Open Arms Of Elevated Plus-maze Research Articles

Anti-anxiety activity of Eucalyptus tereticornis n-hexane extract in Wistar albino rats

Background: To find out a new agent with a high therapeutic index for the treatment of anxiety, an indigenous medicinal plant Eucalyptus terteticornis was screened for its effect on anxiety in experimental animal model.Methods: Thirty six adult Wistar albino rats of both sexes weighing 175-200g were divided into three groups: Group I: DMSO 10% (0.1ml/200g), Group II: hexane extract of leaves of Eucalyptus terteticornis (ETHE) (100mg/kg/body weight), Group III: Diazepam (1mg/kg orally). All test compounds were administered orally for ten days. On tenth day, after one hour of test compounds administration, Wistar rats were taken for elevated plus maze (EPM) and light dark arena (LDA) tests. Statistical comparisons among the groups were performed by One-way analysis of variance (ANOVA) followed by Tukey Krammer test.Results: The results showed that ETHE treated animals (Group II) significantly (p <0.001) increased the time spent in open arms of EPM and in bright arena of LDA on comparing with normal (Group I).Conclusions: The anti-anxiety activity of Eucalyptus terteticornis can be due to its effect on brain neurotransmitters or due to antioxidant property.

Activation of type 4 dopaminergic receptors in the prelimbic area of medial prefrontal cortex is necessary for the expression of innate fear behavior

The prelimbic area (PL) of the medial Prefrontal cortex (mPFC) is involved in the acquisition and expression of conditioned and innate fear. Both types of fear share several neuronal pathways. It has been documented that dopamine (DA) plays an important role in the regulation of aversive memories in the mPFC. The exposure to an aversive stimulus, such as the smell of a predator odor or the exposure to footshock stress is accompanied by an increase in mPFC DA release. Evidence suggests that the type 4 dopaminergic receptor (D4R) is the molecular target through which DA modulates fear expression. In fact, the mPFC is the brain region with the highest expression of D4R; however, the role of D4R in the expression of innate fear has not been fully elucidated. Therefore, the principal objective of this work was to evaluate the participation of mPFC D4R in the expression of innate fear. Rats were exposed to the elevated plus-maze (EPM) and to the cat odor paradigm after the intra PL injection of L-745,870, selective D4R antagonist, to measure the expression of fear-related behaviors. Intra PL injection of L-745,870 increased the time spent in the EPM open arms and decreased freezing behavior in the cat odor paradigm. Our results also showed that D4R is expressed in GABAergic and pyramidal neurons in the PL region of PFC. Thus, D4R antagonism in the PL decreases the expression of innate fear-behavior indicating that the activation of D4R in the PL is necessary for the expression of innate fear-behavior.

Effects of Dimethoate Exposure on Locomotor Activity and Anxiety-Like Behavior in Female Wistar Rat

Developmental exposure to organophosphate insecticide is well known to induce neurobehavioral impairments, at late period. The present study aims to investigate the effects of subchronic exposure to Dimethoate, on locomotors skills and anxiety like behavior among wistar rat. Two groups of female’s rats are used. The intoxicated group receives daily, during five weeks, by intragastric gavage, a dose of Dimethoate dissolved in corn oil (100 mg/kg body weight). The control group receives only the corn oil. Spontaneous locomotors activity is evaluated using the Open Field test (OF) and anxiety-like behavior is measured using Elevated Plus-Maze (EPM). Dimethoate induced significant impairment of spontaneous locomotors activities, which is reflected by high decrease of number of squares crossed (SC) in OF. Females exposed to Dimethoate develop further anxiety-like response, expressed by significant reductions of the time spent in open arm of Elevated Plus-Maze.

Effects of Mimosa pudica L. leaves extract on anxiety, depression and memory.

