Folic acid administration produces an antidepressant-like effect in mice: evidence for the involvement of the serotonergic and noradrenergic systems

Clinical studies have shown that folic acid plays a role in the pathophysiology of depression. However, very few studies have investigated its effect in behavioral models of depression. Hence, this study tested its effect in the forced swimming test (FST) and the tail suspension test (TST), two models predictive of antidepressant activity, in mice. Folic acid administered by oral route (p.o.) produced a reduction in the immobility time in the FST (50-100mg/kg) and in the TST (10-50mg/kg). The administration of folic acid by i.c.v. route also reduced the immobility time in the FST (10nmol/site) and in the TST (1-10nmol/site). Both folic acid administered by oral and i.c.v. route produced no psychostimulant effect, which indicates that its antidepressant-like effect is specific. Pretreatment of mice with p-chlorophenylalanine methyl ester (PCPA; 100mg/kg, i.p., an inhibitor of serotonin (5-HT) synthesis, for 4 consecutive days), ketanserin (5mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist), prazosin (1mg/kg, i.p., an alpha(1)-adrenoceptor antagonist) or yohimbine (1mg/kg, i.p., an alpha(2)-adrenoceptor antagonist) prevented the anti-immobility effect of folic acid (50mg/kg, p.o.) in the FST. Moreover, the pretreatment of mice with WAY100635 (0.1mg/kg, s.c., a selective 5-HT(1A) receptor antagonist) blocked the decrease in immobility time in the FST elicited by folic acid (50mg/kg, p.o.), but produced a synergistic effect with a subeffective dose of folic acid (10mg/kg, p.o.). In addition, a subeffective dose of folic acid (10mg/kg, p.o.) produced a synergistic antidepressant-like effect with fluoxetine (10mg/kg, p.o.) in the FST. Overall, the results firstly indicate that folic acid produced an antidepressant-like effect in FST and in TST and that this effect appears to be mediated by an interaction with the serotonergic (5-HT(1A) and 5-HT(2A/2C) receptors) and noradrenergic (alpha(1)- and alpha(2)-adrenoceptors) systems.     

Antidepressant-like effect of extract from Polygala paniculata: Involvement of the monoaminergic systems

Context: Polygala paniculata Linnaeus (Polygalaceae) has shown neuroprotective effects, but there is no report about its antidepressant potential.

Objective: The antidepressant-like effect of the hydroalcoholic extract from P. paniculata and some of the possible mechanisms involved in this effect were investigated in forced swimming test (FST).

Materials and methods: Mice received extract by oral route and were submitted to FST and open-field test. Animals were forced to swim and the total immobility time was registered (6-min period). A reduction in the immobility time is considered an antidepressant-like effect. In order to investigate the involvement of the monoaminergic systems, mice were treated with pharmacological antagonists before administration of the extract.

Results: The acute administration of the hydroalcoholic extract from P. paniculata produced an antidepressant-like effect, since it significantly reduced the immobility time in FST (0.01–30?mg/kg) as compared to control group, without changing locomotor activity. Pretreatment of mice with yohimbine (1?mg/kg, i.p., α₂-adrenoceptor antagonist), propranolol (1?mg/kg, i.p., β-adrenoceptor antagonist), SCH23390 (0.05?mg/kg, s.c., dopamine D₁ receptor antagonist) or sulpiride (50?mg/kg, i.p., dopamine D₂ receptor antagonist) prevented the antidepressant-like effect of the extract in FST (30?mg/kg). Moreover, ketanserin (5?mg/kg, i.p., preferential 5-HT_2A receptor antagonist) enhanced the effect of the extract in FST.

Discussion and conclusion: The results of the present study indicate that the extract from P. paniculata has an antidepressant-like action that is likely mediated by an interaction with the serotonergic (5-HT_2A receptors), noradrenergic (α₂ and β-receptor) and dopaminergic (D₁ and D₂ receptors) systems.     

