Activity In Forced Swim Test Research Articles

An experimental study evaluating antidepressant activity of methanolic leaf and fruit pulp extracts of Aegle marmelos in Wistar rats

Background: Aegle marmelos (common name: Bel/wood apple/Tamil name: Vilvam/Telugu name: Sandiliyamu) has numerous therapeutic values in Indian traditional systems of medicine. The crude extracts of various parts of this plant have numerous properties including anti-inflammatory, antiulcer, antipyretic, and antioxidant. This study was taken to explore the antidepressant activity of A. marmelos. Aim and Objectives: The objectives of the study are as follows: (1) To identify the antidepressant activity of methanolic leaf and the fruit pulp extracts of A. marmelos. (2) To compare the dose-dependent effect of methanolic leaf and the fruit pulp extracts of A. marmelos with the standard drug, Imipramine. Materials and Methods: Forced swim test (FST) and shock-induced depression (SID) models were used in this study. Six groups (n = 6) of Wistar rats (150–200 g) of either sex were used for each experimental model. About 1% Carboxymethylcellulose (CMC-1), 20 mg/kg of Imipramine (Imi-20), 150 and 300 mg/kg of methanolic leaf extract, and 150 and 300 mg/kg of methanolic fruit pulp extract were given to Groups 1–6, respectively, by oral route for 7 days. The number of movements was measured using an Photoactometer for SID and the duration of immobility (in sec) were measured for FST. Results: Data were statistically analyzed by one-way ANOVA for FST and by Kruskal–Wallis test for SID, P < 0.05 was considered statistically significant. Both standard and test drugs exhibited significant antidepressant activity. Conclusion: Fruit pulp extract (300 mg/kg) of A. marmelos has demonstrated maximum antidepressant activity in FST and SID models, which was comparable to standard drug.

New Ketene Dithioacetals Generated from 2‐Nitroperchlorobutadiene and Investigation of Their Antibacterial, Antifungal, Anticonvulsant and Antidepressant Activities

The ketene dithioacetal 3 generated from 2-nitroperchlorobutadiene 1 reacted with various heterocyclic amines and aliphatic, aromatic and heterocyclic thiols to produce functionalized new ketene-N,S,S-acetals and S,S,S-acetals 4a-f, 5a-h as heterocyclic dithiolanes. They were separated/purified by chromatographic methods and their exact structure characterization were made clear by spectroscopic methods. These compounds synthesized could act as effective drugs for versatile activity. Evaluation of the antimicrobial effect of the obtained substances determined derivatives 4e and 5h, which have MIC=15.6 μg/mL for the test culture of Mycobacterium luteum bacteria closing to the control drug Vancomycin. The obtained compounds can be proposed as a promising synthetic objects for future molecular design to enhance the antimicrobial action. Ketene dithioacetals 3, 4a, 4b, 4e, 5g (50 mg/kg) exhibited antiseizure effect comparable with reference drug (valproic acid) on the model of pentylenetetrazole-induced convulsions after single oral administration both at 3 h and 24 h. Furthermore, tested dithioacetals possessed prolonged antidepressant activity in forced swim test (FST) considerable decreasing the duration of immobility time compared to reference drug amitriptyline. This is the first study of the investigation of anticonvulsant and antidepressant activities of ketene dithioacetals.

Immune cells as a potential therapeutic agent in the treatment of depression

IntroductionThere are sufficient amount data on the immune cells and their biologically active products leading role in the pathogenesis of depression, which allows viewing modulated immune cells as model objects for developing new approaches to depression immunotherapy.ObjectivesWe first demonstrated the ability of immune cells modulated outside the body by caffeine to edit depression-like behavior and showed the central cytokines-mediated mechanisms of this effect. Considering theimportant role of the peripheral immune system in the pathogenesis of depression, we investigated the main parameters of its functional activity after transplantation of modulated immunocytes.Methods(CBAxC57Bl/6) F1 depressive-like male mice, developed under the long-term social stress, were undergoing the transplantation of syngeneic immune cells with in vitro caffeine-modulated functional activity. Recipient’s behavior and immune systems functional activity parameters were studied.ResultsWe showed earlier significant positive psychoneuromodulatory effect of caffeine-treated immune cells in depressive-like recipients which manifests itself in the behavioral editing (anhedonia reduction, stimulation of exploratory behavior and activity in forced swimming test); hippocampal neurogenesis stimulation against the background of increased BDN and modulation of brain cell’s cytokines production. Transplantation of caffeine-modulated immune cells in syngeneic depressive-like recipients also leads to positive changes in the immune system functional activity as evidenced by enhanced immune response, splenocytes proliferation stimulation on the background of modulation of cell’s cytokines production and decreased tryptophan catabolism, reducing systemic inflammation.ConclusionsResults demonstrated that in vitro caffeine-modulated immune cells caused positive psychoneuroimmunomodulating effect in depressive-like recipients. So, its may be considered as a potential therapeutic agent in the treatment of depression.DisclosureNo significant relationships.

