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.     

The antidepressant effects of curcumin in the forced swimming test involve 5-HT1 and 5-HT2 receptors

Curcuma longa is a main constituent of many traditional Chinese medicines, such as Xiaoyao-san, used to manage mental disorders effectively. Curcumin is a major active component of C. longa and its antidepressant-like effect has been previously demonstrated in the forced swimming test. The purpose of this study was to explore the possible contribution of serotonin (5-HT) receptors in the behavioral effects induced by curcumin in this animal model of depression. 5-HT was depleted by the tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA, 100 mg/kg, i.p.) prior to the administration of curcumin, and the consequent results showed that PCPA blocked the anti-immobility effect of curcumin in forced swimming test, suggesting the involvement of the serotonergic system. Moreover, pre-treatment of pindolol (10 mg/kg, i.p., a beta-adrenoceptors blocker/5-HT(1A/1B) receptor antagonist), 4-(2'-methoxy-phenyl)-1-[2'-(n-2'-pyridinyl)-p-iodobenzamino-]ethyl-piperazine (p-MPPI, 1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist), or 1-(2-(1-pyrrolyl)-phenoxy)-3-isopropylamino-2-propanol (isamoltane, 2.5 mg/kg, i.p., a 5-HT(1B) receptor antagonist) was found to prevent the effect of curcumin (10 mg/kg) in forced swimming test. On the other hand, a sub-effective dose of curcumin (2.5 mg/kg, p.o.) produced a synergistic effect when given jointly with (+)-8-hydroxy-2-(di-n-propylamino)tetralin, (8-OH-DPAT, 1 mg/kg, i.p., a 5-HT(1A) receptor agonist), anpirtoline (0.25 mg/kg, i.p., a 5-HT(1B) receptor agonist) or ritanserin (4 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist), but not with ketanserin (5 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist with higher affinity to 5-HT(2A) receptor) or R(-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 1 mg/kg, i.p., a 5-HT(2A) receptor agonist). Taken together, these results indicate that the antidepressant-like effect of curcumin in the forced swimming test is related to serotonergic system and may be mediated by, at least in part, an interaction with 5-HT(1A/1B) and 5-HT(2C) 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.     

Evidence for the involvement of the monoaminergic system, but not the opioid system in the antidepressant-like activity of ellagic acid in mice

Dietary flavonoids possess a multiplicity of neuroprotective actions in various central nervous pathophysiological conditions including depression. Ellagic acid is a polyphenolic compound that occurs in plants such as raspberries, nuts and eucalyptus species. The present study was designed to investigate the antidepressant-like effect of ellagic acid in mice using forced swimming test (FST) and tail suspension test (TST). The involvement of the monoaminergic and opioid systems in the antidepressant-like activity of ellagic acid was also studied. Our results showed that ellagic acid when administered acutely or chronically to mice (25, 50 and 100mg/kg, p.o.), produced a significant reduction in the duration of immobility, with a profile comparable to that of fluoxetine (20mg/kg, p.o.). However, ellagic acid treatment had no effect on the locomotor activity of mice when tested in actophotometer. The reduction in immobility time observed with ellagic acid treatment (50mg/kg, p.o.) was prevented by pretreatment with p-chlorophenylalanine (100mg/kg, i.p., a serotonin synthesis inhibitor), pindolol (10mg/kg, i.p., a β-adrenoceptors blocker/5HT(1A/1B) receptor antagonist), ketanserin (5mg/kg, i.p., a 5HT(2A/2B) receptor antagonist), ondansetron (1mg/kg, i.p., a 5HT(3) receptor antagonist), prazosin (1mg/kg, i.p., an α(1)-adrenoceptor antagonist) and yohimbine (1mg/kg, i.p., an α(2)-adrenoceptor antagonist), but not with naloxone (1mg/kg, i.p., an opioid receptor antagonist). Our results suggest that ellagic acid produced an antidepressant-like effect which was unrelated to its locomotor activity. Furthermore, this anti-immobility effect seems most likely to be mediated through an interaction with the monoaminergic system (serotonergic and noradrenergic systems) and not through the opioid 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.     

Involvement of 5-HT1A receptors in the antidepressant-like activity of gepirone in the forced swimming test in rats.