The present study was carried out to investigate the neuropharmacological activities of ethyl acetate extract of Mimosa pudica (EAMP) leaves on anxiety, depression and memory in a mouse model. Anti-anxiety potential of EAMP was evaluated by elevated plus maze (EPM), light-dark box (LDB) and social interaction (SI) tests in mice.Anti-depressant potential of EAMP was evaluated by forced swimming (FST), tail suspension (TST), and open field tests (OFT). The behavioral findings were further corroborated with estimation of neurotransmitters and their metabolites from mouse brain homogenate. Effect on learning and memory was evaluated by EPM, passive avoidance (PA) tests. Further, it was confirmed with assessment of acetylcholinesterase and caspase-3 activity in brain homogenate. EAMP showed significant anti-anxiety activity by increasing the time spent in open arm of EPM, light box of LDB. Social interaction time was increased significantly (p<0.01) as compared to vehicle control. There was also significant reduction of immobility time in both FST and TST without any changes in locomotor activity in the OFT. Monoamine neurotransmitters (dopamine and norepinephrine) concentrations were increased significantly (p<0.01) after 4 weeks of treatment as compared to stress control and substantiated the anti-depressant activity. Step down latency was increased (p<0.01) in PA test and transfer latency was decreased (p<0.01) in EPM test of EAMP-treated mice. Acetylcholinesterase and caspase-3 activity was significantly (p<0.05) changed in mice treated with EAMP (200 and 400 mg/kg). The results revealed that EAMP has anti-anxiety, anti-depressant and memory enhancing activities that are mediated through multiple mechanisms.

Neuropharmacological evaluation of a novel 5-HT3 receptor antagonist (4-benzylpiperazin-1-yl)(3-methoxyquinoxalin-2-yl) methanone (6g) on lipopolysaccharide-induced anxiety models in mice.

5-HT3 receptor antagonists play a key role in the management of psychiatric disorders such as, depression and anxiety. They may act through modulation of serotonergic transmission. In the present study, a novel and potential 5-HT3 receptor antagonist, 6g (4-benzylpiperazin-1-yl)(3-methoxyquinoxalin-2-yl) methanone, which exhibited good log P (3.08) and pA2 (7.5) values was screened for its anxiolytic property in lipopolysaccharide (LPS) induced anxiety models. LPS, an endotoxin, present in the cell wall of Gram negative bacteria was injected 0.83 mg/kg, i.p. as a single dose to induce anxiety-like symptoms in mice. Compound 6g (1 and 2 mg/kg, p.o.) and standard fluoxetine (FLX) (20 mg/kg, p.o.) were injected to treatment groups for 7 days and evaluated in various behavioral paradigms such as elevated plus maze (EPM), light and dark (L/D) test, and open field test (OFT). Their effects on serotonin levels in mice brain were also examined. The results showed that LPS induced anxiety-like symptoms in mice, as indicated by a significantly decreased percentage open arm entries and percentage time spent in open arms in EPM; decreased time spent in light area and number of transition between chambers in L/D test; decreased ambulation and rearing scores in OFT. Compound 6g (1 and 2 mg/kg, p.o., 7 days) and FLX treatment (20 mg/kg, p.o., 7 days) reversed the LPS-induced behavioral changes and significantly affected all the behavioral parameters mentioned above. In addition 6g (1 and 2 mg/kg, p.o., 7 days) and FLX treatment (20 mg/kg, p.o., 7 days) increased the levels of serotonin in mice brain. Compound 6g produced anxiolytic-like effects in various anxiety paradigms in LPS-treated mice as well as restored the decreased serotonin levels in mice brain.