Overcoming undesirable hERG affinity by incorporating fluorine atoms: A case of MAO-B inhibitors derived from 1 H-pyrrolo-[3,2-c]quinolines

The incorporation of the fluorine motif is a strategy widely applied in drug design for modulating the activity, physicochemical parameters, and metabolic stability of chemical compounds. In this study, we attempted to reduce the affinity for ether-à-go-go-related gene (hERG) channel by introducing fluorine atoms in a group of 1H-pyrrolo[3,2-c]quinolines that are capable of inhibiting monoamine oxidase type B (MAO-B). A series of structural modifications guided by in vitro evaluation of MAO-B inhibition and antitargeting for hERG channels were performed, which led to the identification of 1-(3-chlorobenzyl)-4-(4,4-difluoropiperidin-1-yl)-1H-pyrrolo[3,2-c]quinoline (26). Compound 26 acted as a reversible MAO-B inhibitor exhibiting selectivity over 45 targets, enzymes, transporters, and ion channels, and showed potent glioprotective properties in cultured astrocytes. In addition, the compound demonstrated good metabolic stability in rat liver microsomes assay, a favorable safety profile, and brain permeability. It also displayed procognitive effects in the novel object recognition test in rats and antidepressant-like activity in forced swim test in mice. The findings of the study suggest that reversible MAO-B inhibitors can have potential therapeutic applications in Alzheimer's disease.

Bioactivity Guided Fractionation and Purification of Anti-Depressant Molecule from Ashwagandha (Withania somnifera)

Background: Ashwagandha (Withania somnifera) is an important herb in the Indian traditional system of medicine for neurological disorders. However, the efforts for isolation and characterisation of a molecule with anti-depressant activity and development as a potent dosage form are limited. Objective: The objective of the present study was to characterize the Ashwagandha extract for its antidepressant fraction or constituent and to improve biological benefits at low doses. Methods: Aqueous methanol extract of Ashwagandha was prepared and fractionated into withanolides and flavonoids rich fractions. Withanolide rich fraction was subjected to phytochemical analysis to identify the active molecule/s. The compound was purified by using a semi-preparative HPLC system; identified using various spectroscopic techniques and anti-depressant activity was evaluated in rats. Enteric coating was performed on the extract and fractions after granulation and anti-depressant activity of coated samples were evaluated in rats. Results: Aqueous methanol extract of Ashwagandha and withanolide rich fraction showed prominent dose-dependent anti-depressant activity in forced swim test in rats. Phytochemical analysis of active fraction resulted in the isolation and characterization of a major withanolide glycoside present, namely withanoside X. Enteric coated aqueous methanol extract, withanolide rich fraction and withanoside X showed significant antidepressant activity at low doses as compared to the uncoated forms. Conclusion: The active fraction/isolated compound is sensitive to low pH of the stomach, thus enteric coating might be beneficial to protect the actives in the stomach, facilitating the sustainable release into the intestine and in turn reduce the dosage.