The antidepressant-like activity of gepirone, a drug with a high and selective affinity for 5-hydroxytryptamine1A (5-HT1A) receptors, was studied in the forced swimming test in rats. The drug, administered intraperitoneally in single doses of 2.5-20 mg/kg, potently and dose-dependently shortened the immobility time. The anti-immobility effect of gepirone (10 mg/kg) was dose-dependently antagonized by the 5-HT1A receptor and alpha 1-adrenoceptor antagonist, NAN-190 (0.25 and 0.5 mg/kg), the beta-adrenoceptor blocker with the affinity for 5-HT1A and 5-HT1B receptors, pindolol (2 and 4 mg/kg), the 5-HT1A, 5-HT2 and dopamine receptor blocker spiperone (0.01 and 0.03 mg/kg) and by the dopamine receptor antagonist, haloperidol (0.125 and 0.25 mg/kg). On the other hand, the non-selective 5-HT receptor antagonist, metergoline (2 and 4 mg/kg), the selective 5-HT2 receptor antagonist, ketanserin (1 and 2 mg/kg), the selective alpha 1-adrenoceptor blocker, prazosin (0.25 and 0.5 mg/kg) and the beta-blockers with no affinity for 5-HT receptors, betaxolol (4 and 8 mg/kg) and ICI 118,551 (4 and 8 mg/kg), did not affect the anti-immobility effect of gepirone. The effect of gepirone was not modified, either, in animals with a lesion of the 5-HT system, produced by p-chloroamphetamine (PCA, 2 x 10 mg/kg) or p-chlorophenylalanine (PCPA, 3 x 300 mg/kg). The results obtained suggest that the anti-immobility effect of gepirone is mediated by activation of 5-HT1A receptors, most probably located postsynaptically and that dopamine may be involved in this action.     

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.     

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-HT₁ and 5-HT₂ 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-HT₂ 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-HT₂ receptors while non-significant effects were obtained with 5-HT₁ receptors.     

5-HT4 receptors do not mediate the antidepressant-like behavioral effects of fluoxetine in a modified forced swim test

The receptors responsible for mediating the antidepressant effects of selective serotonin reuptake inhibitors are largely unknown. The role of the 5-HT4 receptor in mediating the antidepressant-like effects of fluoxetine in a modified rat forced swim test was examined. Fluoxetine (20 mg/kg) decreased immobility and increased swimming, a pattern shown to represent its actions on the serotonergic system. The selective 5-HT4 receptor antagonist, SB 204070A [8-amino-7-chloro-(N-butyl-4-piperidyl)methylbenzo-1, 4-dioxan-5-carboxylate hydrochloride] (0.1-3 mg/kg), failed to change any of the active behaviors in the test compared with saline-treated animals. Upon combination, SB 204070A (3 mg/kg) failed to alter the effects of fluoxetine effects in the test. These data therefore suggest that activation of postsynaptic 5-HT4 receptors, subsequent to reuptake inhibition by fluoxetine, is not necessary for its antidepressant-like behavioral effects in this test.     

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.     

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.     

A role for serotonin in the antidepressant activity of N-Nitro-L-arginine, in the rat forced swimming test