Elevated plus maze as an animal model of state anxiety in Kunming mice:test-retest reliability

Objective To explore the test-retest reliability of elevated plus maze (EPM) which is taken as an animal model of state anxiety in Kunming mice. Methods The behavior of adult, male and female, Kunming mice in EPM was recorded twice with one-week inter-trial interval for lasting five minutes.The following parameters were evaluated: percentage of time on EPM open arms (Otime%), percentage of time on EPM closed arms (Ctime%), time on EPM open arms (Otime), time on EPM closed arms (Ctime), percentage of entries into EPM open arms (Oentries%), entries into EPM open arms (Oentries), entries into EPM closed arms (Centries), total entries into EPM open and closed arms (Entries). Subsequently, the intraclass correlation coefficient (ICC) and the kappa agreement index (κ) were calculated for these parameters. Results ICC for Otime% (♂ ICC=0.506, P<0.05; ♀ ICC=0.456, P<0.05; ♂+ ♀ ICC=0.492, P<0.01), Oentries (♂ ICC=0.673, P<0.01; ♀ ICC=0.648, P<0.01; ♂+ ♀ ICC=0.665, P<0.01), Centries (♂ ICC=0.704, P<0.01; ♀ ICC=0.661, P<0.01; ♂+ ♀ ICC=0.686, P<0.01), Entries (♂ ICC=0.701, P<0.01; ♀ ICC=0.661, P<0.01; ♂+ ♀ ICC=0.685, P<0.01) showed a fair test-retest reliability, respectively. Only κ for Entries (♂ κ=0.253, P<0.05; ♀ κ=0.339, P<0.05; ♂+ ♀ κ=0.298, P<0.01) displayed a significant but poor reliability between the test-retest trials. Conclusion The Otime% Entries parameters as an acceptable index for Kunming mice in EPM can be used for exploratory and locomotion activity. Sex and repeated measurement have different effects on the Otime% and Entries parameters, especially the more on the former. Therefore, Otime% and Entries can be considered when EPM as an animal model of state anxiety in Kunming mice; meanwhile, more attention should be paid to both the sex (male animals recommended to EPM, especially) and repeated measurement effects. Key words: Elevated plus maze; State anxiety; Animal model; Test-retest reliability; Sex; Repeated measurement; Kunming mice

Preclinical Pharmacokinetic and Pharmacodynamic Studies of Pharmaceutical Compositions of the Dipeptide Anxiolytic GB-115

Four pharmaceutical compositions for oral use that contained the dipeptide anxiolytic GB-115 as the active ingredient underwent preclinical trials in male laboratory white rats. Various excipients added to the compositions and their preparation technologies had significant effects on the dipeptide pharmacokinetics. It was shown that compositions 2 and 4 had advantages according to the main pharmacokinetic characteristics reflecting the bioavailability of GB-115. The pharmacological activities of GB-115 compositions 1 – 4 at oral doses of 0.3 – 0.9 mg/kg were studied in an elevated plus-maze (EPM) test. It was established that composition 4, which included micronized substance and a hydrophilic matrix with controlled release of the active ingredient (hydroxypropylmethylcellulose), possessed the highest anxiolytic activity and increased the residence time in the EPM open arms at doses of 0.3 mg/kg (p < 0.01) and 0.9 mg/kg (p < 0.01) as compared with the placebo group. Pharmaceutical composition 4 could be recommended for creating a controlled-release solid dosage form based on the comprehensive studies.

Swimming exercise attenuates psychological dependence and voluntary methamphetamine consumption in methamphetamine withdrawn rats.

This study evaluated the effect of swimming exercise during spontaneous methamphetamine (METH) withdrawal on the anxiety, depression, obsessive-compulsive disorder (OCD) and voluntary METH consumption in METH-dependent rats. Male Wistar rats were repeatedly administered with bi-daily doses of METH (2 mg/kg, subcutaneous) over a period of 14 days. Exercised rats were submitted to swimming sessions (45 min/day, five days per week, for 14 days) during spontaneous METH-withdrawal. Then, all animals were tested for the assessment of anxiety by using the elevated plus-maze (EPM), the grooming behaviors (OCD), and depression using forced swimming test (FST) and voluntary METH consumption using a two-bottle choice (TBC) paradigm for the assessment of craving. The results showed that the swimmer METH-withdrawn rats exhibited an increase in EPM open arm time and entries and a reduction of immobility and grooming behaviors compared with the sedentary METH groups. Also, voluntary METH consumption was less in the swimmer METH-withdrawn rats than the sedentary METH groups throughout 5-8 days. This study showed that regular swimming exercise reduced voluntary METH consumption in animal models of craving by reducing anxiety, OCD, and depression in the METH-withdrawn rats. Thus, physical training may be ameliorating some of the withdrawal behavioral consequences of METH.