Antidepressant activity and HPTLC fingerprinting of stearic acid in different days of wheat seedlings

Abstract Depression is a chronic, recurring and potentially life threatening illness and affects up to 20% of the world population and in the year 2020, depression will become the second most common disease in the world. To find the remedy from nutraceuticals, the present study was designed to evaluate the antidepressant activity of stearic acid (SA) and to quantify its maximum content in different dayold wheat seedlings and wheat grains. Forced swimming test (FST) and tail suspension test (TST) were done to evaluate the antidepressant activity of SA. HPTLC fingerprinting of SA was done in different days (3 , 5 and 7 d) of wheat seedlings and wheat grains to quantify its maximum content. In the antidepressant study, when compared with the control (326.67 ± 3.02 s), SA showed potential antidepressant activity in TST (131.67 ± 2.60 s) and SA also showed very good antidepressant activity in FST (124.83 ± 5.37 s) when compared with the control (215.83 ± 6.64 s). In HPTLC fingerprinting, the maximum content of SA was identified in 3-d-old wheat seedlings (89.43 μg) when compared to wheat grains (84.69 μg), 5-d-old (86.43 μg) and 7-d-old (85.32 μg) wheat seedlings. Hence, the present study concludes that SA has a potential antidepressant activity and 3-d-old wheat seedlings are the essential sources of SA among the different dayold wheat seedlings.

The depressive-like behaviors of chronic unpredictable mild stress-treated mice, ameliorated by Tibetan medicine Zuotai: involvement in the hypothalamic-pituitary-adrenal (HPA) axis pathway.

BackgroundZuotai, a famous Tibetan medicinal mixture containing metacinnabar, is traditionally used for the purpose of tranquilizing minds and soothing nerves. However, it still lacks substantial experimental data for it to be approved for use.AimThis study was designed to assess the effects of Zuotai on depressive-like symptoms in a chronic unpredictable mild stress (CUMS) mouse model, and to explore its potential mechanism, particularly the hypothalamic–pituitary–adrenal (HPA) axis pathway.Materials and methodsFirst, Kunming mice were exposed to the CUMS procedure and simultaneously administered Zuotai or imipramine (positive control) by gavage continuously for 6 weeks. Then, depressive-like behaviors of mice in each group were tested with the sucrose preference test, forced swimming test, tail suspension test, and open field test. Meanwhile, the three key neuroendocrine hormones (corticotropin releasing hormone, adrenocorticotropic hormone and corticosterone) in HPA axis pathway, and the level of the emotion-related monoamine neurotransmitters (5-hydroxytryptamine and norepinephrine) were measured using enzyme-linked immunosorbent assay. Furthermore, total mercury in the hypothalamus and hippocampus were determined using an automatic, direct mercury analyzer.ResultsZuotai or imipramine significantly increased the body weight and the sucrose preference ratio in sucrose preference test, and dramatically improved motor activity in forced swimming test, tail suspension test, and open field test in CUMS mice. Zuotai or imipramine remarkably decreased levels of corticotropin-releasing hormone, adrenocorticotropic hormone, and corticosterone in the HPA axis, and increased levels of 5-hydroxytryptamine and norepinephrine in the serum in CUMS mice. However, a small amount of mercury was deposited in the hypothalamus and hippocampus in Zuotai-treated mice, which may pose a potential risk to the central nervous system.ConclusionZuotai has a strong ability to ameliorate depressive-like behaviors in CUMS-treated mice through inhibition of the HPA axis and upregulation of monoamine neurotransmitters. These findings provide new insight into the pharmacological effect of Zuotai on depression.

Antidepressant-like deliverables from the sea: evidence on the efficacy of three different brown seaweeds via involvement of monoaminergic system.

Brown seaweeds exhibit several health benefits in treating and managing wide array of ailments. In this study, the antidepressant-like effect of methaolic extracts from Sargassum swartzii (SS), Stoechospermum marginatum (SM), and Nizamuddinia zanardinii (NZ) was examined in forced swimming test (FST), in rats. Oral administration of SS, SM, and NZ extract (30-60mg/kg) exhibited antidepressant-like activity in FST by reducing immobility time as compared to control group, without inducing significant change in ambulatory behavior in open field test. In order to evaluate the involvement of monoaminergic system, rats were pretreated with the inhibitor of brain serotonin stores p-chlorophenylalanin (PCPA), dopamine (SCH23390 and sulpiride), and adrenoceptor (prazosin and propranolol) antagonists. Rats receiving treatment for 28days were decapitated and brains were analyzed for monoamine levels. It may be concluded that the extracts of SS, SM, and NZ produces antidepressant-like activity via modulation of brain monoaminergic system in a rat model.

Antidepressant-like activity of EMD 386088, a 5-HT6 receptor partial agonist, following systemic acute and chronic administration to rats.

