Stress-induced Hyperthermia Test Research Articles

Anxiolytic and antipyretic effects of the aqueous extract of the leaves of Solanum aethiopicum (Solanaceae) in the white mouse Mus musculus Swiss (Muridae)

The anxiolytic and antipyretic effects of the aqueous extract of the leaves of Solanum aethiopicum (plant used in traditional medicine in Africa) were evaluated by oral administration of doses 17.5; 43.75; 87.5 and 175 mg/kg to mice of the Mus musculus Swiss strain. Four psychopharmacological tests were performed: the stress-induced hyperthermia test; the elevated plus maze test; the open arena test and the hole board test. A significant decrease in stress-induced hyperthermia was observed in mice receiving the 175 mg/kg dose (1°C) unlike those treated with distilled water (3°C). The 175 mg/kg dose of S. aethiopicum extract and diazepam significantly increase the number of entries and the percentage of time spent in the open arms of the maze. Diazepam and doses of S. aethiopicum significantly decrease the number of uprights and the number of head tilts. Solanum aethiopicum significantly increases the number of lines crossed and the time spent in the center of the open arena. On the hole board, there was a significant increase in the number of head tilts (11.2±1,64) in the mice that received the 175 mg/kg dose of S. aethiopicum and in the number of lines crossed in the mice treated with all doses of the extract. This shows that the extract of S. aethiopicum would contain compounds with antipyretic and anxiolytic properties.

Anxiolytic and antipyretic properties of the root aqueous extract of Bombax costatum Pellegr. et Vuillet. (Bombacaceae) in mice: Implication of behavioural and neurochemical approaches

Ethnopharmacological relevance: Bombax costatum Pellegr. et Vuillet. (Bombacaceaea) is a plant used in traditional medicine in Cameroon to treat memory impairment, anxiety, insomnia and agitation. Aim of the study: The aqueous extract of Bombax costatum is evaluated for its anxiolytic like effect in mice using experimental models. Materials and methods: The plant extract is administered orally to mice. They were tested one hour later in the stress-induced hyperthermia, hole board, and open field or elevated plus maze tests, respectively. Finally, the brain Gamma aminobutyric acid [GABA] content and GABA-T were quantified in Bombax costatum aqueous extract-treated mice at the end of elevated plus maze test. Results: Bombax costatum aqueous extract showed anxiolytic activity. In stress-induced hyperthermia test, the plant extract significantly antagonised the increase of temperature. There is a significant reduction in the stress-induced hyperthermia from 1.13 ± 0.06℃ in the negative control group treated with distilled water to 0.26 ± 0.02℃ in the group of mice administered 100 mg/kg aqueous extract. In addition, Bombax costatum showed antipyretic activity by reducing the body temperature. In the elevated plus maze test, the aqueous extract increased the number of entries into, percentage of entries into, and percentage of time in open arms. It also reduced the percentage of entries and time in closed arms. Conclusion: The obtained results suggested that Bombax costatum aqueous extracts possess anxiolytic-like and antipyretic activities in mice. This plant could be helpful in the treatment of anxiety and fever in traditional medicine in Cameroon.

Behavioral consequences of co-administration of MTEP and the COX-2 inhibitor NS398 in mice. Part 1