Antidepressant-like and antinociceptive-like actions of 4-(4'-chlorophenyl)-6-(4''-methylphenyl)-2-hydrazinepyrimidine Mannich base in mice

This study investigated the possible antidepressant and antinociceptive action of CPMPH Mannich base, as well as the involvement of serotonergic, dopaminergic, noradrenergic and opioid systems and the L-arginine-nitric oxide pathway in the antidepressant-like effect of CPMPH in the forced swimming test (FST) in mice. The immobility time in the FST was significantly reduced by CPMPH (0.1-10 mg/kg, i.p.), without accompanying changes in the ambulation in an open-field. CPMPH at high doses (i.p. or s.c. routes) produced a significant inhibition of acetic acid-induced writhing. The antidepressant-like effect of CPMPH (1 mg/kg, i.p.) in the FST was prevented by pre-treatment of mice with methysergide (2 mg/kg, i.p., a non-selective serotonin receptor antagonist), sulpiride (32 mg/kg, i.p., a D2 receptor antagonist) or yohimbine (1 mg/kg, i.p., an alpha2-adrenoceptor antagonist). In contrast, the antidepressant-like effect of CPMPH was not affected by pre-treatment (i.p.) with naloxone (1 mg/kg, a non-selective opioid receptor antagonist) or L-arginine (750 mg/kg, a nitric oxide precursor). The results demonstrate that CPMPH had an antidepressant-like action that appears to be mediated through its interaction with serotonergic, dopaminergic and noradrenergic systems.     

Antidepressant-like effect of m-trifluoromethyl-diphenyl diselenide in the mouse forced swimming test involves opioid and serotonergic systems

Serotonergic and opioid systems have been implicated in major depression and in the action mechanism of antidepressants. The organoselenium compound m-trifluoromethyl-diphenyl diselenide (m-CF(3)-PhSe)(2) shows antioxidant and anxiolytic activities and is a selective inhibitor of monoamine oxidase A activity. The present study was designed to investigate the antidepressant-like effect of (m-CF(3)-PhSe)(2) in female mice, employing the forced swimming test. The involvement of the serotonergic and opioid systems in the antidepressant-like effect of (m-CF(3)-PhSe)(2) was appraised. (m-CF(3)-PhSe)(2) at doses of 50 and 100mg/kg (p.o.) exhibited antidepressant-like action in the forced swimming test. The effect of (m-CF(3)-PhSe)(2) (50mg/kg p.o.) was prevented by pretreatment of mice with WAY100635 (0.1mg/kg, s.c. a selective 5-HT(1A) receptor antagonist), ritanserin (4 mg/kg, i.p., a non-selective 5HT(2A/2C) receptor antagonist), ondansetron (1mg/kg, i.p., a selective 5-HT(3) receptor antagonist) and naloxone (1mg/kg, i.p., a non-selective antagonist of opioid receptors). These results suggest that (m-CF(3)-PhSe)(2) produced an antidepressant-like effect in the mouse forced swimming test and this effect seems most likely to be mediated through an interaction with serotonergic and opioid systems.     

Antidepressant-like effect of ursolic acid isolated from Rosmarinus officinalis L. in mice: Evidence for the involvement of the dopaminergic system

Ursolic acid, a constituent from Rosmarinus officinalis, is a triterpenoid compound which has been extensively known for its anticancer and antioxidant properties. In the present study, we investigated the antidepressant-like effect of ursolic acid isolated from this plant in two predictive tests of antidepressant property, the tail suspension test (TST) and the forced swimming test (FST) in mice. Furthermore, the involvement of dopaminergic system in its antidepressant-like effect was investigated in the TST. Ursolic acid reduced the immobility time in the TST (0.01 and 0.1 mg/kg, p.o.) and in the FST (10 mg/kg, p.o.), similar to fluoxetine (10 mg/kg, p.o.), imipramine (1 mg/kg, p.o.) and bupropion (10 mg/kg, p.o.). The effect of ursolic acid (0.1 mg/kg, p.o.) in the TST was prevented by the pretreatment of mice with SCH23390 (0.05 mg/kg, s.c., a dopamine D₁ receptor antagonist) and sulpiride (50 mg/kg, i.p., a dopamine D₂ receptor antagonist). The administration of a sub-effective dose of ursolic acid (0.001 mg/kg, p.o.) in combination with sub-effective doses of SKF38393 (0.1 mg/kg, s.c., a dopamine D₁ receptor agonist), apomorphine (0.5 μg/kg, i.p., a preferential dopamine D₂ receptor agonist) or bupropion (1 mg/kg, i.p., a dual dopamine/noradrenaline reuptake inhibitor) reduced the immobility time in the TST as compared with either drug alone. Ursolic acid and dopaminergic agents alone or in combination did not cause significant alterations in the locomotor and exploratory activities. These results indicate that the antidepressant-like effect of ursolic acid in the TST is likely mediated by an interaction with the dopaminergic system, through the activation of dopamine D₁ and D₂ receptors.     