The study was designed to examine the potency of EMD 386088, a 5-HT6 receptor partial agonist, to exert antidepressant-like properties in animal models following acute and chronic intraperitoneal administration to rats. The modified rat forced swim test (FST) was utilized to examine a potential antidepressant effect of EMD 386088 after acute treatment (30min before the test) and three times in a 24-h administration scheme (24h, 5h, and 30min prior to the FST). The olfactory bulbectomy (OB) model was used to assess its antidepressant-like properties after chronic treatment (the drug was administered once daily for 14days). EMD 386088 showed an antidepressant-like effect in all conducted tests. Its activity in FST after its acute administration (5mg/kg) was blocked by the selective 5-HT6 receptor antagonist SB 271046. The obtained results seem to be specific, as there was no observed locomotor stimulation by the drug given at a lower/antidepressant dose. In the three times in the 24-h treatment scheme, EMD 386088 (2.5mg/kg) exerted antidepressant properties in FST as well as increased locomotor activity in the open field test. Chronic administration of EMD 386088 (2.5mg/kg) significantly improved the learning deficit in OB rats without affecting performance in Sham-operated (SH) animals in the passive avoidance test, and reduced OB-related rats' locomotor hyperactivity, but did not change the number of rearing + peeping episodes. The obtained findings suggest that EMD 386088 produces antidepressant-like activity after systemic acute and chronic administration which may result from direct stimulation of 5-HT6 receptors.

Enduring effects of post-weaning rearing condition on depressive- and anxiety-like behaviors and motor activity in male rats

Environmental manipulation at early critical periods could have long-lasting effects. In spite of the great interest in the biological effects of the environmental condition so far, its long-lasting effects are less documented. This study looks at the enduring effects of rearing condition on tasks that measure affective responses and exploratory behavior in male Wistar rats. The animals were reared from weaning to adulthood in an enriched environment, standard laboratory condition, or isolated condition. Then, all rats were housed in standard laboratory cages to provide a common environment, and successively exposed to different tests between 0 and 11weeks post-manipulation. The open field test indicated a more efficient exploratory behavior in the enriched group, and an enhanced spontaneous motor activity in both standard and isolated groups. In addition, rats reared in standard condition showed heightened motor activity in forced swimming test and elevated plus maze. Forced swimming test showed an antidepressive-like effect in the enriched environment group by increased climbing behavior. In respect to the anxiety behavior, environmental enrichment improved threat detection ability. It is concluded that rearing condition from weaning to adulthood has important and long-lasting effects on depressive- and anxiety-like and exploratory behaviors as well as motor activity.

Antidepressant-like activity of a new piperazine derivative of xanthone in the forced swim test in mice: The involvement of serotonergic system

BackgroundThe studied compound: 3-chloro-5-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}-9H-xanthen-9-one dihydrochloride (HBK-6) is a new xanthone derivative. In this study we investigated its antidepressant-like properties and possible mechanism of action. MethodsAntidepressant-like activity was evaluated in the forced swim test (FST) in mice. The influence on locomotor activity in mice was analyzed to determine whether the observed in FST effect is specific. Rotarod test was used to determine neurotoxic properties. ResultsHBK-6 reduced immobility time in mice in FST at the doses 5 and 10mg/kg, whereas fluoxetine (FX) at 15mg/kg, reboxetine (RX) at 10mg/kg and bupropion (BPR) at 5mg/kg. Joint administration of sub-effective doses of HBK-6 and FX, but not RX or BPR, reduced immobility in mice in FST. HBK-6 at the dose 5mg/kg did not show activity in FST after pretreatment with p-chlorophenylalanine. The studied xanthone derivative at the doses 5 and 10mg/kg did not impair motor coordination in mice. ConclusionsWe demonstrated that HBK-6 has a potent antidepressant-like activity in FST, stronger than that of FX and RX, and seems to mediate its effect through serotonergic system. Moreover, at antidepressant-like doses it does not show neurotoxic properties. Given the promising results, HBK-6 may have potential in the treatment of depression, but this needs extended studies.

Antidepressant activity of brahmi in albino mice.

