Antidepressant-like action of the ethanolic extract from Tabebuia avellanedae in mice: Evidence for the involvement of the monoaminergic system

The antidepressant-like effect of the ethanolic extract obtained from barks of Tabebuia avellanedae, a plant widely employed in folk medicine, was investigated in two predictive models of depression: forced swimming test (FST) and tail suspension test (TST) in mice. Additionally, the mechanisms involved in this antidepressant-like action and the effects of the association of the extract with the antidepressants fluoxetine, desipramine and bupropion in the TST were investigated. The extract from T. avellanedae produced an antidepressant-like effect, in the FST (100 mg/kg, p.o.) and in the TST (10–300 mg/kg, p.o.), without accompanying changes in ambulation when assessed in the open-field test. The anti-immobility effect of the extract (30 mg/kg, p.o.) in the TST was prevented by pre-treatment of mice with ketanserin (5 mg/kg, i.p., a preferential 5-HT_2A receptor antagonist), prazosin (1 mg/kg, i.p., an α₁-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α₂-adrenoceptor antagonist), propranolol (2 mg/kg, i.p., a β-adrenoceptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D₂ receptor antagonist) and SCH23390 (0.05 mg/kg, s.c., a dopamine D₁ receptor antagonist). The combined administration of a subeffective dose of WAY100635 (0.1 mg/kg, s.c., a selective 5-HT_1A receptor antagonist) and a subeffective dose of the extract (1 mg/kg, p.o.) produced a significant reduction in the immobility time in the TST. In addition, the combination of fluoxetine (1 mg/kg, p.o.), desipramine (0.1 mg/kg, p.o.), or bupropion (1 mg/kg, p.o.) with a subeffective dose of the extract (1 mg/kg, p.o.) produced a synergistic antidepressant-like effect in the TST, without causing hyperlocomotion in the open-field test. It may be concluded that the extract from T. avellanedae produces an antidepressant-like effect in the FST and in the TST that is dependent on the monoaminergic system. Taken together, our results suggest that T. avellanedae deserves further investigation as a putative alternative therapeutic tool that could help the conventional pharmacotherapy of depression.     

Antidepressant-like effect of the extract of Rosmarinus officinalis in mice: Involvement of the monoaminergic system

Rosemary, Rosmarinus officinalis L. (Labiatae) has several therapeutic applications in folk medicine in curing or managing a wide range of diseases, including depression. In this study, the effect of the hydroalcoholic extract of the stems and leaves of this plant was investigated in two behavioral models, the forced swimming test (FST) and tail suspension test (TST) in mice. The extract of R. officinalis produced an antidepressant-like effect, since the acute treatment of mice with the extract by p.o. route significantly reduced the immobility time in the FST (100 mg/kg) and TST (10–100 mg/kg), as compared to a control group, without accompanying changes in ambulation in the open-field test. Moreover, the repeated administration (14 days) of the hydroalcoholic extract of R. officinalis by p.o. route also produced an antidepressant-like effect in the TST (100–300 mg/kg). The pretreatment of mice with p-chlorophenylalanine (PCPA, 100 mg/kg, i.p., an inhibitor of serotonin synthesis, for 4 consecutive days), NAN-190 (0.5 mg/kg, i.p., a 5-HT_1A receptor antagonist), ketanserin (5 mg/kg, i.p., a 5-HT_2A receptor antagonist), 1-(m-chlorophenyl) biguanide (mCPBG, 10 mg/kg, i.p., a 5-HT₃ receptor agonist), prazosin (1 mg/kg, i.p., an α_1-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), but not yohimbine (1 mg/kg, i.p., an α_2-adrenoceptor antagonist) was able to reverse the anti-immobility effect of the extract (10 mg/kg, p.o.) in the TST. The combination of MDL72222, (0.1 mg/kg, i.p., a 5-HT₃ receptor antagonist) with a sub-effective dose of the extract of R. officinalis (1 mg/kg, p.o.) produced an anti-immobility effect in the TST. The results suggest that the antidepressant action of the extract of R. officinalis is mediated by an interaction with the monoaminergic system and that this plant should be further investigated as an alternative therapeutic approach for the treatment of depression.     