Evaluation of antioxidant effect of Nerium indicum in anxious rats.

Aim:The aim of this study was to analyze the ethyl acetate extract of Nerium indicum (NIE) flower for its antioxidant effect in anxious Sprague–Dawley rats.Materials and Methods:Animals were divided into six groups (n = 6) and treated with 200 mg/kg and 400 mg/kg p.o. of NIE for 21 days to assess its preventive and curative effects. Anxiety was induced by isolating animals socially for 21 days. Elevated plus maze (EPM) and light and dark model were used for measuring anxiety in animals. Oxidative stress parameters such as lipid peroxidation (LPO), superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH) in blood and brain tissue homogenate were monitored after 21 days of social isolation in animals.Results:Rats were treated with NIE 200 mg/kg and 400 mg/kg p.o. Both the treatments showed a significant (P < 0.001) increase in the number of open arm entries and time spent in open arm in EPM when compared with the negative control. Results also demonstrated that there was a significant (P < 0.001) increase in the number of lightbox entries and time spent in light box in light and dark model when compared with negative control. There was a significant (P < 0.001) improvement in endogenous anti-oxidants such as SOD, CAT, reduced GSH, and decreased levels of LPO in blood and brain tissue when compared with the negative control.Conclusion:The present study suggests the role of NIE in the treatment of anxiety, possibly by modulating the oxidative stress.

Sedative and Anxiolytic-Like Actions of Ethanol Extract of Leaves of Glinus oppositifolius (Linn.) Aug. DC.

Glinus oppositifolius is a small herb, widely used in the traditional medicine of Bangladesh in treatment of a variety of diseases and disorders such as insomnia, pain, inflammation, jaundice, and fever. The present study evaluated the sedative and anxiolytic potentials of the ethanol extract of leaves of G. oppositifolius (EEGO) in different behavioral models in mice. The sedative activity of EEGO was investigated using hole cross, open field, rotarod, and thiopental sodium- (TS-) induced sleeping time determination tests, where the elevated plus maze (EPM) and light-dark box (LDB) exploration tests were employed to justify the anxiolytic potentials in mice at the doses of 50, 100, and 200 mg/kg. The results demonstrated that EEGO significantly inhibited the exploratory behavior of the animals both in hole cross and in open field tests in a dose-dependent manner. It also decreased motor coordination and modified TS-mediated hypnosis in mice. In addition, EEGO showed anxiolytic potential by increasing the number and time of entries in the open arm of EPM, which is further strengthened by increase in total time spent in the light part of LDB. Therefore, this study suggests the sedative and anxiolytic properties of the leaves of G. oppositifolius and supports the traditional use of this plant in treatment of different psychiatric disorders including insomnia.

Behavioral characterization of CD36 knockout mice with SHIRPA primary screen

CD36 is a member of the class B scavenger receptor family of cell surface proteins, which plays a major role in fatty acid, glucose and lipid metabolism. Besides, CD36 functions as a microglial surface receptor for amyloid beta peptide. Regarding this, we suggest CD36 might also contribute to neuropsychiatric disease. The aim of this study was to achieve a behavioral phenotype of CD36 knockout (CD36−/−) mice. We characterized the behavior of CD36−/− mice and C57BL/6J mice by subjecting them to a series of tests, which include SHIRPA primary behavioral screen test, 1% sucrose preference test, elevated plus-maze test, open-field test and forced swimming test. The results showed that CD36−/− mice traversed more squares, emitted more defecation, exhibited higher tail elevation and had more aggressive behaviors than C57BL/6J mice. The CD36−/− mice spent more time and traveled longer distance in periphery zone in the open-field test. Meanwhile, the numbers that CD36−/− mice entered in the open arms of elevated plus-maze were reduced. These findings suggest that CD36−/− mice present an anxious phenotype and might be involved in neuropsychiatric disorders.