The present study determined regional serotonin (5-HT) synthesis and metabolism changes associated with the nitric oxide synthase (NOS) inhibitor N^G-nitro-L-arginine (L-NA) and the influence of 5-HT receptor blockade in the antidepressant-like actions of L-NA in the forced swimming test (FST). Regional effects of L-NA (5,10 and 20 mg/kg i.p.) on tryptophan hydroxylase (TPH) activity, the rate limiting enzyme for 5-HT synthesis, were determined by measuring accumulation of the transient intermediate 5-hydoxytryptophan (5-HTP) following in vivo administration of the amino acid decarboxylase inhibitor, NSD 1015 (100 mg/kg). L-NA (5-20 mg/kg) dose dependently increased 5-HTP accumulation, particularly in the amygdaloid cortex, following exposure to the FST. L-NA also provoked an increase in regional brain 5-HIAA concentrations and in the 5-HIAA:5-HT metabolism ratio. Co-treatment with NSD-1015 failed to consistently modify the antidepressant-like effects of L-NA in the FST. Sub-active doses of L-NA (1 mg/kg) and the 5-HT re-uptake inhibitor fluoxetine (2.5 mg/kg) acted synergistically to increase swimming in the test. Co-treatment with the non-selective 5-HT receptor antagonist metergoline (1, 2 and 4 mg/kg), attenuated the L-NA (20 mg/kg)-induced reduction in immobility and increase in swimming behaviours. Metergoline alone however provoked an increase in immobility and reduction in swimming behaviours in the test. A similar response was obtained following co-treatment with the preferential 5-HT_2A receptor antagonist ketanserin (5 mg/kg) and the 5-HT_2C receptor antagonist RO-430440 (5 mg/kg). Co-treatment with the 5-HT_1A receptor antagonist WAY 100635 (0.3 mg/kg) or the 5-HT_1B receptor antagonist GR 127935 (4 mg/kg) failed to influence the antidepressant-like activity of L-NA. Taken together these data provide further support for a role for 5-HT in the antidepressant-like properties of NOS inhibitors.     

Antidepressant-like effect of combined treatment with selective sigma receptor agonists and a 5-HT1A receptor agonist in the forced swimming test in rats

The interaction between the selective sigma (sigma) receptor agonists and 8-OH-DPAT, a serotonin (5-HT)(1A) receptor agonist, was examined in the forced swimming test in rats. The results indicate that joint administration of DTG (5 mg/kg) or SA4503 (3 mg/kg), the selective sigma(1)/sigma(2)- or sigma(1)-receptor agonists, respectively, and 8-OH-DPAT (0.1 or 0.3 mg/kg) induces an antidepressant-like effect. The doses of sigma agonists and 8-OH-DPAT used in the study were inactive per se in this model. The effect of DTG and 8-OH-DPAT co-administration was partly counteracted by WAY 100635 (0.1 mg/kg) as well as by BD 1047 (3 mg/kg), a 5-HT(1A) and sigma(1) receptor antagonists, respectively, suggesting the involvement of both receptor types in the anti-immobility effect in rats.     

Antidepressant-like effect of the selective 5-HT1B receptor agonist CP 94253: a possible mechanism of action

The mechanism of the antidepressant-like activity of the selective 5-hydroxytryptamine(1B) (5-HT(1B)) receptor agonist 5-propoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-pyrrolo[3,2-b]pyridine (CP 94253) was studied in the forced swimming test in mice. CP 94253 administered intraperitoneally at a single dose of 5 mg/kg potently shortened the immobility time of mice. The anti-immobility effect of CP 94253 was wholly blocked by the selective 5-HT(1B) receptor antagonist N-[3-(2-dimethylamino)ethoxy-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-carboxamide (SB 216641, 5 mg/kg), the dopamine D2-like receptor antagonist sulpiride (50 mg/kg) and the alpha(2)-adrenoceptor antagonist idazoxan (2 mg/kg), but was not modified in animals with a lesion of the 5-HT system produced by p-chlorophenylalanine (p-CPA, 3 x 300 mg/kg). The obtained results suggest that the anti-immobility effect of CP 94253 is mediated by activation of 5-HT(1B) receptors-most probably located postsynaptically and/or as heteroreceptors, and that the dopamine and the noradrenaline systems are involved in this action.     

Mechanism of synergistic action following co-treatment with pramipexole and fluoxetine or sertraline in the forced swimming test in rats