Evidence for the involvement of the serotonergic 5-HT2A/C and 5-HT3 receptors in the antidepressant-like effect caused by oral administration of bis selenide in mice

The present study investigated a possible antidepressant-like activity of bis selenide using two predictive tests for antidepressant effect on rodents: the forced swimming test (FST) and the tail suspension test (TST). Bis selenide (0.5–5 mg/kg, p.o.) decreased the immobility time in the mouse FST and TST. The anti-immobility effect of bis selenide (1 mg/kg, p.o.) in the TST was prevented by the pretreatment of mice with p-chlorophenylalanine methyl ester (PCPA; 100 mg/kg, i.p., an inhibitor of serotonin synthesis), ketanserin (1 mg/kg, i.p., a 5-HT_2A/2C receptor antagonist), and ondasentron (1 mg/kg, i.p., a 5-HT₃ receptor antagonist). Pretreatment of mice with prazosin (1 mg/kg, i.p., an α₁-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α₂-adrenoceptor antagonist), propranolol (2 mg/kg, i.p., a β-adrenoceptor antagonist), SCH23390 (0.05 mg/kg, s.c., a dopamine D₁ receptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D₂ receptor antagonist), or WAY 100635 (0.1 mg/kg, s.c., a selective 5-HT_1A receptor antagonist) did not block the antidepressant-like effect of bis selenide (1 mg/kg, p.o.) in the TST. Administration of bis selenide (0.1 mg/kg, p.o.) and fluoxetine (1 mg/kg), at subeffective doses, produced an antidepressant-like effect in the TST. Bis selenide did not alter Na⁺ K⁺ ATPase, MAO-A and MAO-B activities in whole brains of mice. Bis selenide produced an antidepressant-like effect in the mouse TST and FST, which may be related to the serotonergic system (5-HT_2A/2C and 5-HT₃ receptors).     

Evidence for the involvement of the monoaminergic system in the antidepressant-like effect of magnesium

Literature data has shown that acute administration of magnesium reduces immobility time in the mouse forced swimming test (FST), which suggests potential antidepressant activity in humans. However, its mechanism of action is not completely understood. Thus, this study is aimed at investigating the antidepressant-like action of magnesium and the possible involvement of the monoaminergic system in its effect in the FST. The immobility time in the FST was significantly reduced by magnesium chloride administration (30–100 mg/kg, i.p.) without accompanying changes in ambulation when assessed in an open-field test. The pre-treatment of mice with NAN-190 (0.5 mg/kg, i.p. a 5-HT_1A receptor antagonist), WAY100635 (0.1 mg/kg, s.c., a selective 5-HT_1A receptor antagonist), ritanserin (4 mg/kg, i.p., a 5-HT_2A/2C receptor antagonist), ketanserin (5 mg/kg, a preferential 5-HT_2A receptor antagonist), prazosin (1 mg/kg, i.p., an α₁-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α₂-adrenoceptor antagonist), haloperidol (0.2 mg/kg, i.p., a non selective dopaminergic receptor 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) 30 min before the administration of magnesium chloride (30 mg/kg, i.p.) significantly prevented its anti-immobility effect in the FST. Moreover, the administration of sub-effective doses of fluoxetine (10 mg/kg, i.p., serotonin reuptake inhibitor), imipramine (5 mg/kg, i.p., a mixed serotonergic noradrenergic reuptake inhibitor), bupropion (1 mg/kg, i.p., dopamine reuptake inhibitor) was able to potentiate the action of sub-effective doses of magnesium chloride. In conclusion, the present study provides evidence indicating that the antidepressant-like effect of magnesium in the FST is dependent on its interaction with the serotonergic (5-HT_1A and 5-HT_2A/2C receptors), noradrenergic (α₁- and α₂- receptors) and dopaminergic (dopamine D₁ and D₂ receptors) systems.     

Evidence for the involvement of the monoaminergic system in the antidepressant-like action of two 4-amine derivatives of 10,11-dihydro-5H-dibenzo [a,d] cycloheptane in mice evaluated in the tail suspension test

Our previous study described the synthesis of 4-amine derivatives of 10,11-dihydro-5H-dibenzo-alkylamine-cycloheptane, 4-amine (3-N,N-dimethylpropylamine)-10,11-dihydro-5H-dibenzo[a,d] cycloheptane-5-one (ADDCH1), and 1,2,3,4,8,9-hexahydro-dibenzocycloheptane[4,4a,5-ef]1,4-diazepin (ADDCH2), and the characterization of their antidepressant-like effect in the forced swimming test in mice. This study investigated the involvement of monoaminergic pathways in the antidepressant-like effect of these compounds in mice evaluated in the tail suspension test (TST), another animal model to screen antidepressant drugs. Our results show that the immobility time in the TST was significantly reduced by ADDCH1 (15 to 50 mg/kg, i.p.) or ADDCH2 (30 and 50 mg/kg, i.p.). The antidepressant-like effect of ADDCH1 (30 mg/kg, i.p.) in the TST was prevented by pre-treatment of mice with methysergide (2 mg/kg, i.p.), a non-selective serotonin receptor antagonist, p-chlorophenylalanine methylester (pCPA, 100 mg/kg, i.p.), an inhibitor of serotonin synthesis, prazosin (62.5 microg/kg, i.p.), an alpha1-adrenoceptor antagonist, or yohimbine (1 mg/kg, i.p.), an alpha2-adrenoceptor antagonist. In contrast, the antidepressant-like effect of ADDCH2 was antagonized only by yohimbine (1 mg/kg) or haloperidol (50 microg/kg, i.p.), a dopamine D2/D3/D4 receptor antagonist, and was not affected by methysergide, pCPA or prazosin. Altogether, the present results strongly suggest the differential involvement of monoaminergic systems, serotonin/noradrenaline (ADDCH1) and noradrenaline/dopamine (ADDCH2) pathways, respectively, in the antidepressant-like effect of dibenzosuberone compounds.     