Evidence for the involvement of the noradrenergic system, dopaminergic and imidazoline receptors in the antidepressant-like effect of tramadol in mice

The involvement of the noradrenergic system, imidazoline, dopaminergic and adenosinergic receptors in the antidepressant-like action of tramadol in the mouse forced swimming test (FST) was evaluated in this study. The antidepressant-like effect of tramadol (40 mg/kg, per oral, p.o.) in the FST was blocked with yohimbine (1 mg/kg, i.p., an α₂-adrenoceptor antagonist), α-methyl-para-tyrosine methyl ester (AMPT, 100 mg/kg, i.p., an inhibitor of tyrosine hydroxylase), efaroxan (1 mg/kg, i.p., an imidazoline I₁/α₂-adrenoceptor antagonist), idazoxan (0.06 mg/kg, i.p., an imidazoline I₂/α₂-adrenoceptor antagonist), antazoline (5 mg/kg, i.p., a ligand with high affinity for the I₂ receptor), haloperidol (0.2 mg/kg, i.p., a non selective dopamine receptor antagonist), SCH23390 (0.05 mg/kg, subcutaneously, s.c., a dopamine D₁ receptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D₂ and D₃ receptor antagonist) but was not reversed by prazosin (1 mg/kg, intraperitoneally, i.p., an α₁-adrenoceptor antagonist) and caffeine (3 mg/kg, i.p., a nonselective adenosine receptor antagonist). Monoamine oxidase-A and -B (MAO-A and MAO-B) activities were neither inhibited in the whole brain nor in specific brain regions of mice treated with tramadol. These data demonstrated that the antidepressant-like effect caused by oral administration of tramadol in the mouse FST is mediated by the noradrenergic system, dopaminergic and imidazoline receptors.     

Evidence for imidazoline receptors involvement in the agmatine antidepressant-like effect in the forced swimming test

This study investigated the involvement of the imidazoline receptors in the antidepressant-like effect of agmatine in the forced swimming test. The antidepressant-like effects of agmatine (10 mg/kg, i.p.) in the forced swimming test was blocked by pretreatment of mice with efaroxan (1 mg/kg, i.p., an imidazoline I1/alpha2-adrenoceptor antagonist), idazoxan (0.06 mg/kg, i.p., an imidazoline I2/alpha2-adrenoceptor antagonist) and antazoline (5 mg/kg, i.p., a ligand with high affinity for the I2 receptor). A subeffective dose of agmatine (0.001 mg/kg, i.p.) produced a synergistic antidepressant-like effect with clonidine (0.06 mg/kg, i.p, an imidazoline I1/alpha2-adrenoceptor agonist), moxonidine (0.5 mg/kg, i.p., an imidazoline I1/alpha2-adrenoceptor agonist), antazoline (1 mg/kg, i.p.) and MK-801 (0.001 mg/kg, i.p., a non-competitive NMDA receptor antagonist), but not with efaroxan (1 mg/kg, i.p.) and idazoxan (0.06 mg/kg, i.p.). Pretreatment of mice with yohimbine (1 mg/kg, i.p., an alpha2-adrenoceptor antagonist) blocked the synergistic antidepressant-like effect of agmatine (0.001 mg/kg, i.p.) with clonidine (0.06 mg/kg, i.p). A subeffective dose of MK-801 (0.001 mg/kg, i.p.) produced a synergistic antidepressant-like effect with antazoline (5 mg/kg, i.p.), but not with efaroxan (1 mg/kg, i.p.) or idazoxan (0.06 mg/kg, i.p.). In conclusion, this study suggests that the anti-immobility effect of agmatine in the forced swimming test is dependent on its interaction with imidazoline I1 and I2 receptors.     