The aim of the present study was to examine the effect of combined treatment of male Wistar rats with pramipexole and fluoxetine or sertraline in the forced swimming test. The obtained results showed that co-treatment with pramipexole (0.1 mg/kg) and fluoxetine (10 mg/kg) or sertraline (5 mg/kg) (in doses inactive per se) exhibited antidepressant-like activity in the forced swimming test. Sulpiride (a dopamine D(2/3) receptor antagonist) and WAY 100635 (a 5-HT(1A) receptor antagonist), either being ineffective in the forced swimming test, inhibited the antidepressant-like effect induced by co-administration of pramipexole and fluoxetine or sertraline. However, SCH 23390 (a dopamine D(1) receptor antagonist) only partly did not alter the effect of pramipexole given jointly with antidepressant drugs; on the other hand, S 33084 (a dopamine D(3) receptor antagonist) only partly decreased (in a statistically insignificant manner) that effect. Moreover, progesterone and BD 1047 (a sigma(1) receptor antagonist) counteracted the antidepressant-like effect induced by co-administration of pramipexole and sertraline (but not pramipexole and fluoxetine). In that test, active behavior did not reflect the increases in general activity, since combined administration of pramipexole and fluoxetine or sertraline failed to enhance the locomotor activity of rats. None of the tested drugs (SCH 23390, sulpiride, S 33084, WAY 100635, BD 1047 and progesterone) - alone or in combination with pramipexole and fluoxetine or sertraline - changed locomotor activity. The results described in the present paper indicate that co-administration of pramipexole and fluoxetine or sertraline may induce a more pronounced antidepressive activity than does treatment with pramipexole alone, and that in addition to other mechanisms, dopamine D(2/3) and 5-HT(1A) receptors may contribute to the antidepressant-like activity of pramipexole and fluoxetine or sertraline in the forced swimming test in rats. Moreover, sigma(1) receptors may constitute one of the possible mechanisms by which co-administration of pramipexole and sertraline induces antidepressant-like activity in that test.     

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.     

Effects of co-treatment with mirtazapine and low doses of risperidone on immobility time in the forced swimming test in mice

The aim of the present study was to examine the effect of mirtazapine (MIR) and risperidone (an atypical antipsychotic drug), given separately or jointly, on immobility time in the forced swimming test in male C57BL/6J mice. Fluoxetine (FLU) was used as a reference drug. MIR (2.5, 5 and 10 mg/kg) and FLU (5 and 10 mg/kg), or risperidone in low doses (0.05 and 0.1 mg/kg) given alone did not change the immobility time of mice in the forced swimming test. Joint administration of MIR (5 and 10 mg/kg) or FLU (10 mg/kg) and risperidone (0.1 mg/kg) produced antidepressant-like activity in the forced swimming test. WAY100636 (a 5-HT(1A) receptor antagonist) inhibited, while yohimbine (an α(2)-adrenergic receptor antagonist) potentiated the antidepressant-like effect induced by co-administration of MIR and risperidone. Active behavior in that test did not reflect an increase in general activity, since combined administration of antidepressants and risperidone failed to enhance the locomotor activity of mice. The obtained results indicate that risperidone applied in a low dose enhances the antidepressant-like activity of MIR and that, among other mechanisms, 5-HT(1A)-, and α(2)-adrenergic receptors may play a role in this effect.     

Mechanisms of L-NG-nitro arginine methyl ester-induced antinociception in mice: a role for serotonergic and adrenergic neurons.

1. The mechanisms involved in the antinociceptive action of L-NG-nitro arginine methyl ester (L-NAME) were investigated in mice. 2. Intraperitoneal administration of L-NAME produced a dose-dependent antinociception in the tail-flick, hot-plate and phenyl-p-quinone-induced writhing tests. 3. Pretreatment with the catecholamine depletors 6-hydroxydopamine (5 micrograms i.c.v.) or reserpine (5 mg/kg i.p.) or the serotonin synthesis inhibitor, p-chlorophenylalanine methyl ester (200 mg/kg i.p. on 2 consecutive days) resulted in a significant decrease in the antinociceptive effect of L-NAME. 4. Similarly, pretreatment with the selective alpha 1-adrenoceptor antagonist prazonin (2.5 mg/kg, i.p.), or the non-selective alpha-adrenoceptor blocker, phentolamine (5 mg/kg, i.p.) antagonized the antinociceptive effect of L-NAME. 5. However, the administration of the selective alpha 2-adrenoceptor antagonist, idazoxan (2.5 mg/kg i.p.) was without effect. 6. Likewise, pretreatment with the serotonin 5-HT2 receptor blocker, ketanserin (1 mg/kg, i.p.), the D2 dopamine receptor antagonist (+/-) sulpiride (30 mg/kg, i.p.) or the opioid antagonist naloxone (5 mg/kg, i.p.) did not inhibit the antinociceptive effect of L-NAME. 7. These results suggest that L-NAME produces antinociception in the mouse probably by an action on adrenergic and serotonergic synapses.     