Antidepressant-like effect of Valeriana glechomifolia Meyer (Valerianaceae) in mice

The antidepressant-like effect of a supercritical CO₂ (SCCO₂) Valeriana glechomifolia extract enriched in valepotriates was investigated in a mice tail suspension test (TST) and forced swimming test (FST). The SCCO₂ extract decreased mice immobility in the FST (0.5-20 mg/kg p.o.) and elicited a biphasic dose-response relationship in the TST (1-20 mg/kg p.o.) with no alterations in locomotor activity and motor coordination (assessed in the open-field and rota-rod tests, respectively). The anti-immobility effect of the SCCO₂ extract (5 mg/kg, p.o.) was prevented by mice pre-treatment with yohimbine (1 mg/kg, i.p., an α2 adrenoceptor antagonist), SCH 23390 (15 μg/kg, s.c., D₁ dopamine receptor antagonist) and sulpiride (50 mg/kg, i.p., D₂ dopamine receptor antagonist). However, mice pre-treatments with prazosin (1 mg/kg, i.p., α1 adrenoceptor antagonist) and p-chlorophenilalanine methyl ester (4 × 100 mg/kg/day, i.p., a serotonin synthesis inhibitor) were not able to block the anti-immobility effect of the SCCO₂ extract. Administration (p.o.) of the SCCO₂ extract (0.25 mg/kg) and imipramine (10 mg/kg), desipramine (5 mg/kg) and bupropion (3 mg/kg) at sub-effective doses significantly reduced mice immobility time in the FST. These data provide the first evidence of the antidepressant-like activity of V. glechomifolia valepotriates, which is due to an interaction with dopaminergic and noradrenergic neurotransmission.     

Ascorbic acid administration produces an antidepressant-like effect: Evidence for the involvement of monoaminergic neurotransmission

Ascorbic acid is highly concentrated in the brain, being considered as a neuromodulator. This study investigated the effect of ascorbic acid in the tail suspension test (TST) and in the forced swimming test (FST) in mice and the contribution of the monoaminergic system to its antidepressant-like effect. Moreover, the effects of fluoxetine, imipramine and bupropion in combination with ascorbic acid in the TST were investigated. Ascorbic acid (0.1–10 mg/kg, i.p., 1–10 mg/kg p.o. or 0.1 nmol/mice i.c.v.) produced an antidepressant-like effect in the TST, but not in the FST, without altering the locomotor activity. The effect of ascorbic acid (0.1 mg/kg, i.p.) in the TST was prevented by i.p. pre-treatment with NAN-190 (0.5 mg/kg), ketanserin (5 mg/kg), MDL72222 (0.1 mg/kg), prazosin (62.5 µg/kg), yohimbine (1 mg/kg), propranolol (2 mg/kg), haloperidol (0.2 mg/kg), sulpiride (50 mg/kg), but not with SCH23390 (0.05 mg/kg, s.c.). Additionally, ascorbic acid (1 mg/kg, p.o.) potentiated the effect of subeffective doses (p.o. route) of fluoxetine (1 mg/kg), imipramine (0.1 mg/kg), or bupropion (1 mg/kg) in the TST. The combined treatment of ascorbic acid with antidepressants produced no alteration in the locomotion in the open-field test. In conclusion, our results show that administration of ascorbic acid produces an antidepressant-like effect in TST, which is dependent on its interaction with the monoaminergic system. Moreover, ascorbic acid caused a synergistic antidepressant-like effect with conventional antidepressants. Therefore, the present findings warrant further studies to evaluate the therapeutical relevance of ascorbic acid for the treatment of depression and as a co-adjuvant treatment with antidepressants.     