BackgroundThe immunologic modulation of glutamate (Glu) neurotransmission is a topic of great interest. Neuroinflammation is an intrinsic component of neurodegenerative diseases, as well as a factor responsible for cognitive and behavioral changes. Cyclooxygenase-2 (COX-2) expression in the brain was shown to be associated with inflammation. COX-2 is also widely expressed in the brain including neurons and glia and participates in fundamental brain functions, e.g. in synaptic plasticity or memory consolidation. Furthermore, COX-2/Glu interplay has been reported, while metabotropic glutamate receptors (mGluRs) are known to contribute to plastic changes and to behavior. The primary goal of this study was to explain the behavioral consequences of the modulation of the glutamatergic pathway via the interaction of the mGlu5 receptor and COX-2, utilizing a panel of behavioral tests. MethodsTo determine whether the glutamatergic pathway and COX-2 are involved in modulating the behavior of mice, C57B1/6 J and CD-1 male mice were injected daily with MTEP an mGluR5 antagonist, or a combination of MTEP and NS398 (COX-2 inhibitor) for 7 and 14 days. The following behavioral tests were used to screen for possible effects of the drug administration and interaction of the 2 compounds: the modified Barnes maze (MBM), stress-induced hyperthermia (SIH), Porsolt test (PT), tail suspension test (TST), modified rotarod (MR), and social interaction (SI) test. ResultsA time-dependent influence on spatial learning was found after the co-administration of MTEP and NS398. Furthermore, NS398 injected chronically amplified the antidepressant-like effects of MTEP in the PT and TST, and influenced the tolerance development observed after MTEP treatment in the SIH test.

Analgesic activity of a Withania somnifera extract in stressed mice

Withania somnifera is an important Ayurvedic Rasayana herb, the roots of which are often used in traditionally known systems of medicine as tonic or for rejuvenation purposes. Effects of a single and ten daily oral doses (10, 20 and 40 mg/kg) of an analytically well standardized Withania somnifera root extract against foot shock stress triggered transient hyperthermia and hotplate test for analgesics in male mice were quantified. Body weights and basal rectal temperatures of animals were recorded on all observational days and on the 11th and 12th day of the experiment, all animals were subjected to tail suspension and pentobarbital hypnosis tests respectively. Daily dose dependent efficacy of the tested extract in stress induced hyperthermia test and in hot plate test increased with increasing number of treatment days, and its dose dependent inhibitory effect on immobility time in tail suspension were observed after its 11 daily oral doses. Daily handling and intermittent foot shock stress triggered body weight losses and elevations in basal core temperatures were almost completely prevented even by its lowest daily dose (10 mg/kg/day) tested. Repeated daily low oral doses of the Withania somnifera extract is effective in suppressing diverse stress responses, and its centrally acting analgesics and anxiolytics or antidepressants like efficacies increase with increasing numbers of treatment days. These observations reaffirm that Withania somnifera is an adaptogenic herb, and suggest that its effective therapeutic doses has to be adjusted according to the pre-existing allostatic load of patients.

Anxiolytic properties of N-acetylcysteine in mice

Anxiety disorders are highly prevalent and often result in poor quality of life. Available anxiolytics show significant adverse effects as well as partial efficacy in a sizable part of patients. Innovative treatments with more favorable risk-benefit ratio are sorely needed. A growing body of clinical data indicates the benefits of N-acetylcysteine (NAC) in psychiatric conditions. NAC modulates antioxidant, glutamatergic, inflammatory and neurotrophic pathways in the central nervous system, all of which are relevant to anxiety pathology. We evaluated the effects of NAC in mice models commonly used to characterize anxiolytic compounds. Male adult CF1 or BALB/c mice were treated (i.p.) acutely or subacutely (4 consecutive days) with NAC (60–150mg/kg) 60min before open field, light/dark, hole-board, social interaction, elevated T-maze or stress-induced hyperthermia tests. Diazepam (2mg/kg) was used as positive control. We found that NAC presents anxiolytic effects in all models, except for the elevated T-maze. Subacute treatments resulted in lower effective doses in comparison to acute treatment. The anxiolytic effects of NAC were comparable to diazepam. NAC is a safe and low cost medicine with suggested benefits in psychiatric conditions often presenting co-morbidity with anxiety. This study contributes evidence to support the validity of clinical trials with NAC in the context of anxiety disorders, especially considering the safety profile in comparison to the limitations of diazepam for long term treatment.