Neonatal tactile stimulation decreases depression-like and anxiety-like behaviors and potentiates sertraline action in young rats

It is well known that events which occur in early life exert a significant influence on brain development, what can be reflected throughout adulthood. This study was carried out in order to assess the influence of neonatal tactile stimulation (TS) on behavioral and morphological responses related to depression-like and anxiety-like behaviors, assessed following the administration of sertraline (SERT), a selective serotonin re-uptake inhibitor (SSRI). Male pups were submitted to daily TS, from postnatal day 8 (PND8) to postnatal day 14 (PND14), for 10min every day. On PND50, adult animals were submitted to forced swimming training (15min). On PND51, half of each experimental group (UH and TS) received a single sub-therapeutic dose of sertraline (SER, 0.3mg/kg body weight, i.p.) or its vehicle (C, control group). Thirty minutes after injection, depression-like behaviors were quantified in forced swimming test (FST, for 5min). On the following day, anxiety-like behaviors were assessed in elevated plus maze (EPM), followed by biochemical assessments. TS per se increased swimming time, decreasing immobility time in FST. Besides, TS per se was able to increase frequency of head dipping and time spent in the open arms of EPM, resulting in decreased anxiety index. In addition, groups exposed to TS showed decreased plasma levels of corticosterone per se. Interestingly, while TS exposure significantly potentiated the antidepressant activity of a subtherapeutic dose of SERT, this drug was able to exacerbate TS-induced anxiolytic activity, as observed in FST and EPM, respectively. Decreased plasma levels of both corticosterone and cortisol in animals exposed to TS and treated with SERT are able to confirm the interesting interaction between this neonatal handling and the antidepressant drug. From our results, we conclude that neonatal TS is able to exert beneficial influence on the ability to cope with stressful situations in adulthood, preventing depression and favorably modulating the action of antidepressant drugs.

Ameliorating effects of gypenosides on chronic stress-induced anxiety disorders in mice

BackgroundEthanol extract from Gynostemma pentaphyllum (GP) shows anti-stress and anxiolytic functions in mice, and also protects dopamine neurons in 6-hydroxydopamine-lesioned rat model of Parkinson’s disease. In addition, gypenosides (the gypenoside-enriched components of GP, GPS) have a protective effect on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson’s disease. In this study, the ameliorating effects of GPS on chronic stress-induced anxiety disorders in mice were investigated.MethodsMice were orally treated with GPS (100 and 200 mg/kg) once a day for 10 days, followed by exposure to electric footshock (EF) stress (0.6 mA, 1 s every 5 s, 3 min). After the final administration of either GPS, water extract of GP (GP-WX) or ethanol extract of GP (GP-EX, positive control), the behavioral tests such as elevated plus-maze, marble burying and locomotor activity tests, and the biochemical parameters including dopamine, serotonin and corticosterone levels, and c-Fos expression were examined.ResultsTreatment with GPS (100 and 200 mg/kg) increased the number of open arm entries and the time spent on open arms in elevated plus-maze which were reduced by chronic EF stress. GPS (100 and 200 mg/kg) reduced the number of marbles buried which increased by chronic EF stress. In these states, the brain levels of dopamine and serotonin decreased by chronic EF stress and they were recovered by GPS. The serum levels of corticosterone increased by chronic EF stress were also reduced by GPS (100 and 200 mg/kg). Finally, chronic EF stress-induced c-Fos expression was markedly reduced by GPS (100 and 200 mg/kg) in the brain. GPS (100 and 200 mg/kg) also showed an equivalent efficacy on anxiolytic functions, as compared with GP-EX (50 mg/kg). However, GP-WX (50 mg/kg) showed a less effect on anxiety disorders than GP-EX (50 mg/kg) and GPS (100 and 200 mg/kg).ConclusionThese results suggest that GPS (100 and 200 mg/kg) has anxiolytic effects on chronic EF stress-induced anxiety disorders by modulating dopamine and serotonin neuronal activities, c-Fos expression and corticosterone levels. GPS may serve as a phytonutrient in chronic stress-induced anxiety disorders.