Monoaminergic agents modulate antidepressant-like effect caused by diphenyl diselenide in rats

In this study, the antidepressant-like effect caused by diphenyl diselenide on rat forced swimming test (FST) was investigated. The involvement of the monoaminergic system in the antidepressant-like effect was also evaluated. Diphenyl diselenide (0.1-30 mg/kg), given by oral route (p.o.), 30 min earlier, reduced the immobility time in the FST, without accompanying changes in ambulation when assessed in an open field. The anti-immobility effect of diphenyl diselenide (1 mg/kg, p.o.) on the FST was prevented by pretreatment of rats with p-chlorophenylalanine methyl ester (PCPA; 100 mg/kg, i.p., an inhibitor of serotonin synthesis, given once a day, for 3 consecutive days), WAY100635 (0.1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist), ketanserin (1 mg/kg, i.p., a 5-HT(2A)/(2C) receptor antagonist), ondasentron (1 mg/kg, i.p., a 5-HT(3) receptor antagonist), haloperidol (1 mg/kg, i.p., a D(1), D(2) and D(3) receptor antagonist), SCH233390 (0.05 mg/kg, s.c., a D(1) receptor antagonist), sulpiride (50 mg/kg, i.p., a D(2) receptor antagonist), prazosin (1 mg/kg, i.p., an alpha(1)-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an alpha(2)-adrenoceptor antagonist). However, the anti-immobility effect caused by diphenyl diselenide (1 mg/kg, p.o.) on the FST was not affected by pretreatment with propanolol (2 mg/kg, i.p., a beta-adrenoceptor antagonist). Furthermore, monoamine oxidase (MAO) activity was inhibited (39%) in the animals treated with diphenyl diselenide (30 mg/kg, p.o.) when compared to the control group. Taken together these data demonstrated that the antidepressant-like effect caused by diphenyl diselenide seems to be mediated by involvement of the central monoaminergic system.     

Evidence for serotonin receptor subtypes involvement in agmatine antidepressant like-effect in the mouse forced swimming test

This study investigated the involvement of 5-HT(1) and 5-HT(2) receptors in the antidepressant-like effect of agmatine in the mouse forced swimming test (FST). Pretreatment with p-chlorophenylalanine methyl ester (PCPA; 100 mg/kg, intraperitoneally (i.p.), an inhibitor of serotonin synthesis, for 4 consecutive days), methysergide (5 mg/kg, i.p., a serotonin (5-HT) antagonist), pindolol (32 mg/kg, i.p., a 5-HT(1A/1B) receptor/beta-adrenoceptor antagonist), N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridynyl)cyclohexanecarboxamide (WAY 100635; 0.3 mg/kg, subcutaneously (s.c.), a selective 5-HT(1A) receptor antagonist), 1-(2-methoxyphenyl)-4[-(2-phthalimido)butyl]piperazine) (NAN-190; 0.5 mg/kg, i.p., a 5-HT(1A) receptor antagonist), 1-(2-(1-pyrrolyl)-phenoxy)-3-isopropylamino-2-propanol (isamoltane; 2.5 mg/kg, i.p., a 5-HT(1B) receptor antagonist), cyproheptadine (3 mg/kg, i.p., a 5-HT(2) antagonist) or ketanserin (5 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist), but not with propranolol (2 mg/kg, i.p., a beta-adrenoceptor antagonist), prevented the effect of agmatine (10 mg/kg, i.p.) in the FST. A subeffective dose of agmatine (0.001 mg/kg, i.p.) produced a synergistic antidepressant-like effect with pindolol (32 mg/kg), NAN-190 (0.5 mg/kg, i.p.), WAY 100635 (0.03 mg/kg, s.c.), (+)-8-hydroxy-2-(di-n-propylamino)tetralin HBr (8-OH-DPAT; 0.01 mg/kg, i.p., a 5-HT(1A) receptor agonist), R(-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI; 1 mg/kg, i.p., a preferential 5-HT(2A) receptor agonist), or fluoxetine (10 mg/kg, i.p., a selective serotonin reuptake inhibitor, SSRI) but not with isamoltane (2.5 mg/kg, i.p.), ritanserin (4 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist) or ketanserin (5 mg/kg, i.p.). Taken together, the results firstly demonstrate that agmatine antidepressant-like effects in the FST seem to be mediated, at least in part, by an interaction with 5-HT(1A/1B) and 5-HT(2) receptors.     