Stress resistance promoting potentials of turmeric oil and curcuminoids in mice

Curcuma longa rhizomes (turmeric) are used as tonic in traditionally known Indian systems of medicine. Aim of this study was to compare stress response suppressing efficacies of a Curcuma longa extract (CLE) enriched in curcuminoids with those of curcumin and turmeric oil (TO). Effects of daily oral treatments with curcumin (5 mg/kg/day) or CLE (5, 20, and 80 mg/kg/day) or TO (1, 3, 10, 30 and 100 mg/kg/day) to male mice on their body weight and core temperature and in stress induced hyperthermia, tail suspension, and pentobarbital sleep tests were quantified. Although their single doses had no significant effects in foot shock stress induced hyperthermia test, curcumin like and dose dependant suppressing effects of CLE were observed after its repeated daily doses. Such effects of TO in the test was also observed after its higher tested daily doses only. Occasional foot shock stress triggered body weight losses and elevated basal core temperatures were also dose dependently antagonized by CLE and TO. Unlike for curcumin or CLE no effects of TO in tail suspension and pentobarbital sleep test were observed after its lower tested 11 daily doses. These observations reveal that volatile bioactive constituents of turmeric other than curcuminoids also possess stress resistance promoting properties and suggest that such efficacy of turmeric powder do not depend on their curcumin or curcuminoids contents only. Mouse bioassay procedure used in this study is well suited for pharmacological standardization of turmeric extracts and also for identifying their bioactive constituents.

Low dose effects of a Withania somnifera extract on altered marble burying behavior in stressed mice.

Aim:Withania somnifera root (WSR) extracts are often used in traditionally known Indian systems of medicine for prevention and cure of psychosomatic disorders. The reported experiment was designed to test whether low daily oral doses of such extracts are also effective in suppressing marble burying behavior in stressed mice or not.Materials and Methods:Groups of mice treated with 10, 20, or 40 mg/kg daily oral doses of WSR were subjected to a foot shock stress-induced hyperthermia test on the 1st, 5th, 7th, and 10th day of the experiment. On the 11th and 12th treatment days, they were subjected to marble burying tests. Stress response suppressing effects of low dose WSR were estimated by its effects on body weight and basal core temperature of animals during the course of the experiment.Results:Alterations in bodyweight and basal core temperature triggered by repeated exposures to foot shock stress were absent even in the 10 mg/kg/day WSR treated group, whereas the effectiveness of the extract in foot shock stress-induced hyperthermia and marble burying tests increased with its increasing daily dose.Conclusion:Marble burying test in stressed mice is well suited for identifying bioactive constituents of W. somnifera like medicinal plants with adaptogenic, anxiolytic and antidepressant activities, or for quantifying pharmacological interactions between them.

Preventive potentials of piperlongumine and a Piper longum extract against stress responses and pain

AimTo compare stress resistance increasing and analgesic activities of piperlongumine and a methanolic Piper longum fruit extract (PLE). MethodsEfficacies of a single and repeated daily oral doses (1–256 mg/kg/day) of PLE, piperlongumine, and 50 mg/kg/day doxycycline against foot shock stress triggered alteration in body weights and core temperatures, and of their 11 daily doses on antidepressants like activity in tail suspension test and on pentobarbital induced sedation in male mice were compared. In another experiment, analgesic activities of single and repeated daily 5 mg/kg oral doses of piperlongumine and PLE in mice hot plate test and in acetic acid induced writing tests were compared with those of aspirin and doxycycline. ResultsAfter their single oral doses no effects of piperlongumine or PLE or doxycycline were observed in the footshock stress induced hyperthermia test or in hot plate test. However, significant effects of piperlongumine and PLE in both the tests were observed after their 5 or more daily doses. Both of them also dose dependently suppressed daily handling and repetitive testing triggered alterations in body weights and core temperatures. Their doxycycline like antidepressant activity in tail suspension test and aspirin like analgesic effects in acetic acid writhing test were observed after their 11 daily 5 mg/kg oral dose. ConclusionPiperlongumine is another bioactive secondary metabolite of P. longum and other plants of piper species with stress response suppressing, analgesic, and anti-inflammatory activities. Its bactericidal activities can also contribute to its therapeutically interesting bio-activity profile.