Antidepressant-like effect of the organoselenium compound ebselen in mice: Evidence for the involvement of the monoaminergic system

Ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one] is a seleno-organic compound which possesses a potent antioxidant activity and has been shown to exert neuroprotective effects in vitro and in vivo in a variety of pro-oxidative insults. The present study investigates a possible antidepressant activity of ebselen using two predictive tests for antidepressant activity in rodents: the forced swimming test and tail suspension test. Additionally, the mechanisms involved in the antidepressant-like effect of ebselen in mice were also assessed. Ebselen (10 mg/kg, s.c.) decreased the immobility time in the forced swimming test without accompanying changes in ambulation in the open-field test. In contrast, the administration of ebselen (10-30 mg/kg) did not produce any effect in the tail suspension test. The anti-immobility effect of ebselen (10 mg/kg, s.c.) was not prevented by pre-treatment of mice with p-chlorophenylalanine (PCPA, 100 mg/kg, i.p., an inhibitor of serotonin synthesis, 4 consecutive days), NAN-190 (0.5 mg/kg, i.p., a serotonin 5-HT_1A receptor antagonist) or ketanserin (5 mg/kg, i.p., a serotonin 5-HT_2A/2C receptor antagonist). On the other hand, the pre-treatment of mice with prazosin (1 mg/kg, i.p., an α₁-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α₂-adrenoceptor antagonist), SCH23390 (0.05 mg/kg, s.c., a dopamine D₁ receptor antagonist) or sulpiride (50 mg/kg, i.p., a dopamine D₂ receptor antagonist) completely blocked the antidepressant-like effect of ebselen (10 mg/kg, s.c.) in the forced swimming test. It may be concluded that ebselen produces an antidepressant-like effect in the forced swimming test that seems to be dependent on its interaction with the noradrenergic and dopaminergic systems, but not with the serotonergic system.     

Antidepressant-like effect of lamotrigine in the mouse forced swimming test: evidence for the involvement of the noradrenergic system

Lamotrigine is an anticonvulsant drug that is also effective in the treatment of mood disorders, especially bipolar disorder. However, few studies have been conducted in animal models of depression to evaluate its mechanism of action. The present study investigated the effect of lamotrigine in the forced swimming test in mice and the involvement of the noradrenergic system in this effect. Lamotrigine (20-30 mg/kg, i.p.) decreased the immobility time in the forced swimming test and the number of crossings in the open-field test. In addition, the pretreatment of mice with the inhibitor of the enzyme tyrosine hydroxylase, alpha-methyl-p-tyrosine (100 or 250 mg/kg), prevented the antidepressant-like effect of lamotrigine (30 mg/kg, i.p.) in the forced swimming test. Besides that, the pretreatment of mice with prazosin (1 mg/kg, i.p., an alpha1-adrenoceptor antagonist) or yohimbine (1 mg/kg, i.p., an alpha2-adrenoceptor antagonist) also prevented the anti-immobility effect of lamotrigine (30 mg/kg, i.p.). Moreover, the administration of subeffective doses of phenylephrine (5 mg/kg, i.p., an alpha1-adrenoceptor agonist) or clonidine (0.06 mg/kg, i.p., an alpha2-adrenoceptor agonist) was able to potentiate the action of a subeffective dose of lamotrigine (10 mg/kg, i.p.) in the forced swimming test. Thus, the present study suggests that the antidepressant-like effect of lamotrigine in the forced swimming test is related to the noradrenergic system, likely due to an activation of alpha1- and alpha2-postsynaptic adrenoceptors.     

Antidepressant-like activity of ellagic acid in unstressed and acute immobilization-induced stressed mice

BackgroundThe aim of present study was to evaluate antidepressant-like activity of ellagic acid in Swiss young male albino mice; and to explore the possible underlying mechanisms for this activity.MethodsMice were immobilized for 150 min once only for induction of stress. Ellagic acid (8.75, 17.5, 35 mg/kg, po) and fluoxetine (20 mg/kg, ip) per se were administered to unstressed and stressed mice; and immobility periods were recorded using tail suspension test and forced swim test. The plasma nitrite levels were also estimated in unstressed and stressed mice. Effects of 7-nitroindazole (nNOS inhibitor), aminoguanidine (iNOS inhibitor), prazosin (α₁-adrenoceptor antagonist), sulpiride (selective D₂-receptor antagonist), and p-chlorophenylalanine (p-CPA – tryptophan hydroxylase inhibitor) on antidepressant-like activity of ellagic acid were also evaluated.ResultsEllagic acid (17.5 and 35 mg/kg, po) and fluoxetine per se significantly decreased immobility periods of unstressed and stressed mice, indicating significant antidepressant-like activity. There was no significant effect on locomotor activity of the mice. Ellagic acid significantly decreased the plasma nitrite levels in stressed mice only. Aminoguanidine significantly potentiated antidepressant-like activity and plasma nitrite decreasing effect of ellagic acid (35 mg/kg) in stressed mice. 7-Nitroindazole did not enhance antidepressant-like activity and plasma nitrite decreasing effect of ellagic acid in unstressed mice. Prazosin and p-CPA significantly attenuated antidepressant-like effect of ellagic acid (35 mg/kg) in unstressed mice only.ConclusionThus, ellagic acid showed antidepressant-like activity in unstressed mice probably by interaction through adrenergic and serotonergic systems. On the other hand, antidepressant-like activity of ellagic acid in stressed mice might be through inhibition of inducible NOS.     