In traditional system of medicine brahmi has been used to enhance memory. Recently it has been reported to have action in psychiatric disorders. With these backgrounds the work has been undertaken to study antidepressant activity of brahmi in albino mice. To evaluate antidepressant activity of brahmi in experimental models. The antidepressant activity was studied in albino mice using forced swimming test (FST), tail suspension test (TST) and shock induced depression (SID). Imipramine (10mg/kg), fluoxetine (30mg/kg) were used as standard drugs and brahmi (10, 20, 30mg/kg) was used as test drug. Brahmi exhibited significant decrease in duration of immobility in FST and reduced the shock induced decrease in activity in SID models. It didn't show any activity in the TST model. Brahmi has shown antidepressant activity in FST and SID.

EVALUATION OF ACUTE TOXICITY AND NEUROPHARMACOLOGICAL ACTIVITIES OF PM-52

The neuropsychological disorders are increasing their importance nowadays. Unfortunately, the therapeutic efficacy is still not in satisfaction level. Therefore, the novel agents that are effective, safe, cheap and easy to approach are in required. Therefore, we aimed to determine the neuropharmacological activities of PM52, the novel herbal supplement. We had developed the PM52, a novel product comprising of Cissampelas pariera and Anethum graveolens at aconcentarion of 1: 5. Then, it was determined acute toxicity and the neuropharmacological activities of PM52. Male Wistar rats, weighing 180-220 g, were orally given PM52 up to the dose of 5000 mg.kg-1 BW and observed acute toxicity. The neuropharmacological activities of PM52 were also determined. Various doses of PM52 ranging from 2, 10 and 50 mg.kg-1 BW were orally given once daily to the animals at a period of 14 days. Anxiolytic, anti-depression and cognitive enhancing effects were evaluated after single administration and every 7 days throughout 14-day experimental period using elevated plus maze, forced swimming test and Morris water maze tests respectively. PM 52 was safe up to dose of 5000 mg kg-1 BW. Moreover, it also showed anxiolytic-like activity and cognitive enhancing effect. Moreover, it also enhanced climbing activity in forced swimming test. PM 52 is the potential novel food supplement to enhance cognitive function and decrease anxiety. However, further researches on subchronic toxicity, possible active gradient and shelf life of product are also necessary before moving forward to clinical trial study.

Antidepressant‐like effect of bis‐eugenol in the mice forced swimming test: evidence for the involvement of the monoaminergic system

Dehydrodieugenol, known as bis-eugenol, is a eugenol ortho dimer, and both compounds were able to exhibit anti-inflammatory and antioxidant activities in previous studies. Furthermore, eugenol showed antidepressant-like effect; however, the biological actions of bis-eugenol on experimental models for screening antidepressant activity are still unknown. The present study investigated a possible antidepressant-like activity of bis-eugenol in the forced swimming test (FST) and tail suspension test (TST) in mice and the involvement in the monoaminergic system in this effect. In addition, a neurochemical analysis on brain monoamines of mice acutely treated with bis-eugenol was also conducted. Bis-eugenol decreased the immobility time in the FST and TST without accompanying changes in ambulation in the open field test at 10 mg/kg, i.p.. Nevertheless, it induced ambulation at 25 and 50 mg/kg doses. The anti-immobility effect of bis-eugenol (10 and 50 mg/kg, i.p.) was prevented by pretreatment of mice with p-chlorophenylalanine (PCPA, 100 mg/kg, i.p., an inhibitor of serotonin synthesis, for four consecutive days), yohimbine (1 mg/kg, i.p., an α2-adrenoceptor antagonist), SCH23390 (15 μg/kg, s.c., a dopamine D1 receptor antagonist) and sulpiride (50 mg/kg, i.p., a dopamine D2 receptor antagonist). Monoamines analysis using high-performance liquid chromatograph revealed significant increase in the 5-HT, NE and DA levels in brain striatum. The present study indicates that bis-eugenol possesses antidepressant-like activity in FST and TST by altering dopaminergic, serotonergic and noradrenergic systems function.

Arylpiperazine-containing pyrimidine 4-carboxamide derivatives targeting serotonin 5-HT2A, 5-HT2C, and the serotonin transporter as a potential antidepressant

Pyrimidine usually has good pharmacokinetic properties as a drug substance and considerable efforts have been devoted to develop pyrimidine derivatives into drug candidates. Arylpiperazine-containing pyrimidine 4-carboxamide derivatives were synthesized and evaluated for binding to serotonin receptors and transporter. Pyrimidine derivatives showed good antidepressant activity in FST (forced swimming test) animal model and also displayed no appreciable inhibitory activity against hERG channel blocking assay. Herein SAR studies of pyrimidine derivatives targeting serotonin receptors and transporter will be disclosed.