STRESS RESPONSE MODULATING EFFECTS OF LACTIC ACID IN MICE

Lactic acid is commonly found in sour milk and is often consumed with food, which plays a role in various biochemical processes and used for trauma, surgery, burn injury and as a neuroprotective. Present pilot study was designed to investigate its putative stress response modulating effects in male mice. A battery of behavioural test models viz. stress-induced hyperthermia, tail suspension test and pentobarbital-induced hypnosis was used to assess the adaptogenic activity of lactic acid. Doses of lactic acid (5, 25, 125 and 625 mg/kg) as solution (10 ml/kg) was prepared in distilled water and administered orally for 11 consecutive days. The body weight and body temperature were recorded daily as a measure of stress induced changes. Stress induced hyperthermia test was performed on 1st, 5th, 7th, and 10th day of the treatments. On 11th day, they were subjected to tail suspension test and on day 12th to pentobarbital induce hypnosis test. Stress-induced hyperthermia was reduced by lactic acid in dose dependent manner and also compensated the changed in body weight and basal rectal temperature due to daily handling and intermittent foot-shock stress. Test drug was also reduced the immobility period in tail suspension test and showed considerable effect on onset and duration of sleep in pentobarbital-induce hypnosis test when compared to control, the significant (p<0.05) activity of lactic acid was found at dose 25 mg/kg onwards. These observations indicate that lactic acid has potential for adaptogenic activity, suggesting its use against varied spectrums of psychopathologies associated with stress.

Adaptogenic potential of andrographolide: An active principle of the king of bitters (Andrographis paniculata)

Andrographolide is a major bioactive secondary plant metabolite isolated Andrographis paniculata (Burm. F.) Wall. Ex. Nees. (穿心蓮 chuān xīn lián), a well-known traditionally used medicinal herb. The aim of the study was to pharmacologically evaluate the beneficial effect of andrographolide on stress-induced thermoregulatory and other physiological responses in mice. A stress-induced hyperthermia test was conducted in mice. The test agents were orally administered once daily for 11 consecutive days, and treatment effects on body weight changes, basal rectal temperature, and foot-shock-triggered hyperthermic responses were quantified on Day 1, Day 5, Day 7, and Day 10 of the experiments. Pentobarbital-induced hypnosis was quantified on the 11th day of treatment. Observations made during a pilot dose finding experiment revealed that, like A. paniculata extracts, pure andrographolide also possess adaptogenic properties. Observed dose-dependent efficacies of 3 mg/kg/d, 10 mg/kg/d, and 30 mg/kg/d andrographolide in the pilot experiment were reconfirmed by conducting two further analogous experiments using separate groups of either male or female mice. In these confirmatory experiments, efficacies of andrographolide were compared with that of 5 mg/kg/d oral doses of the standard anxiolytic diazepam. Significantly reduced body weights and elevated core temperatures of the three vehicle-treated control groups observed on the 5th day and subsequent observational days were completely absent even in the groups treated with the lowest andrographolide dose (3 mg/kg/d) or diazepam (5 mg/kg/d). Benzodiazepine-like potentiation of pentobarbital hypnosis was observed in andrographolide-treated animals. These observations reveal that andrographolide is functionally a diazepam-like desensitizer of biological mechanisms, and processes involved in stress trigger thermoregulatory and other physiological responses.

Bifidobacteria exert strain-specific effects on stress-related behavior and physiology in BALB/c mice.