Involvement of 5-HT1A receptors in the antidepressant-like effect of adenosine in the mouse forced swimming test

This study investigated the involvement of 5-HT1 and 5-HT2 receptors in the antidepressant-like effect of adenosine in the mouse forced swimming test (FST). The pre-treatment of mice with PCPA (100mg/kg, i.p., an inhibitor of serotonin synthesis, for four consecutive days), NAN-190 (0.5mg/kg, i.p., a 5-HT1A receptor antagonist), pindolol (32 mg/kg, i.p., a 5-HT1A/1B receptor/beta-adrenoceptor antagonist) or WAY100635 (0.1 and 0.3mg/kg, s.c., a selective 5-HT1A receptor antagonist), but not with ketanserin (5mg/kg, i.p., a 5-HT2A/2C receptor antagonist), prevented the antidepressant-like effect of adenosine (10mg/kg, i.p.) in the FST. Moreover, the pre-treatment of animals with WAY100635 (0.1mg/kg, s.c.) blocked the decrease in immobility time in the FST elicited by adenosine (5 or 10mg/kg, i.p.), but produced a synergistic effect with a sub-effective dose of adenosine (1mg/kg, i.p.) and did not cause any alteration at the highest dose of adenosine administered (50mg/kg, i.p.). Adenosine (1mg/kg, i.p.) produced a synergistic antidepressant-like effect with pindolol (32 mg/kg), NAN-190 (0.5mg/kg, i.p.), WAY100635 (0.03 mg/kg, s.c.), 8-OH-DPAT (1mg/kg, i.p., a 5-HT1A receptor agonist), but not with DOI (1mg/kg, i.p., a preferential 5-HT2A receptor agonist) or ketanserin. The pre-treatment of mice with DPCPX (2mg/kg, i.p., a selective adenosine A1 receptor antagonist) or ZM241385 (1mg/kg, i.p., a selective adenosine A2A receptor antagonist) did not prevent the effect of fluoxetine (32 mg/kg, i.p., a preferential serotonin reuptake inhibitor) in the FST. Besides that, adenosine (1mg/kg, i.p.) did not produce a synergistic antidepressant-like effect with fluoxetine (10mg/kg, i.p.). Taken together, the results indicate that the antidepressant-like effect of adenosine in the FST appears to be mediated, at least in part, by an interaction with 5-HT1A receptors.     

Antidepressant-like activity of Glycyrrhiza glabra L. in mouse models of immobility tests

The present study was undertaken to investigate the effects of aqueous extract of Glycyrrhiza glabra L. (Family: Fabaceae), popularly known as liquorice, on depression in mice using forced swim test (FST) and tail suspension test (TST). The extract of G. glabra (75, 150, and 300 mg/kg) was administered orally for 7 successive days in separate groups of Swiss young male albino mice. The dose of 150 mg/kg of the extract significantly reduced the immobility times of mice in both FST and TST, without any significant effect on locomotor activity of mice. The efficacy of extract was found to be comparable to that of imipramine (15 mg/kg i.p.) and fluoxetine (20 mg/kg i.p.). Liquorice extract reversed reserpine-induced extension of immobility period of mice in FST and TST. Sulpiride (50 mg/kg i.p.; a selective D2 receptor antagonist) and prazosin (62.5 microg/kg i.p.; an alpha1-adrenoceptor antagonist) significantly attenuated the extract-induced antidepressant-like effect in TST. On the other hand, p-chlorophenylalanine (100 mg/kg i.p.; an inhibitor of serotonin synthesis) did not reverse antidepressant-like effect of liquorice extract. This suggests that antidepressant-like effect of liquorice extract seems to be mediated by increase of brain norepinephrine and dopamine, but not by increase of serotonin. Monoamine oxidase inhibiting effect of liquorice may be contributing favorably to the antidepressant-like activity. Thus, it is concluded that liquorice extract may possess an antidepressant-like effect.     

Uliginosin B, a phloroglucinol derivative from Hypericum polyanthemum: a promising new molecular pattern for the development of antidepressant drugs

In this study we have demonstrated that cyclohexane extract of Hypericum polyanthemum (POL) and its main phloroglucinol derivative uliginosin B (ULI) present antidepressant-like activity in rodent forced swimming test (FST). The involvement of monoaminergic neurotransmission on the antidepressant-like activity of ULI was evaluated in vivo and in vitro. POL 90 mg/kg (p.o.) and ULI 10 mg/kg (p.o.) reduced the immobility time in the mice FST without altering locomotion activity in the open-field test. The combination of sub-effective doses of POL (45 mg/kg, p.o.) and ULI (5 mg/kg, p.o.) with sub-effective doses of imipramine (10 mg/kg, p.o.), bupropion (3 mg/kg, p.o.) and fluoxetine (15 mg/kg, p.o.) induced a significant reduction on immobility time in FST. The pretreatment with SCH 23390 (15 μg/kg, s.c., dopamine D1 receptor antagonist), sulpiride (50 mg/kg, i.p., dopamine D2 receptor antagonist), prazosin (1 mg/kg, i.p., α1-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., α2-adrenoceptor antagonist) and pCPA (100 mg/kg/day, i.p., p-chlorophenilalanine methyl ester, inhibitor of serotonin synthesis, for four consecutive days) before ULI administration (10 mg/kg, p.o.) significantly prevented the anti-immobility effect in FST. ULI was able to inhibit synaptosomal uptake of dopamine (IC₅₀ = 90 ± 38 nM), serotonin (IC₅₀ = 252 ± 13 nM) and noradrenaline (280 ± 48 nM), but it did not bind to any of the monoamine transporters. These data firstly demonstrated the antidepressant-like effect of POL and ULI, which depends on the activation of the monoaminergic neurotransmission in a different manner from the most antidepressants.     