脑5-HT1A/1B、α2受体及腺苷酸环化酶参与了胍丁胺的抗抑郁作用

为了在单胺受体及受体后腺苷酸环化酶(adenylate cyclase,AC)水平探讨胍丁胺(agmatine,AGM)抗抑郁作用的精细机制,采用小鼠悬尾实验和强迫游泳实验观察AGM抗抑郁行为改变。采用放射免疫方法测定大鼠前额皮层突触膜蛋白AC活性。结果表明,AGM(5～40 mg·kg^-1,ig)在小鼠悬尾实验和强迫游泳实验模型上均有显著抗抑郁活性。同时伍用β受体/5-HT_1A/1B受体阻断剂吲哚洛尔(pindolol, PIN, 20 mg·kg^-1, ip)、 α₂肾上腺素受体拮抗剂育亨宾(yohimbine, YOH, 5～10 mg·kg^-1, ip)或咪唑克生(idazoxan, IDA, 4 mg·kg^-1, ip)对AGM(40 mg·kg^-1, ig)的抗抑郁活性具有显著拮抗效应; 而β受体阻断剂普萘洛尔(propranolol, PRO, 5～20 mg·kg^-1, ip)或5-HT₃受体拮抗剂曲匹西隆(tropisetron, TRO, 5～40 mg·kg^-1, ip)对AGM(40 mg·kg^-1, ig)的抗抑郁活性无显著影响。AGM(0.1～6.4 μmol·L^-1)与大鼠前额皮层提取的突触膜共孵可剂量依赖地激活AC活性, 而PIN(1 μmol·L^-1)或YOH(0.25～1 μmol·L^-1)均显著拮抗AGM(6.4 μmol·L^-1)对AC的激活作用; 慢性给予大鼠AGM(10 mg·kg^-1, ig, bid)或氟西汀(fluoxetine, FLU, 10 mg·kg^-1, ig, bid) 2 w也显著增强大鼠前额皮层基础及Gpp(NH)p 预激活的AC活性。本研究表明, 调节脑内5-HT_1A/1B和α₂等受体功能, 并激活前额皮层AC可能是AGM抗抑郁活性的重要机制之一。     

Evidence that imipramine activates 5-HT1C receptor function.

The anti-immobility effect of imipramine (15 mg/kg) in the forced swimming test in mice was antagonized by the non-selective 5-hydroxytryptamine (5-HT) antagonist, metitepine (0.5 mg/kg), by the 5-HT1C/5-HT2 antagonist, mesulergine (15 mg/kg), and by the dopamine D2 antagonist, d,l-sulpiride (50 mg/kg). These three antagonists did not alter the behaviour of imipramine-treated mice in an open-field and did not reduce imipramine brain levels. The 5-HT2 antagonist, ritanserin (0.06 mg/kg), the 5-HT1A/5-HTB antagonist, l-propranolol (20 mg/kg), and the 5-HT3 antagonists, endo-2,3-dihydro-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2-oxo-1H- benzimidazole-1-carboxamide hydrochloride (DAU 6215; 0.1 mg/kg) and 1,2,3,9-tetrahydro-9-methyl-3[(2-methyl-1H-imidazol-1-yl)methyl]-4H- carbazol-4-one, HCl.2H2O) (GR 38032F; 0.1 mg/kg), failed to reduce imipramine-induced anti-immobility. Subthreshold doses of 8-hydroxy-2-(di-n-propylamino)tetralin hydrochloride (8-OH-DPAT; 0.5 mg/kg) and imipramine (7.5 mg/kg) did not synergize in reducing immobility. d,l-Sulpiride, but not mesulergine, antagonized the effect of desipramine (15 mg/kg) in the forced swimming test. All compounds were administered i.p. 6 min before imipramine or desipramine, given i.p. 30 min before the testing. Imipramine produced 50% inhibition of [3H]mesulergine binding to 5-HT1C receptors at 10 microM, a concentration below that obtained following i.p. imipramine administration. The results suggest a contribution of 5-HT1C receptors in the mechanism of the imipramine effect in the forced swimming test.