Antidepressant-like pharmacological profile of 3-(4-fluorophenylselenyl)-2,5-diphenylselenophene: Involvement of serotonergic system

This study evaluated the effect of 3-(4-fluorophenylselenyl)-2,5-diphenylselenophene (DPS) in the mouse forced swim test (FST) and tail suspension test (TST), two assays predictive of depressant activity. The involvement of serotonergic system in the effect caused by DPS was studied. The antidepressant-like effect of combined treatment with subeffetive doses of DPS and paroxetine, a selective serotonin reuptake inhibitor (SSRI) was investigated. Further, we verified the possible mechanism responsible for antidepressive-like effect of DPS. The results show that DPS (50 and 100 mg/kg, p.o.) significantly reduced the immobility time during the FST and TST, without accompanying changes in ambulation when assessed in the open-field test. The anti-immobility effect of DPS (50 mg/kg, p.o.) in the FST was prevented by pretreatment of mice with pCPA (100 mg/kg, i.p., once a day for 4 consecutive days, an inhibitor of 5-HT synthesis), WAY 100635 (0.1 mg/kg, s.c., a selective 5-HT1A receptor antagonist), ritanserin (1 mg/kg, i.p., a 5-HT2 receptor antagonist) or ondansetron (1 mg/kg, i.p., a 5-HT3 receptor antagonist). Combined treatment with paroxetine and DPS reduced the immobility time in the FST. DPS at the doses of 10-100 mg/kg did not produce any change in the cerebral activity of MAO-A or MAO-B. DPS at the dose of 50 mg/kg inhibited significantly 5-HT uptake in synaptosomes. These results suggest that DPS produced an antidepressant-like effect in the mouse FST and TST and this effect seems most likely to be mediated through an interaction with serotonergic system, particularly by 5-HT reuptake inhibition.     

Mechanisms involved in the antinociception caused by agmatine in mice

The present study examined the antinociceptive effects of agmatine in chemical behavioural models of pain. Agmatine (1-30 mg/kg), given by i.p. route, 30 min earlier, produced dose-dependent inhibition of acetic acid-induced visceral pain, with mean ID50 value of 5.6 mg/kg. Given orally, 60 min earlier, agmatine (10-300 mg/kg) also produced dose-related inhibition of the visceral pain caused by acetic acid, with mean ID50 value of 147.3 mg/kg. Agmatine (3-100 mg/kg, i.p.) also caused significant and dose-dependent inhibition of capsaicin- and glutamate-induced pain, with mean ID50 values of 43.7 and 19.5 mg/kg, respectively. Moreover, agmatine (1-100 mg/kg, i.p.) caused marked inhibition of both phases of formalin-induced pain, with mean ID50 values for the neurogenic and the inflammatory phases of 13.7 and 5.6 mg/kg, respectively. The antinociception caused by agmatine in the acetic acid test was significantly attenuated by i.p. treatment of mice with L-arginine (precursor of nitric oxide, 600 mg/kg), naloxone (opioid receptor antagonist, 1 mg/kg), p-chlorophenylalanine methyl ester (PCPA, an inhibitor of serotonin synthesis, 100 mg/kg once a day for 4 consecutive days), ketanserin (a 5-HT2A receptor antagonist, 0.3 mg/kg), ondansetron (a 5-HT3 receptor antagonist, 0.5 mg/kg), yohimbine (an alpha2-adrenoceptor antagonist, 0.15 mg/kg) or by efaroxan (an I1 imidazoline/alpha2-adrenoceptor antagonist, 1 mg/kg). In contrast, agmatine antinociception was not affected by i.p. treatment of animals with pindolol (a 5-HT1A/1B receptor antagonist, 1 mg/kg) or idazoxan (an I2 imidazoline/alpha2-adrenoceptor antagonist, 3 mg/kg). Likewise, the antinociception caused by agmatine was not affected by neonatal pre-treatment with capsaicin. Together, these results indicate that agmatine produces dose-related antinociception in several models of chemical pain through mechanisms that involve an interaction with opioid, serotonergic (i.e., through 5-HT2A and 5-HT3 receptors) and nitrergic systems, as well as via an interaction with alpha2-adrenoceptors and imidazoline I1 receptors.     

