutase (SOD) levels in cortex. In contrast, both forms of neonatal handling were able to prevent reduction in SP, anxiety behavior in DBT, and CMS-induced adrenal weight increase. Furthermore, they were also able to prevent plasma VIT C reduction, hippocampal PC levels increase, CAT activity increase in hippocampus and cortex, and SOD levels increase in cortex following CMS. Only TS was able to prevent CMS-induced anxiety symptoms in EPM and PC levels in cortex. Taken together, these findings show the protective role of neonatal handling, especially TS, which may enhance ability to cope with stressful situations in adulthood.

Effects of Cistanche deserticola on behavior and signs of cataract and retinopathy in senescence-accelerated OXYS rats

Ethnopharmacological relevanceCistanche deserticola (СD) has been traditionally used in the Chinese medicine as a tonic, vasodilator and neuroprotective agent. Aim of the studyTo investigate the effect of CD on the age-related behavior decline and cataract and retinopathy development in senescent accelerated OXYS rats. Materials and methodsOXYS and Wistar (control) rats were supplemented with 15mg CD on kg of body weight during 2months from the age of 12 months. Behavioral responses of animals were assessed in the elevated plus-maze (EPM), open field (OF) and in a Morris water maze (MWM). Before and after CD treatment OXYS rats were examined by an ophthalmologist. Results14-month-old OXYS rats had demonstrated considerably reduced activities in OF, increased anxiety in EPM, and manifestly impaired learning abilities in the MWM as compared to Wistar rats. Supplementation of CD had no effect on motor and exploratory activity of Wistar and OXYS rats in the OF, but it reduced their anxiety in the EPM compared to age-matched controls. CD significantly improved visual ability of the rats, reducing the severity of the developed signs of retinopathy and cataract while having no impact on OXYS rats’ spatial memory in the MWM. CD-treated Wistar rats exhibited slower learning ability in the MWM task comparison to the control group. The effect of CD on the learning ability in OXYS and Wistar rats may be associated with differences in their redox homeostasis. ConclusionAll in all, the findings suggest that CD improves the age-related behavioral decline, which makes it an attractive candidate for treatment of various neurodegenerative disorders. Primarily it demonstrated its ability to slow development and to reduce to some extent severity of pathological manifestations of cataract and retinopathy in OXYS rats, which makes it an attractive candidate for treatment of age-related eye diseases too.

Rats that binge eat fat-rich food do not show somatic signs or anxiety associated with opiate-like withdrawal: Implications for nutrient-specific food addiction behaviors

Previous studies suggest that binge eating sugar leads to behavioral and neurochemical changes similar to those seen with drug addiction, including signs of opiate-like withdrawal. Studies are emerging that show multiple neurochemical and behavioral indices of addiction when animals overeat a fat-rich diet. The goal of the present study was to utilize liquid and solid diets high in sugar and fat content to determine whether opiate-like withdrawal is seen after binge consumption of these diets in Sprague–Dawley rats. Control groups were given ad libitum access to the sweet–fat food or standard chow. All rats were then given a battery of tests to measure signs of opiate-like withdrawal, which included somatic signs of distress, elevated plus-maze anxiety, and locomotor hypoactivity. Neither naloxone-precipitated (3mg/kg) nor deprivation-induced withdrawal was observed in rats that were maintained on a nutritionally complete pelleted sweet–fat diet or a sweet, high-fat diet supplemented with standard rodent chow. Naloxone-precipitated withdrawal was also not seen in rats fed a liquid sweet–fat food. Further, body weight reduction to 85%, which is known to potentiate the reinforcing effects of substances of abuse, did not affect naloxone-precipitated signs of opiate-like withdrawal. Thus, unlike previous findings reported regarding rats with binge access to a sucrose solution, rats that binge eat sweet–fat combinations do not show signs of opiate-like withdrawal under the conditions tested. These data support the idea that excessive consumption of different nutrients can induce behaviors associated with addiction in different ways, and that the behaviors that could characterize “food addiction” may be subtyped based on the nutritional composition of the food consumed.