The potential antidepressant-like effect of imidazoline I2 ligand 2-BFI in mice

The compound 2-(2-benzofuranyl)-2-imidazoline (2-BFI) is a 2-imidazoline derivative that selectively inhibits the in vitro activity of monoamine oxidase-A and it is also an imidazoline I(2) agonist. However, the antidepressant potential of this compound and its mechanism of action have not been well defined. Therefore, in this study we investigated the antidepressant-like effect of 2-BFI in mice. 2-BFI (100 and 300μmol/kg, s.c.) significantly reduced the immobility time on the tail suspension test (TST) without changing locomotion in the open field test. The reduced the immobility time of 2-BFI (100μmol/kg, s.c.) was confirmed with the forced swimming test (FST). The antidepressant-like effect of 2-BFI (100μmol/kg, s.c.) in the TST was prevented by pretreatment with idazoxan (0.4μmol/kg, i.p., a I(2) site antagonist), methysergide (4μmol/kg, i.p., a non-selective serotonergic receptor antagonist) and haloperidol (0.1μmol/kg, i.p., a non-selective dopaminergic receptor antagonist). The anxiolytic effect of 2-BFI was also evaluated, using the elevated plus-maze test. 2-BFI (300μmol/kg, s.c.) was able to significantly increase the % of number of entries and the % of time spent in the open arms, indicating that it possesses an anxiolytic effect at high doses. In conclusion, these results suggest that the antidepressant-like effect of 2-BFI might involve serotonergic, dopaminergic and imidazoline systems, and then the imidazoline site could represent a new pharmacological target for the treatment of depression.     

Effect of delta-9-tetrahydrocannabinol on behavioral despair and on pre- and postsynaptic serotonergic transmission

Preclinical and clinical studies suggest that direct and indirect cannabinoid agonists, including enhancers of endocannabinoids, engender stress-relieving, anxiolytic and antidepressant effects, mediated by central CB(1) receptors (CB(1)Rs). The effect of the main pharmacologically active principle in cannabis, (-)-trans-Δ(9)-tetrahydrocannabinol (delta-9-THC), on depressive behavior and on the serotonin (5-HT) system, which is implicated in the mechanism of action of antidepressants, has not been extensively clarified. Here, we showed that repeated (5 days), but not single (acute) intraperitoneal (ip) treatment with delta-9-THC (1mg/kg) exerts antidepressant-like properties in the rat forced swim test (FST). This effect was CB(1)R-dependent because it was blocked by the CB(1)R antagonist rimonabant (1mg/kg, ip). Using in vivo electrophysiology, we demonstrated that delta-9-THC modulated dorsal raphe (DR) 5-HT neuronal activity through a CB(1)R-dependent mechanism. Acute intravenous delta-9-THC administration (0.1-1.5mg/kg) elicited a complex response profile, producing excitatory, inhibitory and inert responses of 5-HT neurons. Only excitatory responses were blocked by rimonabant. Finally, repeated but not single delta-9-THC administration (1mg/kg, ip) enhanced tonic 5-HT(1A) receptor activity in the hippocampus, a postsynaptic event commonly elicited by standard antidepressants. These results suggest that delta-9-THC, like other CB(1)R agonists and endocannabinoid enhancers, may possess antidepressant properties at low doses, and could modulate 5-HT transmission in the DR and hippocampus as standard antidepressants such as selective serotonin reuptake inhibitors.     

Involvement of mGlu5 and NMDA receptors in the antidepressant-like effect of acamprosate in the tail suspension test

Accumulating evidence supports the hypothesis that modulation of glutamatergic system via NMDA receptors and mGlu5 receptors might be an effective antidepressant therapy. However, clinical application of NMDA and mGlu5 antagonists in the therapy of depression is still an open question. In the present study we investigated potential antidepressant-like effect of a functional NMDA and mGlu5 receptor antagonist, acamprosate, which has been used in the therapy of human alcoholics as an anti-craving drug for more than 20 years and is considered as a safe substance. We have found potential antidepressant-like effect of acamprosate at doses of 100-400 mg/kg in the TST in C57BL/6J mice. Furthermore we have shown that the antidepressant-like effect of acamprosate used at a dose of 200 mg/kg was dependent on NMDA and mGlu5 receptor blockade, since NMDA (25 mg/kg) and mGlu5 receptor positive allosteric modulator, CDPPB (3 mg/kg), antagonized its activity in the TST. These data suggest that acamprosate may induce antidepressant-like effect and that NMDA and mGlu5 receptors are crucial targets of acamprosate in this action.     