Effects of environmental enrichment on behavioral deficits and alterations in hippocampal BDNF induced by prenatal exposure to morphine in juvenile rats

Prenatal morphine exposure throughout pregnancy can induce a series of neurobehavioral and neurochemical disturbances by affecting central nervous system development. This study was designed to investigate the effects of an enriched environment on behavioral deficits and changes in hippocampal brain-derived neurotrophic factor (BDNF) levels induced by prenatal morphine in rats. On pregnancy days 11–18, female Wistar rats were randomly injected twice daily with saline or morphine. Offspring were weaned on postnatal day (PND) 21. They were subjected to a standard rearing environment or an enriched environment on PNDs 22–50. On PNDs 51–57, the behavioral responses including anxiety and depression-like behaviors, and passive avoidance memory as well as hippocampal BDNF levels were investigated. The light/dark (L/D) box and elevated plus maze (EPM) were used for the study of anxiety, forced swimming test (FST) was used to assess depression-like behavior and passive avoidance task was used to evaluate learning and memory. Prenatal morphine exposure caused a reduction in time spent in the EPM open arms and a reduction in time spent in the lit side of the L/D box. It also decreased step-through latency and increased time spent in the dark side of passive avoidance task. Prenatal morphine exposure also reduced immobility time and increased swimming time in FST. Postnatal rearing in an enriched environment counteracted with behavioral deficits in the EPM and passive avoidance task, but not in the L/D box. This suggests that exposure to an enriched environment during adolescence period alters anxiety profile in a task-specific manner. Prenatal morphine exposure reduced hippocampal BDNF levels, but enriched environment significantly increased BDNF levels in both saline- and morphine-exposed groups. Our results demonstrate that exposure to an enriched environment alleviates behavioral deficits induced by prenatal morphine exposure and up-regulates the decreased levels of BDNF. BDNF may contribute to the beneficial effects of an enriched environment on prenatal morphine-exposed to rats.

Chronic nicotine administration does not alter cognitive or mood associated behavioural parameters

Nicotine, the major specific alkaloid in tobacco smoke, exhibits widespread pharmacological effects and may contribute to deterioration in behaviour. The present study thus examined the effects of its chronic administration on some cognitive and mood associated behaviours. Adult rats weighing between 150 and 200g were randomly divided into 4 groups each of 5 females and 5 males. Three groups were administered graded doses of nicotine at 0.25, 2 and 4mg/kg body weight via subcutaneous injections. One group served as control and received normal saline (vehicle for nicotine). Behavioural tests were performed using the Y-maze, elevated-plus maze (EPM) and tail suspension tests (TST) at various time points. Nicotine produced no significant effect in spontaneous alternation on Y-maze, nor on six parameters scored on EPM (open arm entries, time spent in open arms, time per open arm entries, open/closed arm quotient, closed arm entries, and total arm entries), and also no significant effect on immobility time in TST. This lack of effects was observed to be independent of sex and dose administered. The study shows that nicotine does not produce long-term changes in some cognitive and mood associated behaviours, thus suggesting it could be well tolerated even following chronic administration.