Accumulating evidence suggests that commensal bacteria consumption has the potential to have a positive impact on stress-related psychiatric disorders. However, the specific bacteria influencing behaviors related to anxiety and depression remain unclear. To this end, we compared the effects of two different Bifidobacteria on anxiety and depression-like behavior; an antidepressant was also used as a comparator. Innately anxious BALB/c mice received daily Bifidobacterium longum (B.) 1714, B. breve 1205, the antidepressant escitalopram or vehicle treatment for 6 weeks. Behavior was assessed in stress-induced hyperthermia test, marble burying, elevated plus maze, open field, tail suspension test, and forced swim test. Physiological responses to acute stress were also assessed. Both Bifidobacteria and escitalopram reduced anxiety in the marble burying test; however, only B. longum 1714 decreased stress-induced hyperthermia. B. breve 1205 induced lower anxiety in the elevated plus maze whereas B. longum 1714 induced antidepressant-like behavior in the tail suspension test. However, there was no difference in corticosterone levels between groups. These data show that these two Bifidobacteria strains reduced anxiety in an anxious mouse strain. These results also suggest that each bacterial strain has intrinsic effects and may be beneficially specific for a given disorder. These findings strengthen the role of gut microbiota supplementation as psychobiotic-based strategies for stress-related brain-gut axis disorders, opening new avenues in the field of neurogastroenterology.

AFQ056/mavoglurant, a novel clinically effective mGluR5 antagonist: Identification, SAR and pharmacological characterization

Here we describe the identification, structure–activity relationship and the initial pharmacological characterization of AFQ056/mavoglurant, a structurally novel, non-competitive mGlu5 receptor antagonist. AFQ056/mavoglurant was identified by chemical derivatization of a lead compound discovered in a HTS campaign. In vitro, AFQ056/mavoglurant had an IC50 of 30nM in a functional assay with human mGluR5 and was selective over the other mGluR subtypes, iGluRs and a panel of 238 CNS relevant receptors, transporter or enzymes. In vivo, AFQ056/mavoglurant showed an improved pharmacokinetic profile in rat and efficacy in the stress-induced hyperthermia test in mice as compared to the prototypic mGluR5 antagonist MPEP. The efficacy of AFQ056/mavoglurant in humans has been assessed in L-dopa induced dyskinesia in Parkinson’s disease and Fragile X syndrome in proof of principle clinical studies.

Anxiolytic- but not antidepressant-like activity of Lu AF21934, a novel, selective positive allosteric modulator of the mGlu4 receptor

Previous studies demonstrated that the Group III mGlu receptor-selective orthosteric agonist, LSP1-2111 produced anxiolytic- but not antidepressant-like effects upon peripheral administration. Herein, we report the pharmacological actions of Lu AF21934, a novel, selective, and brain-penetrant positive allosteric modulator (PAM) of the mGlu4 receptor in the stress-induced hyperthermia (SIH), four-plate, marble-burying and Vogel's conflict tests. In all models, except Vogel's conflict test, a dose-dependent anxiolytic-like effect was seen. The anti-hyperthermic effect of Lu AF21934 (5 mg/kg) in the SIH test was inhibited by the benzodiazepine receptor antagonist flumazenil (10 mg/kg) and was not serotonin-dependent, as it persisted in serotonin-deficient mice and upon blockade of either 5-HT1A receptors by WAY100635, or 5-HT2A/2C receptors by ritanserin. These results suggest that the GABAergic system, but not the serotonergic system, is involved in the mechanism of the anxiolytic-like phenotype of Lu AF21934 in rodents. Lu AF21934 did not produce antidepressant-like effects in the tail suspension test (TST) in mice; however, it decreased the basal locomotor activity of mice that were not habituated to activity cages.This article is part of a Special Issue entitled ‘Metabotropic Glutamate Receptors’.