Behavioral Effects Induced by Mitochondria-Targeted Antioxidant SkQ1 in Wistar and Senescence-Accelerated OXYS Rats

Mitochondrial dysfunction is involved in aging and in neurodegenerative diseases and, therefore, pharmacological agents that alleviate mitochondrial dysfunction are expected to have neuroprotective effects. Promising in this respect is mitochondrial-targeted antioxidant plastoquinonyl-decyl-triphenylphosphonium (SkQ1). We investigated the effects of SkQ1 (250 nmol SkQ1/kg x day with food) on behavior in the elevated plus-maze (EPM) and open field (OF) and on spatial memory in a Morris water maze (MWM) in middle-aged (12 mo) Wistar and senescence-accelerated OXYS rats. Given that changes in the behavior of OXYS rats may be associated with visual impairment, the condition of the retina and the lens was evaluated by ophthalmoscopy. 14-month-old as well as 3-month-old OXYS rats had considerably reduced activities in OF, increased anxiety in EPM, and manifested impaired learning abilities in the MWM in comparison with Wistar rats. SkQ1-treated rats of both strains displayed significantly higher locomotor and exploratory activity in the OF and less anxiety in the EPM compared to age-matched controls. SkQ1 significantly improved visual ability of the rats reducing the severity of the developed signs of retinopathy and cataract but had no impact on OXYS rat's spatial memory in the MWM. SkQ1-treated Wistar rats exhibited slower learning in the MWM task comparison to the control group. Thus, SkQ1 had beneficial effects on locomotor and exploratory functions of the rat brain. Nevertheless, SkQ1 did not alter learning performance in the MWM in OXYS rats and slightly reduced it in the Wistar strain, which may be associated with differences in redox homeostasis.

Role of Heparin-Binding Growth-Associated Molecule (HB-GAM) in Hippocampal LTP and Spatial Learning Revealed by Studies on Overexpressing and Knockout Mice

Heparin-binding growth-associated molecule (HB-GAM) is an extracellular matrix-associated protein with neurite outgrowth-promoting activity and which is suggested to be implicated in hippocampal synaptic plasticity. To study the functions of HB-GAM in adult brain we have produced HB-GAM overexpressing mice and compared phenotypic changes in the transgenic mice to those in the HB-GAM null mice. Both mutants were viable and displayed no gross morphological abnormalities. The basal synaptic transmission was normal in the area CA1 of hippocampal slices from the genetically modified mice. However, long-term potentiation (LTP) was attenuated in the mice overexpressing HB-GAM, whereas enhanced LTP was detected in the HB-GAM-deficient mice. Changes in LTP seen in vitro were paralleled by behavioral alterations in vivo. The animals overexpressing HB-GAM displayed faster learning in water maze and decreased anxiety in elevated plus-maze, while the HB-GAM knockouts demonstrated an opposite behavioral phenotype. These results show that HB-GAM suppresses LTP in hippocampus and plays a role in regulation of learning-related behavior.

Anxiety-induced antinociception in mice: effects of systemic and intra-amygdala administration of 8-OH-DPAT and midazolam.

Mice exhibit antinociception after a single experience in the elevated plus maze (EPM), an animal model of anxiety. This study investigated the mechanisms involved in this form of anxiety-induced antinociception. Nociception was evaluated by means of the writhing test in mice confined either to the open or enclosed arms of the EPM. The effects of systemic (naloxone, midazolam and 8-OH-DPAT) or intra-amygdala (8-OH-DPAT, NAN-190 and midazolam) drug infusions were investigated in mice previously treated i.p. with 0.6% acetic acid, an algic stimulus that induces abdominal contortions. The effects of these drugs on conventional measures of anxiety (% entries and % time in open arms) in a standard EPM test were also independently investigated. Open-arm confinement resulted in a high-magnitude antinociception (minimum 85%, maximum 450%) compared with enclosed arm confinement. The opiate antagonist naloxone (1 mg/kg and 10 mg/kg) neither blocked this open arm-induced antinociception (OAIA) nor modified indices of anxiety in EPM. Administration of midazolam (0.5-2 mg/kg, s.c.) increased OAIA and produced antinociception in enclosed confined animals, as well as attenuating anxiety in the EPM. The 5-HT(1A) receptor agonist 8-OH-DPAT (0.05-1 mg/kg, s.c.) had biphasic effects on OAIA, antagonising the response at the lowest dose and intensifying it at the highest dose. In addition, low doses of this agent reduced anxiety in the EPM. Although bilateral injections of 8-OH-DPAT (5.6 nmol/0.4 microl) or NAN-190 (5.6 nmol and 10 nmol/0.4 microl) into the amygdala did not alter OAIA, increased anxiety was observed in the EPM. In contrast, intra-amygdala administration of midazolam (10 nmol and 30 nmol/0.4 microl) blocked both OAIA and anxiety. These results with systemic and intracerebral drug infusion suggest that 5-HT(1A) receptors localised in the amygdala are not involved in the pain inhibitory processes that are "recruited" during aversive situations. However, activation of these receptors does phasically increase anxiety. Although the intrinsic antinociceptive properties of systemically administered midazolam confounded interpretation of its effects on OAIA, intra-amygdala injections of this compound suggest that benzodiazepine receptors in this brain region modulate both the antinociceptive and behavioural (anxiety) responses to the EPM.