Antidepressant-like effect of the methanolic extract from Bupleurum falcatum in the tail suspension test

In traditional Oriental medicine, some herbal combinations that include Bupleurum falcatum (BFM) as a major ingredient are known to effectively treat depressive-like disorders. In the present study, the antidepressant-like effect of methanolic extract of BFM and its neuropharmacological mechanism were investigated in mice. After oral administration of BFM extract, a tail suspension test (TST) and open field test (OFT) were performed to assess the antidepressant activity and psycho-stimulant side-effects, respectively. Pre-treatment with p-chlorophenylalanine (PCPA, a serotonin synthesis inhibitor) and α-methyl-p-tyrosine (AMPT, a catecholamine synthesis inhibitor) was used to assess the influence of BFM extract on the antidepressant activity in the TST. At doses of 150 and 300 mg/kg body weight, p.o., the BFM extract significantly reduced the total duration of immobility in the TST, while individual differences in locomotor activities between experimental groups were not observed in the OFT. Moreover, pre-treatment with PCPA (100 mg/kg i.p., for 4 consecutive days) or AMPT (100 mg/kg i.p.) significantly inhibited the antidepressant-like activity of BFM extract (300 mg/kg p.o.), as well as we confirmed the reversal of the antidepressant effect of fluoxetine (30 mg/kg i.p.) by PCPA and bupropion (20 mg/kg i.p.) by AMPT in the TST. Taken together, these findings suggest that the methanolic BFM extract has dose-dependent possibility of antidepressant-like activity valuable to alternative therapy for depression and that the mechanism of action involves the serotonergic and noradrenergic systems although underlying mechanism still remains to be further elucidated.     

The opposite effect of a 5-HT(1B) receptor agonist on 5-HT synthesis, as well as its resistant counterpart, in an animal model of depression

Flinders Sensitive Line (FSL) rat is as an animal model of depression with altered parameters of the serotonergic (5-HT) system function (5-HT synthesis rates, tissue concentrations, release, receptor density and affinity), as well as an altered sensitivity of these parameters to different 5-HT based antidepressants. The effects of acute and chronic treatments with the 5-HT(1B) agonist, CP-94253 on 5-HT synthesis, in the FSL rats and the Flinders Resistant Line (FRL) controls were measured using α-[(14)C]methyl-L-tryptophan (α-MTrp) autoradiography. CP-94253 (5mg/kg), or an adequate volume of saline, was injected i.p. as a single dose in the acute experiment or delivered via the subcutaneously implanted osmotic minipump (5 mg/kg/day for 14 days) in the chronic experiment. The acute treatment with CP-94253 significantly decreased the 5-HT synthesis in both the FRL and FSL rats, with a more widespread effect in the FRL rats. Chronic treatment with CP-94253 significantly decreased 5-HT synthesis in the FRL rats, while 5-HT synthesis in the FSL rats was significantly increased throughout the brain. In both the acute and chronic experiment, the FRL rats had higher brain 5-HT synthesis rates, relative to the FSL rats. The shift in the direction of the treatment effect from acute to chronic, using the 5-HT(1B) agonist, CP-94253, on 5-HT synthesis in the FSL model of depression, with an opposite effect on the control FRL rats, suggests the differential adaptation of the 5-HT system in the FSL and FRL rats to chronic stimulation of 5-HT(1B) receptors.     

Guanosine produces an antidepressant-like effect through the modulation of NMDA receptors, nitric oxide-cGMP and PI3K/mTOR pathways