Behavioural phenotypic characterization of CD-1 mice lacking the neuropeptide S receptor

Neuropeptide S (NPS) is the endogenous ligand of a previously orphan receptor now named NPSR. In the brain NPS regulates several biological functions including anxiety, arousal, locomotion, food intake, learning and memory, pain and drug abuse. Mice lacking the NPSR gene (NPSR(−/−)) represent an useful tool to investigate the neurobiology of the NPS/NPSR system. NPSR(−/−) mice have been generated in a 129S6/SvEv genetic background. In the present study we generated CD-1 congenic NPSR(+/+) and NPSR(−/−) mice and investigated their phenotype and sensitivity to NPS in various behavioural assays. The phenotype analysis revealed no locomotor differences between NPSR(+/+) and NPSR(−/−) mice. The behaviour of NPSR(+/+) and NPSR(−/−) mice in the righting reflex test was superimposable. No differences were recorded between the two genotypes in the elevated plus maze, open field and stress-induced hyperthermia tests, with the exception of rearing behaviour that was reduced in knockout animals. Moreover the behaviour of NPSR(+/+) and NPSR(−/−) mice in the forced swimming, novel object recognition and formalin assays was similar. The stimulatory effects of NPS in the locomotor activity test and its anxiolytic-like actions in the elevated plus maze and open field assays were evident in NPSR(+/+) but not NPSR(−/−) animals. In conclusion, the present study indicates that the NPS/NPSR system does not tonically control locomotion, sensitivity to diazepam, anxiety, depressive-like behaviours, memory and pain transmission in mice. Furthermore our results clearly show that the product of the NPSR gene represents the mandatory protein for all the NPS biological effects so far described.

Lifelong CRF overproduction is associated with altered gene expression and sensitivity of discrete GABAA and mGlu receptor subtypes

RationaleRepeated activation of corticotropin-releasing factor (CRF) receptors is associated with increased anxiety and enhanced stress responsivity, which may be mediated via limbic GABAergic and glutamatergic transmission.ObjectiveThe present study investigated molecular and functional alterations in GABAA receptor (GABAAR) and metabotropic glutamate receptor (mGluR) responsivity in transgenic mice that chronically overexpress CRF.MethodsCRF1 receptor, GABAAR, and mGluR sensitivity were determined in CRF-overexpressing mice using the stress-induced hyperthermia (SIH) test. In addition, we measured mRNA expression levels of GABAAR α subunits and mGluRs in the amygdala and hypothalamus.ResultsCRF-overexpressing mice were less sensitive to the anxiolytic effects of the CRF1 receptor antagonists CP154,526 and DMP695, the GABAAR α3-selective agonist TP003 (0–3 mg/kg) and the mGluR2/3 agonist LY379268 (0–10 mg/kg) in the SIH test. The hypothermic effect of the non-selective GABAAR agonist diazepam (0–4 mg/kg) and the α1-subunit-selective GABAAR agonist zolpidem (0–10 mg/kg) was reduced in CRF-overexpressing mice. No genotype differences were found using the GABAAR α5-subunit preferential compound SH-053-2′F-R-CH3 and mGluR5 antagonists MPEP and MTEP. CRF-overexpressing mice showed decreased expression levels of GABAAR α2 subunit and mGluR3 mRNA levels in the amygdala, whereas these expression levels were increased in the hypothalamus. CRF-overexpressing mice also showed increased hypothalamic mRNA levels of α1 and α5 GABAAR subunits.ConclusionsWe found that lifelong CRF overproduction is associated with altered gene expression and reduced functional sensitivity of discrete GABAA and mGluR receptor subtypes. These findings suggest that sustained over-activation of cerebral CRF receptors may contribute to the development of altered stress-related behavior via modulation of GABAergic and glutamatergic transmission.