Galantamine (Reminyl) delays cardiac ventricular repolarization and prolongs the QT interval by blocking the HERG current

Ferulic acid (4-hydroxy-3-methoxycinnamic acid) is a phenolic compound present in several plants with claimed beneficial effects in prevention and treatment of disorders linked to oxidative stress and inflammation. In this study, we aimed to verify the possible antidepressant-like effect of acute oral administration of ferulic acid in the forced swimming test (FST) and tail suspension test (TST) in mice. Additionally, the mechanisms involved in the antidepressant-like action and the effects of the association of ferulic acid with the antidepressants fluoxetine, paroxetine, and sertraline in the TST were investigated. Ferulic acid produced an antidepressant-like effect in the FST and TST (0.01-10 mg/kg, p.o.), without accompanying changes in ambulation. The pretreatment of mice with WAY100635 (0.1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist) or ketanserin (5 mg/kg, i.p., a 5-HT(2A) receptor antagonist) was able to reverse the anti-immobility effect of ferulic acid (0.01 mg/kg, p.o.) in the TST. The combination of fluoxetine (5 mg/kg, p.o.), paroxetine (0.1 mg/kg, p.o.) or sertraline (1 mg/kg, p.o.) with a sub-effective dose of ferulic acid (0.001 mg/kg, p.o.) produced a synergistic antidepressant-like effect in the TST, without causing hyperlocomotion in the open-field test. Taken together, these results demonstrate that ferulic acid exerts antidepressant-like effect in the FST and TST in mice through modulation of the serotonergic system.     

Kappa-opioid receptors mediate the antidepressant-like activity of hesperidin in the mouse forced swimming test

The opioid system has been implicated as a contributing factor for major depression and is thought to play a role in the mechanism of action of antidepressants. This study investigated the involvement of the opioid system in the antidepressant-like effect of hesperidin in the mouse forced swimming test. Our results demonstrate that hesperidin (0.1, 0.3 and 1 mg/kg; intraperitoneal) decreased the immobility time in the forced swimming test without affecting locomotor activity in the open field test. The antidepressant-like effect of hesperidin (0.3 mg/kg) in the forced swimming test was prevented by pretreating mice with naloxone (1 mg/kg, a nonselective opioid receptor antagonist) and 2-(3,4-dichlorophenyl)-Nmethyl-N-[(1S)-1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl] acetamide (DIPPA (1 mg/kg), a selective κ-opioid receptor antagonist), but not with naloxone methiodide (1 mg/kg, a peripherally acting opioid receptor antagonist), naltrindole (3 mg/kg, a selective δ-opioid receptor antagonist), clocinnamox (1 mg/kg, a selective μ-opioid receptor antagonist) or caffeine (3 mg/kg, a nonselective adenosine receptor antagonist). In addition, a sub-effective dose of hesperidin (0.01 mg/kg) produced a synergistic antidepressant-like effect in the forced swimming test when combined with a sub-effective dose of morphine (1 mg/kg). The antidepressant-like effect of hesperidin in the forced swimming test on mice was dependent on its interaction with the κ-opioid receptor, but not with the δ-opioid, μ-opioid or adenosinergic receptors. Taken together, these results suggest that hesperidin possesses antidepressant-like properties and may be of interest as a therapeutic agent for the treatment of depressive disorders.     

Study into a possible mechanism responsible for the antidepressant-like activity of the selective 5-HT6 receptor antagonist SB-399885 in rats

The mechanism of the antidepressant-like activity of the selective 5-hydroxytryptamine(6) (5-HT(6) receptor antagonist N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide (SB-399885) was studied in the forced swim test in rats. SB-399885 administered intraperitoneally at a single dose of 10 mg/kg potently shortened the immobility time in rats. That potential antidepressant-like effect of SB-399885 was not modified in animals with a lesion of the 5-HT system produced by p-chloroamphetamine (p-CA, 2 x 10 mg/kg). The anti-immobility effect of SB-399885 was blocked by the dopamine D(1)- and D(2)-like receptor antagonists SCH 23390 (0.063 mg/kg) and sulpiride (10 mg/kg), respectively, as well as by the alpha(2)-adrenoceptor antagonist idazoxan (4 mg/kg), but it was not changed by the alpha(1)-adrenoceptor antagonist prazosin (1 mg/kg). Neither sulpiride (10 mg/kg) or idazoxan (4 mg/kg) nor SCH-23390 (0.063 mg/kg) administered jointly with SB-399885 (10 mg/kg) noticeably changed the exploratory locomotor activity of rats evaluated by the open field test. The results described in the present paper indicate that the anti-immobility activity of SB-399885 is not connected with 5-HT innervation, and that D(1)- and D(2)-like receptors and alpha(2)-adrenoceptors are involved in this action.     