Anticonvulsant and anxiolyic activities of ethyl acetate fraction of Cassia fistula Linn. pods in mice

Context: Cassia fistula L. (Leguminacea) is used by Indian and Tanzanian traditional healers for treating various ailments related to the central nervous system. Aims: The present study aimed to evaluate the anticonvulsant and anxiolytic activity of the ethyl acetate fraction obtained from a hydroalcoholic extraction of Cassia fistula pods (EAFCF) and thereby to provide scientific validation for its traditional use. Methods: Preliminary phytochemical analysis and estimation of the flavonoid content of the ethyl acetate fraction was performed. Anticonvulsant activity was assessed by the subcutaneous pentylenetetrazole test (s.c. PTZ test). Anxiolytic activity was assessed by elevated plus maze (EPM) and open field tests (OFT). The sedative and motor toxicity was evaluated by a phenobarbitone induced sleep test and rotarod behavior respectively. Results: Photochemical analysis revealed the presence of a high flavanoid content in the ethyl acetate fraction. Treatment of EAFCF (50 and 100 mg/kg) significantly increased the latency to the onset of minimal clonic seizure and generalized tonic clonic seizure and animals were completely protected from death due to PTZ administration. Administration of EAFCF at the dose of 100 mg/kg markedly increased the open arm entries and time spent in open arm in EPM. In OFT, EAFCF increased the number of central squares crossed and time spent in the central compartment. EAFCF in the doses used in this experiment did not produce sedation or motor toxicity. Conclusion: The results obtained herein clearly indicate the anticonvulsant and anxiolytic activity of EAFCF which may be due to the high flavonoid content. These findings give the scientific support for common use of this plant for treating epilepsy and anxiety.

Paternal line multigenerational passage of altered risk assessment behavior in female but not male rat offspring of mothers fed a low protein diet

Maternal low protein (MLP) diets in pregnancy and lactation impair offspring brain development and modify offspring behavior. We hypothesized multigenerational passage of altered behavioral outcomes as has been demonstrated following other developmental programming challenges. We investigated potential multigenerational effects of MLP in rat pregnancy and/or lactation on offspring risk assessment behavior. Founder generation mothers (F0) ate 20% casein (C) or restricted (R) 10% casein diet, providing four groups: CC, RR, CR, and RC (first letter pregnancy, second letter lactation diet) to evaluate offspring (F1) effects influenced by MLP in F0. On postnatal day (PND 250), F1 males were mated to non-colony siblings producing F2. On PND 90, F2 females (in diestrous) and F2 males were tested in the elevated plus maze (EPM) and open field. Corticosterone was measured at PND 110. Female but not male CR and RC F2 made more entries and spent more time in EPM open arms than CC females. Overall activity was unchanged as observed in male F1 fathers. There were no open field differences in F2 of either sex, indicating that multigenerational MLP effects are due to altered risk assessment, not locomotion. MLP in pregnancy reduced F1 male and F2 female corticosterone. We conclude that MLP in pregnancy and/or lactation increases the innate tendency to explore novel environments in F2 females via the paternal linage, suggesting lower levels of caution and/or higher impulsiveness to explore unknown spaces. Further studies will be necessary to identify the epigenetic modifications in the germ line through the paternal linage.

Anxiolytic-Like Effect of Underground Parts of Ajuga remota Benth (Lamiaceae) and Its Bioactive Constituents in Mice: A Behavioral Study