On the mechanism of anti-hyperthermic effects of LY379268 and LY487379, group II mGlu receptors activators, in the stress-induced hyperthermia in singly housed mice

Earlier studies have demonstrated that the agonists of the mGlu2/3 receptors produced anxiolytic actions after peripheral administration. However, the mechanism of their action is still not clear. Therefore the aim of the present study was to specify the role of the GABAergic and serotonergic system in the mechanism of the anxiolytic activity of group II mGlu receptor activators by using the stress induced hyperthermia test (SIH) in singly housed mice. We used an orthosteric mGlu2/3 receptor agonist, LY379268, which induced anti-hyperthermic efficacy in the doses of 1–5mg/kg (73% of inhibition after a highest dose). The effect of the second ligand used, a mGlu2 receptor positive modulator (PAM), LY487379, was observed in a dose range of 0.5–5mg/kg and reached 53% of the inhibition. The blockade of GABAergic system by GABAA receptor antagonist flumazenil (10mg/kg) or GABAB receptor antagonist CGP55845 (10mg/kg), and the blockade of serotonergic system by 5-HT1A receptor antagonist WAY100635 (0.1 and 1mg/kg) or 5-HT2A/2C receptor antagonist ritanserin (0.5mg/kg) had no influence on the anti-hyperthermic effect induced by effective dose of LY379268. However, the action of the effective dose of LY487379 was enhanced when co-administered with flumazenil, WAY100635 (0.1mg/kg) and ritanserin. Similar results were observed for the subeffective dose of LY379268 (0.5mg/kg). WAY100635 in a dose of 1mg/kg did not induce any enhancing effect on the activity of compounds. Therefore, it seems that the antagonism towards GABAA receptors, presynaptic 5-HT1A and postsynaptic 5-HT2A/2C receptors is responsible for the phenomenon.This article is part of a Special Issue entitled ‘Anxiety and Depression’.

Anxiolytic Activity Evaluation of Four Medicinal Plants from Cameroon

Afrormosia laxiflora (A. laxiflora), Chenopodium ambrosioides (C. ambrosioides), Microglossa pyrifolia (M. pyrifolia) and Mimosa pudica (M. pudica) are plants used in traditional medicine in Cameroon to treat insomnia, epilepsy, anxiety, and agitation. They were evaluated for their anxiolytic like activity in mice. Animal models (elevated plus maze and stress-induced hyperthermia tests) were used. The four plants showed anxiolytic activity. In stress-induced hyperthermia test, A. laxiflora, C. ambrosioides, M. pyrifolia and M. pudica significantly antagonised the increase of temperature. ΔT° decreased from 0.75°C in the control group to 0.36°C at the dose of 110 mg/kg for A. laxiflora; from 1°C in the control group to -1.1°C at the dose of 120 mg/kg for C. ambrosioides; from 1.7°C in the control group to 0.2°C at the dose of 128 mg/kg for M. pyrifolia and from 1.3°C in the control group to 0.5°C at the dose of 180 mg/kg for M. pudica. In the elevated plus maze test, the four plants increased the number of entries into, percentage of entries into, and percentage of time in open arms. A. laxiflora, C. ambrosioides and M. pudica also reduced the percentage of entries and time in closed arms. In addition, C. ambrosioides, M. pyrifolia and M. pudica showed antipyretic activity by reducing the body temperature. The results suggested that C. ambrosioides, M. pyrifolia and M. pudica posses anxiolytic-like and antipyretic activities while A. laxiflora possesses only anxiolytic-like properties. These plants could be helpful in the treatment of anxiety and fever in traditional medicine in Cameroon.

Metabotropic glutamate receptor 4 novel agonist LSP1-2111 with anxiolytic, but not antidepressant-like activity, mediated by serotonergic and GABAergic systems