Involvement of PI3K, GSK-3β and PPARγ in the antidepressant-like effect of folic acid in the forced swimming test in mice

Preclinical and clinical studies indicate that deficiency in folic acid plays a role in the pathophysiology of depression. Considering that alterations in the signaling pathways that regulate neuroplasticity and cellular survival are implicated in depressive disorders, the present study investigated the involvement of the phosphoinositide 3-kinase (PI3K), glycogen synthase kinase-3 (GSK-3β), and peroxisome proliferator-activated receptor-γ (PPARγ) in the antidepressant-like effect of folic acid in the forced swimming test (FST). The intracerebroventricular (i.c.v.) pre-treatment of mice with LY294002 (10 nmol/site, a PI3K inhibitor) or GW-9662 (1 μg/site, a PPARγ antagonist) prevented the antidepressant-like effect of folic acid (50 mg/kg, p.o.) in the FST. In addition, the administration of subeffective doses of the selective GSK-3β inhibitor, AR-A014418 (3 mg/kg, i.p.), a non-selective GSK-3β inhibitor, lithium chloride (10 mg/kg, p.o) or a PPARγ agonist, rosiglitazone (1 μg/site, i.c.v.) in combination with a subeffective dose of folic acid (10 mg/kg, p.o.) significantly reduced the immobility time in the FST as compared with either drug alone, without altering the locomotor activity. These results indicate that the antidepressant-like effect of folic acid in the FST might be dependent on inhibition of GSK-3β and activation of PPARγ, reinforcing the notion that these are important targets for antidepressant activity.     

The antidepressant-like action of a simple selenium-containing molecule, methyl phenyl selenide, in mice

Selenium-containing molecules show promising pharmacological properties. The antidepressant-like action of CH(3)SePh in the mouse forced swimming test (FST) and the tail suspension test (TST), models predictive of depressant activity, were investigated in this study. Moreover, the involvement of dopaminergic system in the antidepressant-like action of CH(3)SePh was studied. The behavioral results showed that CH(3)SePh significantly reduced the immobility time in the FST (25 and 50 mg/kg, intragastrically; i.g.) and the TST (50 mg/kg, i.g.), without accompanying changes in ambulation when assessed in the open-field test (OFT). The anti-immobility effect of CH(3)SePh (50 mg/kg, intragastrically; i.g.) in the FST was prevented by pretreatment of mice with haloperidol (0.2 mg/kg, i.p., a dopamine D(2) receptor antagonist), SCH 23390 (R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol) (0.05 mg/kg, s.c., a dopamine D(1) receptor antagonist) and sulpiride (50 mg/kg, i.p., a dopamine D(2) and D(3) antagonist). These results suggest that CH(3)SePh produced an antidepressant-like action in the mouse FST and TST. The antidepressant-like action of CH(3)SePh, a simple selenium-containing molecule, seems most likely to be mediated through an interaction with the dopaminergic system.     

Antidepressant-like effect of rutin isolated from the ethanolic extract from Schinus molle L. in mice: evidence for the involvement of the serotonergic and noradrenergic systems