Involvement of serotonin receptor subtypes in the antidepressant-like effect of trim in the rat forced swimming test

Depression is a common illness with severe morbidity and mortality. Nitric oxide synthase (NOS) inhibitors are shown to elicit antidepressant-like effect in various animals models. It is widely known that serotonin plays an important role in the antidepressant-like effect of drugs. The aim of this study is to investigate the involvement of 5-HT 1 and 5-HT 2 receptor subtypes in the antidepressant-like effect of TRIM, a nNOS inhibitor, in the rat forced swimming test (FST). TRIM displays an antidepressant-like activity in FST which is blocked by pretreatment with the NOS substrate l-arginine. Depletion of endogenous serotonin using para-chlorophenylalanine (pCPA; 3 × 150 mg/kg, i.p.) partially attenuated TRIM (50 mg/kg)-induced reductions in immobility time in FST. Pretreatment with methiothepin (0.1 mg/kg, i.p, a non-selective 5-HT receptor antagonist), cyproheptadine (3 mg/kg i.p, a 5-HT 2 receptor antagonist) or ketanserin (5 mg/kg i.p, a 5HT 2A/2C receptor antagonist) prevented the effect of TRIM (50 mg/kg) in the FST. WAY 100635 (0.1 mg/kg i.p, a selective 5-HT 1A receptor antagonist) and GR 127935 (3 mg/kg i.p, a selective 5-HT 1B/1D receptor antagonist) slightly reversed the immobility-reducing effect of TRIM in the FST, but this failed to reach a statistically significant level. The results of this study demonstrate that antidepressant-like effect of TRIM in the FST seems to be mediated, at least in part, by an interaction with 5-HT 2 receptors while non-significant effects were obtained with 5-HT 1 receptors.

NMDA/glutamate mechanism of antidepressant-like action of magnesium in forced swim test in mice

Antidepressant-like activity of magnesium in forced swim test (FST) was demonstrated previously. Also, enhancement of such activity by joint administration of magnesium and antidepressants was shown. However, the mechanism(s) involved in such activity remain to be established. In the present study we examined the involvement of NMDA/glutamate pathway in the magnesium activity in FST in mice. In the present study we investigated the effect of NMDA agonists on magnesium-induced activity in FST and the influence of NMDA antagonists with sub-effective doses of magnesium in this test. Magnesium-induced antidepressant-like activity was antagonized by N-methyl- d-aspartic acid (NMDA). Moreover, low, ineffective doses of NMDA antagonists (CGP 37849, L-701,324, d-cycloserine, and MK-801) administered together with low and ineffective doses of magnesium exhibit significant reduction of immobility time in FST. The active in FST doses of examined agents did not alter the locomotor activity (with an exception of increased activity induced by MK-801). The present study indicates the involvement of NMDA/glutamate pathway in the antidepressant-like activity of magnesium in mouse FST and further suggests antidepressant properties of magnesium.

Involvement of dopamine (DA)/serotonin (5-HT)/sigma (σ) receptor modulation in mediating the antidepressant action of ropinirole hydrochloride, a D 2/D 3 dopamine receptor agonist