Our earlier studies have demonstrated that the non-selective group III mGlu receptor agonist, ACPT-I, produced anxiolytic rather than antidepressant-like actions after its peripheral administration. Here, we describe the effects of LSP1-2111 ((2S)-2-amino-4-[hydroxy[hydroxy(4-hydroxy-3-methoxy-5-nitro-phenyl)methyl]phosphoryl]butanoic acid), a novel orthosteric, preferential agonist of the mGlu4 receptor, a member of the group III mGlu receptors family, in the stress-induced hyperthermia (SIH) and elevated plus-maze (EPM) tests in mice. In both tests an anxiolytic-like effect was clearly seen in doses of 2 and 5 mg/kg, i.p. The compound did not produce antidepressant-like effects in the tail suspension test (TST) or in the forced swim test (FST) in mice. The potential anxiolytic effect of LSP1-2111 (5 mg/kg) in the SIH test was inhibited by the benzodiazepine receptor antagonist flumazenil (given i.p., 10 mg/kg), and by a 5-HT 1A receptor antagonist N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridynyl)cyclohexane-carboxamide (WAY100635) (0.1 mg/kg, s.c.). At the same time, ritanserin (0.5 mg/kg i.p.), the 5-HT 2A/C receptor antagonist, did not change the anxiolytic-like effects of LSP1-2111. Moreover, the compound was not effective in 5-HT depleted animals. The results of these studies indicate that the GABAergic and serotonergic systems are involved in the potential anxiolytic action of LSP1-2111.

CaV1.3 L-type Ca2+ channels modulate depression-like behaviour in mice independent of deaf phenotype

Mounting evidence suggests that voltage-gated L-type Ca2+ channels can modulate affective behaviour. We therefore explored the role of CaV1.3 L-type Ca2+ channels in depression- and anxiety-like behaviours using CaV1.3-deficient mice (CaV1.3-/-). We showed that CaV1.3-/- mice displayed less immobility in the forced swim test as well as in the tail suspension test, indicating an antidepressant-like phenotype. Locomotor activity in the home cage or a novel open-field test was not influenced. In the elevated plus maze (EPM), CaV1.3-/- mice entered the open arms more frequently and spent more time there indicating an anxiolytic-like phenotype which was, however, not supported in the stress-induced hyperthermia test. By performing parallel experiments in Claudin 14 knockout mice (Cldn14-/-), which like CaV1.3-/- mice are congenitally deaf, an influence of deafness on the antidepressant-like phenotype could be ruled out. On the other hand, a similar EPM behaviour indicative of an anxiolytic phenotype was also found in the Cldn14-/- animals. Using electroretinography and visual behavioural tasks we demonstrated that at least in mice, CaV1.3 channels do not significantly contribute to visual function. However, marked morphological changes were revealed in synaptic ribbons in the outer plexiform layer of CaV1.3-/- retinas by immunohistochemistry suggesting a possible role of this channel type in structural plasticity at the ribbon synapse. Taken together, our findings indicate that CaV1.3 L-type Ca2+ channels modulate depression-like behaviour but are not essential for visual function. The findings raise the possibility that selective modulation of CaV1.3 channels could be a promising new therapeutic concept for the treatment of mood disorders.

The group III mGlu receptor agonist ACPT-I exerts anxiolytic-like but not antidepressant-like effects, mediated by the serotonergic and GABA-ergic systems

Our earlier studies have demonstrated that (1 S,3 R,4 S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid ACPT-I, a group III mGlu receptor agonist, produced anxiolytic-like and antidepressant-like actions after central administration. Here we describe the anxiolytic-like effects of ACPT-I after intraperitoneal administration in the stress-induced hyperthermia (SIH), elevated plus-maze (PMT) tests in mice and in the Vogel test in rats. However, the compound did not produce antidepressant-like effects in the tail suspension test (TST) or in the forced swim test (FST) in mice. The potential anxiolytic effect of ACPT-I (20 mg/kg) in the SIH test was inhibited by the benzodiazepine receptor antagonist flumazenil (given i.p., 10 mg/kg), and by a 5-HT 1A receptor antagonist N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}- N-(2-pyridynyl) cyclohexane-carboxamide (WAY100635) (0.1 mg/kg s.c.). At the same time, ritanserin (0.5 mg/kg i.p.), the 5-HT2A/C receptor antagonist, did not change the anxiolytic-like effects of ACPT-I. The results of these studies indicate that the GABA-ergic and serotonergic systems are involved in the potential anxiolytic action of ACPT-I.