We have recently shown that the hexanic extract from leaves of Schinus molle produces antidepressant-like effects in the tail suspension test in mice. This study investigated the antidepressant-like effect of the ethanolic extract from aerial part of S. molle in the forced swimming test and tail suspension test in mice, two predictive models of depression. Moreover, we investigated the antidepressant potential of rutin, a flavonoid isolated from the ethanolic extract of this plant and the influence of the pretreatment with the inhibitors of serotonin or noradrenaline synthesis, p-chlorophenylalanine methyl ester (PCPA) and alpha-methyl-p-tyrosine (AMPT), respectively in the antidepressant-like effect of this flavonoid. The administration of the ethanolic extract produced a reduction in the immobility time in the tail suspension test (dose range 600-1000 mg/kg, p.o.), but not in the forced swimming test. It also produced a reduction in the ambulation in the open-field test in mice not previously habituated to the arena, but no effect in the locomotor activity in mice previously habituated to the open-field. The administration of rutin reduced the immobility time in the tail suspension test (0.3-3 mg/kg, p.o.), but not in the forced swimming test, without producing alteration in the locomotor activity. In addition, pretreatment of mice with PCPA (100 mg/kg, i.p., for 4 consecutive days) or AMPT (100 mg/kg, i.p.) prevented the anti-immobility effect of rutin (0.3 mg/kg, p.o.) in the tail suspension test. The results firstly indicated the antidepressant-like effect of the ethanolic extract of S. molle in the tail suspension test may be dependent on the presence of rutin that likely exerts its antidepressant-like effect by increasing the availability of serotonin and noradrenaline in the synaptic cleft.     

Involvement of dopamine D1 receptors and alpha1-adrenoceptors in the antidepressant-like effect of chlorpheniramine in the mouse tail suspension test

It has been reported that chlorpheniramine, a classical antihistamine, has antidepressant-like effects in animal models of depression. In this study, we examined the involvement of dopaminergic (dopamine D(1) and dopamine D(2) receptors), noradrenergic (alpha(1)- and beta-adrenoceptors) and serotonergic (5-HT(1A) and 5-HT(2) receptors) receptors in the antidepressant-like effect of chlorpheniramine in the mouse tail suspension test. We also investigated the involvement of these monoamine receptors in the antidepressant-like effect of imipramine for comparison with the mechanisms of the effect of chlorpheniramine. Both imipramine and chlorpheniramine significantly reduced the duration of immobility in the tail suspension test without affecting spontaneous locomotor activity in mice. The anti-immobility effect of imipramine (30 mg/kg, i.p.) was significantly antagonized by the selective dopamine D(1) receptor antagonist SCH23390 but not by the other receptor antagonists. In contrast, the anti-immobility effect of chlorpheniramine was significantly inhibited by SCH23390 and the selective alpha(1)-adrenoceptor antagonist prazosin, but not by the other receptor antagonists. In conclusion, these results suggest that chlorpheniramine exerts an antidepressant-like effect in the mouse tail suspension test that is mediated by at least the activation of dopamine D(1) receptors and alpha(1)-adrenoceptors. In addition, the antidepressant-like effect of chlorpheniramine may be induced by several mechanisms that are different from those involved in the antidepressant-like effect of imipramine.     

Stimulation of dopamine D-2 but not D-1 receptors reduces immobility time of rats in the forced swimming test: implication for antidepressant activity

The involvement of dopamine D-1 and D-2 receptor mechanisms was investigated in the forced swimming test with rats. d,1-Sulpiride, a D-2 receptor antagonist, reported to reduce desipramine-induced anti-immobility, did not alter the brain levels of desipramine. In addition, the anti-immobility effect of desipramine was not antagonized by SCH 23390, a D-1 receptor antagonist. Amineptine (20 mg/kg i.p., 60 min before testing), a dopamine uptake blocker, and LY171555 (0.2 mg/kg i.p., 60 min before testing), a dopaminergic D-2 stimulant reduced immobility time in the forced swimming test, but benserazide + 1-DOPA (200 mg/kg p.o., 45 min before testing), which increases dopamine release, or SKF 38393A (20 mg/kg s.c., 60 min before testing), a D-1 agent, did not. The anti-immobility effect but not the stereotypy was increased following chronic (21 days) LY171555 (0.1 and 0.2 mg/kg i.p.) treatment. The effect of acute or repeated (7 days) LY171555 (0.2 mg/kg i.p.) treatment was antagonized by 1-sulpiride (50 mg/kg i.p., 90 min before testing), a D-2 receptor antagonist. Neither SKF 38393A (20 mg/kg s.c., 60 min before testing) nor SCH 23390 (0.05 mg/kg s.c., 30 min before testing) modified the acute anti-immobility effect of LY171555 (0.2 mg/kg i.p.) SCH 23390 (0.025 and 0.05 mg/kg) increased the immobility time at doses which decreased motor activity. The increase in immobility time brought about by SCH 23390 was not antagonized by SKF 38393A (20 mg/kg). The findings indicate that activation of dopamine D-2 receptors could reduce immobility time.