Several undesirable side effects as well as tolerance and physical dependence associated with use of benzodiazepine (BZD) derivatives for the management of anxiety are important challenges which motivate the search for safer and better tolerated anxiolytic compounds devoid of dependence. This study isolated the potential active constituents from methanol underground parts of Ajuga remota (Lamiaceae) with anxiolytic-like effects. In vivo anxiolytic activity in mice of the samples and diazepam (positive control) was assessed using the hole board and elevated plus maze (EPM) experiments. Chromatographic procedures led to the isolation of harpagide (1), 8-O-acetylharpagide (2), 2ʹ,3ʹ- diacetylharpagide (3), 6,8-acetylharpagide-O-2ʹ,3ʹ-diacetylglycoside (4), 6-rhamnosylharpagide (5), 6-galloyl-7,8- dehydroharpagide (6), cyasterone (7) and ergosterone-5,8-endoperoxide (8) from the methanol extracts. Oral administration of cyasterone (7) and ergosterone-5,8-endoperoxide (8) (5 mg/kg) increased the duration of open arm exploration and number of head-dips in EPM and hole-board tests, respectively (P≤0.05) compared to negative control. However, compound 1, 2, 3, and 4 elicited negative responses in open arm in EPM. Compounds 7 and 8 (25 and 50 mg/kg) showed dose dependent (P≤0.01) rise in number and duration of head-dips comparable to the anxiolytic effect of diazepam which suggests their potential use for management of anxiety disorder. Keywords: Ajuga remota, anxiety anxiolytic activity, lamiaceae, sedative.

Swimming reduces the severity of physical and psychological dependence and voluntary morphine consumption in morphine dependent rats

Previous studies have indicated that voluntary exercise decreases the severity of the anxiogenic-like behaviors in both morphine-dependent and withdrawn rats. This study examined the effects of regular swimming exercise during the development of dependency and spontaneous morphine withdrawal on the anxiety-depression profile and voluntary morphine consumption in morphine dependent rats. The rats were chronically treated with bi-daily doses (10mg/kg, at 12h intervals) of morphine over a period of 14 days. The exercising rats were allowed to swim (45min/d, five days per a week, for 14 or 21 days) during the development of morphine dependence and withdrawal. Then, rats were tested for the severity of morphine dependence, the elevated plus-maze (EPM), sucrose preference test (SPT) and voluntary morphine consumption using a two-bottle choice paradigm in animal models of craving. The results showed that withdrawal signs were decreased in swimmer morphine dependent rats than sedentary rats (P<0.05). Also, the swimmer morphine-dependent and withdrawn rats exhibited an increase in EPM open arm time and entries (P<0.05), higher levels of sucrose preference (P<0.001) than sedentary rats. Voluntary consumption of oral morphine was less in the swimmer morphine-withdrawn rats than the sedentary groups during four periods of the intake of drug (P<0.01). We conclude that regular swimming exercise reduces the severity of morphine dependence and voluntary morphine consumption with reducing anxiety and depression in morphine-dependent and withdrawn rats. Thus, swimming exercise may be a potential method to ameliorate some of the deleterious behavioral consequences of morphine dependence.

Anxiogenic-like effects induced by hemopressin in rats

Hemopressin (PVNFKFLSH; HP) is an orally active peptide derived from rat hemoglobin α-chain that could act as an inverse agonist at cannabinoid type 1 receptors (CB1). Here, we aim to investigate possible behavioral effects of HP in male Wistar rats tested in the elevated plus maze (EPM), following HP intraperitoneal (i.p., 0.05mg/kg), oral (P.O., 0.05 and 0.5mg/kg) or intracerebroventricular (I.C.V., 3 and 10nmol) administration. HP induced a decrease in EPM open arm exploration, indicating an anxiogenic-like effect. However, i.p. administration of HP (1mg/kg) followed by mass spectrometry analysis of brain-peptide extracts suggested that the intact HP does not cross the blood brain barrier. I.C.V. administrated HP produced anxiogenic-like effects that were prevented by Transient Receptor Potential Vanilloid Type 1 (TRPV1) antagonists, 6-iodonordihydrocapsaicin (1nmol) or SB366791 (1nmol), but not by the CB1 receptor antagonist AM251 (0.1 and 1nmol). Altogether, these data suggest that I.C.V. administrated HP induces anxiogenic-like effects by activating TRPV1 receptors. The similar anxiogenic effects observed after i.p. or P.O. administration could be due to HP fragment(s) crossing the blood brain barrier. The present results advance our knowledge about HP pharmacology and suggest concerns in future clinical studies.