Guanosine is an extracellular signaling molecule implicated in the modulation of glutamatergic transmission and neuroprotection. The present study evaluated the antidepressant-like effect of guanosine in the forced swimming test (FST) and in the tail suspension test (TST) in mice. The contribution of NMDA receptors as well as l-arginine-NO-cGMP and PI3K-mTOR pathways to this effect was also investigated. Guanosine administered orally produced an antidepressant-like effect in the FST (0.5-5mg/kg) and TST (0.05-0.5mg/kg). The anti-immobility effect of guanosine in the TST was prevented by the treatment of mice with NMDA (0.1pmol/site, i.c.v.), d-serine (30μg/site, i.c.v., a co-agonist of NMDA receptors), l-arginine (750mg/kg, i.p., a substrate for nitric oxide synthase), sildenafil (5mg/kg, i.p., a phosphodiesterase 5 inhibitor), LY294002 (10μg/site, i.c.v., a reversible PI3K inhibitor), wortmannin (0.1μg/site, i.c.v., an irreversible PI3K inhibitor) or rapamycin (0.2nmol/site, i.c.v., a selective mTOR inhibitor). In addition, the administration of ketamine (0.1mg/kg, i.p., a NMDA receptor antagonist), MK-801 (0.001mg/kg, i.p., another NMDA receptor antagonist), 7-nitroindazole (50mg/kg, i.p., a neuronal nitric oxide synthase inhibitor) or ODQ (30pmol/site i.c.v., a soluble guanylate cyclase inhibitor) in combination with a sub-effective dose of guanosine (0.01mg/kg, p.o.) reduced the immobility time in the TST when compared with either drug alone. None of the treatments affected locomotor activity. Altogether, results firstly indicate that guanosine exerts an antidepressant-like effect that seems to be mediated through an interaction with NMDA receptors, l-arginine-NO-cGMP and PI3K-mTOR pathways.     

Serotonergic agents modulate antidepressant-like effect of the neurosteroid 3α-hydroxy-5α-pregnan-20-one in mice

The present study demonstrated the antidepressant-like effect of neurosteroid 3α-hydroxy-5α-pregnan-20-one (3α, 5α THP) in mouse forced swim test of depression and its modulation by different serotonergic agents. Pretreatment with the selective serotonin reuptake inhibitor, fluoxetine (5 mg/kg, i.p.), the 5-HT releaser, fenfluramine (10 mg/kg, i.p.), the 5-HT_1A receptor agonist, 8-OH-DPAT (0.1 mg/kg, s.c.), the 5-HT_1B/1C receptor agonist, TFMPP (4 mg/kg, s.c.) and the 5-HT_2A/1C receptor agonist, DOI (2 mg/kg, s.c.) potentiated the antidepressant-like effect of 3α, 5α THP. At these doses the serotonergic agents per se did not modify the duration of immobility. However, fluoxetine (20 mg/kg, i.p.), fenfluramine (20 mg/kg, i.p.) or imipramine (5 or 20 mg/kg, i.p.) not only reduced immobility but also enhanced the antidepressant-like effect of 3α, 5α THP. Such a potentiating effect of the 5-HT_1A or the 5-HT_2A/1C receptor agonist was not antagonized by the sub-effective dose (0.1 mg/kg, s.c.) of their respective antagonists p-MPPI or ketanserin. Pretreatment with p-CPA (300×3 mg/kg, i.p.), a depleter of 5-HT neuronal store failed to block the influence of fluoxetine and fenfluramine on antidepressant-like effect of 3α, 5α THP. The accelerated effect of 3α, 5α THP in presence of serotonergic agents was antagonized by the GABA_A receptor antagonist, bicuculline (1 mg/kg, i.p.) or the 3α-hydroxysteroid oxidoreductase enzyme inhibitor, indomethacin (5 mg/kg, i.p.). These findings for the first time demonstrate that serotonergic agents potentiate the antidepressant-like action of 3α, 5α THP, by enhancing the GABAergic tone as a likely consequence of increased brain content of this neurosteroid.     

Involvement of nitric oxide-cGMP pathway in the antidepressant-like effect of ascorbic acid in the tail suspension test

Clinical and preclinical data reported that ascorbic acid has antidepressant properties. The present study was designed to investigate the participation of l-arginine-NO-cGMP pathway in the antidepressant-like effect of ascorbic acid in the tail suspension test (TST) in mice. The antidepressant-like effect of ascorbic acid (1 mg/kg, p.o.) in the TST was prevented by the pre-treatment of mice with NMDA (0.1 pmol/site, i.c.v.), l-arginine (750 mg/kg, i.p., a substrate for nitric oxide synthase) or sildenafil (5 mg/kg, i.p., a phosphodiesterase 5 inhibitor). The administration of MK-801 (0.001 mg/kg, i.p), 7-nitroindazole (25 mg/kg, i.p., a neuronal nitric oxide synthase inhibitor) or ODQ (30 pmol/site i.c.v., a soluble guanylate cyclase inhibitor) in combination with a sub-effective dose of ascorbic acid (0.1 mg/kg, p.o.) reduced the immobility time in the TST test when compared with either drug alone. None of the results in the TST appears to be due to a nonspecific locomotor effect. Our findings provide evidence that the effect of ascorbic acid in the TST involve an interaction with NMDA receptors and l-arginine-NO-cGMP pathway, contributing to the understanding of the mechanisms underlying the antidepressant-like effect of this vitamin.