Multiple lines of investigation have explored the role of dopaminergic systems in mental depression. Chronic treatment with antidepressant drugs has been reported to alter dopaminergic neurotransmission, most notably a sensitization of behavioural responses to agonists acting at D 2/D 3 dopamine receptors within the nucleus accumbens. Recent clinical evidences have shown that ropinirole, a D 2/D 3 dopamine receptor agonist, augments the action of various standard antidepressant drugs in treatment-resistant depression. The present study was undertaken to elucidate the possible mechanism of antidepressant action of ropinirole employing various behavioral paradigms of despair supported by the measurements of neurochemical changes in the tissue contents of dopamine (DA) and serotonin (5-HT) in the whole brain using high-performance-liquid chromatography (HPLC) with electrochemical detectors (ECD). In the mouse forced swim test (FST) or tail-suspension test (TST), ropinirole (1–10 mg/kg, i.p.) produced S-shaped dose–response curve in the percentage decrease in immobility period. Compared with vehicle, ropinirole (10 mg/kg., i.p.) had a significant anti-immobility effect without affecting locomotor activity. The reduction in the immobility period elicited by ropinirole (10 mg/kg, i.p.) in the FST was reversed by dopaminergic and sigma receptor antagonist, haloperidol (0.5 mg/kg, i.p.), and specific D 2 dopamine receptor antagonist sulpiride (5 mg/kg i.p.), but not by SCH 23390 (0.5 mg/kg i.p), a D 1 dopamine receptor antagonist. Rimcazole (5 mg/kg i.p.) (a sigma receptor antagonist), progesterone (10 mg/kg i.p.) (a sigma receptor antagonistic neurosteroid), BD 1047 (1 mg/kg i.p.) (a novel sigma receptor antagonist with preferential affinity for sigma-1 sites) also reversed the anti-immobility effect of ropinirole (10 mg/kg i.p.). The neurochemical studies of whole brain revealed that ropinirole at 10 mg/kg i.p. did not affect the tissue levels of dopamine but significantly increased serotonin levels. The study indicated that ropinirole possessed anti-immobility activity in FST by altering dopaminergic, serotonergic or sigma receptor function.

Combined administration of PHCCC, a positive allosteric modulator of mGlu4 receptors and ACPT-I, mGlu III receptor agonist evokes antidepressant-like effects in rats

Numerous pharmacological data indicate involvement of glutamate, the major excitatory neurotransmitter in the brain, in the pathophysiology of several neuropsychiatric disorders. It was shown in the preclinical studies that compounds which can reduce the excess of glutamate release (for example group III metabotropic receptors agonists) possess potential therapeutic properties. Thus we focused our interests on (-)-N-phenyl-7-(hydroxyimino) cyclopropa[b]chromen-1a-carboxamide (PHCCC), which is a positive allosteric modulator of mGlu4 receptor. We examined the potential antidepressant-like activity of PHCCC after injection into the brain ventricles alone, or together with (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid (ACPT-I), a nonselective group III mGlu receptor agonist, using the forced swimming test (FST) in rats. We found that ACPT-I induced a dose dependent antidepressant-like effect in FST, which was blocked by an antagonist of group III mGlu receptors (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG). PHCCC injected intracerebroventricular was not effective, however when the compound was administered together with non-effective dose of ACPT-I, a profound antidepressant-like activity in FST was demonstrated. This effect was reversed by CPPG, group III mGlu receptors antagonist. Results of our studies indicate that a combined administration positive allosteric modulation of mGlu4 receptor and agonists of group III mGlu receptors may be a promising target in the future treatment of depressive disorder.

The Neuropeptide Y (NPY) Y1 Receptor Subtype Mediates NPY-induced Antidepressant-like Activity in the Mouse Forced Swimming Test

The present study was undertaken to investigate the possible antidepressant-like effects of neuropeptide Y (NPY) in the mouse forced swimming test, an animal model widely used for the screening of potential antidepressant drugs. In addition, experiments were performed, using agonists and selective antagonists, to assess the potential role of NPY Y1 and Y2 receptor subtypes in this model. Complementary studies were performed in an open field apparatus to rule out any changes in locomotor activity that might have interfered with the interpretation of data from the mouse forced swimming test. Intracerebroventricular injections (0.03 nmole-3 nmole) of NPY, [Leu31Pro34]PYY (Y1 agonist), NPY13-36 (Y2 agonist), BIBP3226, BIBO3304 (Y1 antagonists) and BIIE0246 (Y2 antagonist) were performed 30 min prior to testing in the mouse forced swimming test and open field. NPY administration significantly reduced immobility time in a dose dependent manner (p < .01 vs. control group), as did [Leu31Pro34]PYY (p < .01 vs. control group) and BIIE0246 (p < .05 vs. control group). In contrast, BIBO3304, BIBP3226 and NPY13-36 did not display any activity at the doses tested. However, pretreatment with BIBO3304 or BIBP3226 significantly blocked the anti-immobility effects of NPY. Data from the open field demonstrated that BIIE0246 increased horizontal ambulation at the dose found to be active in the forced swimming test. Taken together, our results demonstrate that NPY displays antidepressant-like activity in the mouse forced swimming test, and suggest that this activity is mediated by the NPY Y1 receptor subtype.