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 effect of the extract from leaves of Schinus molle L. in mice: evidence for the involvement of the monoaminergic system

Schinus molle L. (Anacardiaceae), among other uses, is popularly employed for the treatment of depression. In this study, the antidepressant-like effect of the hexanic extract from leaves of S. molle was investigated in the mouse tail suspension test (TST), a predictive model of depression. The immobility time in the TST was significantly reduced by the extract (dose range 30-600 mg/kg, p.o.), without accompanying changes in ambulation when assessed in an open-field test. The efficacy of extract was found to be comparable to that of fluoxetine (10 mg/kg, p.o.). The anti-immobility effect of the extract (100 mg/kg, p.o.) was prevented by pretreatment of mice with p-chlorophenylalanine methyl ester (PCPA, 100 mg/kg, i.p., an inhibitor of serotonin synthesis, for four consecutive days), 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), ketanserin (5 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist), MDL72222 (0.1 mg/kg, i.p., a 5-HT(3) receptor antagonist), prazosin (1 mg/kg, i.p., an alpha(1)-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an alpha(2)-adrenoceptor antagonist), SCH23390 (0.05 mg/kg, s.c., a D(1) receptor antagonist) or sulpiride (50 mg/kg, i.p., a D(2) receptor antagonist). It may be concluded that the hexanic extract of S. molle produces an antidepressant-like effect that seems to be dependent on its interaction with the serotonergic, noradrenergic and dopaminergic systems. These results provide evidence that the extract from S. molle shares with established antidepressants some pharmacological effects, at least at a preclinical level.     

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.     

Involvement of the adenosine A1 and A2A receptors in the antidepressant-like effect of zinc in the forced swimming test

It was previously shown that the acute administration of zinc chloride elicits an antidepressant-like effect in the mouse forced swimming test (FST). We have also shown that the activation of adenosine A₁ and A_2A receptors produces an antidepressant-like effect in FST. Thus, this study investigated the involvement of adenosine receptors in the antidepressant-like effect of zinc in the FST. The antidepressant-like effect of ZnCl₂ (30 mg/kg, i.p.) in the FST was prevented by the pretreatment of animals with caffeine (3 mg/kg, i.p., a non-selective adenosine receptor antagonist), DPCPX (2 mg/kg, i.p., a selective adenosine A₁ receptor antagonist) or ZM241385 (1 mg/kg, i.p., a selective adenosine A_2A receptor antagonist), administered at doses that per se produced no anti-immobility effect. Moreover, the treatment of mice with CHA (0.05 mg/kg, i.p., a selective adenosine A₁ receptor agonist), DPMA (0.1 mg/kg, i.p., a selective adenosine A_2A receptor agonist) or dipyridamole (0.1 µg/site, i.c.v., an adenosine transporter inhibitor) was able to potentiate the action of sub-effective doses of ZnCl₂. Taken together, the results suggest that the antidepressant-like effect of zinc in the mouse FST might involve a direct or indirect activation of adenosine A₁ and A_2A receptors.     

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.     

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.     

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).     

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.     

Involvement of dopamine (DA)/serotonin (5-HT)/sigma (sigma) receptor modulation in mediating the antidepressant action of ropinirole hydrochloride, a D2/D3 dopamine receptor agonist

Multiple lines of investigation have explored the role of dopaminergic systems in mental depression. Chronic treatment with antidepressant drugs has been reported to alter dopaminergic neurotransmission, most notably a sensitization of behavioural responses to agonists acting at D2/D3 dopamine receptors within the nucleus accumbens. Recent clinical evidences have shown that ropinirole, a D2/D3 dopamine receptor agonist, augments the action of various standard antidepressant drugs in treatment-resistant depression. The present study was undertaken to elucidate the possible mechanism of antidepressant action of ropinirole employing various behavioral paradigms of despair supported by the measurements of neurochemical changes in the tissue contents of dopamine (DA) and serotonin (5-HT) in the whole brain using high-performance-liquid chromatography (HPLC) with electrochemical detectors (ECD). In the mouse forced swim test (FST) or tail-suspension test (TST), ropinirole (1-10 mg/kg, i.p.) produced S-shaped dose-response curve in the percentage decrease in immobility period. Compared with vehicle, ropinirole (10 mg/kg., i.p.) had a significant anti-immobility effect without affecting locomotor activity. The reduction in the immobility period elicited by ropinirole (10 mg/kg, i.p.) in the FST was reversed by dopaminergic and sigma receptor antagonist, haloperidol (0.5 mg/kg, i.p.), and specific D2 dopamine receptor antagonist sulpiride (5 mg/kg i.p.), but not by SCH 23390 (0.5 mg/kg i.p), a D1 dopamine receptor antagonist. Rimcazole (5 mg/kg i.p.) (a sigma receptor antagonist), progesterone (10 mg/kg i.p.) (a sigma receptor antagonistic neurosteroid), BD 1047 (1 mg/kg i.p.) (a novel sigma receptor antagonist with preferential affinity for sigma-1 sites) also reversed the anti-immobility effect of ropinirole (10 mg/kg i.p.). The neurochemical studies of whole brain revealed that ropinirole at 10 mg/kg i.p. did not affect the tissue levels of dopamine but significantly increased serotonin levels. The study indicated that ropinirole possessed anti-immobility activity in FST by altering dopaminergic, serotonergic or sigma receptor function.     

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.     

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.     

Evidence for the activity of lamotrigine at 5-HT(1A) receptors in the mouse forced swimming test

BACKGROUND: The antiepileptic drug lamotrigine is effective in the treatment of focal epilepsies. It is thought to act by inhibition of glutamate release through blockade of voltage-sensitive sodium channels and stabilization of the neuronal membrane. Lamotrigine is also effective in the treatment of mood disorders such as bipolar disorder. However, its exact mechanism of action in these conditions remains unclear. The aim of the present study was to evaluate the antidepressant-like effect of lamotrigine in a mouse model of depression, namely the forced swimming test (FST). Association studies using specific and nonspecific ligands acting on serotonin (5-hydroxytryptamine; 5-HT1) receptor subtypes were undertaken to evaluate the potential role of these receptors in the anti-immobility effect of lamotrigine. METHODS: The mouse FST was performed after single administration of lamotrigine. Subactive doses of lamotrigine were administered in association with subactive doses of the following 5-HT1 receptor agonists or antagonists: 8-hydroxy-2-(di-n-propilamino)-tetralin (8-OH-DPAT, a standard 5-HT(1A) receptor selective agonist), pindolol (a presynaptic and postsynaptic 5-HT(1A/1B) receptor antagonist), NAN-190 (a 5-HT(1A) receptor antagonist), RU 24969 (a 5-HT(1A/1B) receptor agonist) and anpirtoline (5-HT(1B) agonist). RESULTS: Lamotrigine impaired spontaneous locomotor activity at doses of 4 mg/kg or greater, and activity decreased by more than 50% at the 16 mg/kg dose. When administered alone, lamotrigine (8 and 16 mg/kg) decreased immobility time in the FST. Only 8-OH-DPAT (1 mg/kg), pindolol (32 mg/kg) and RU 24969 (0.5 mg/kg) enhanced the antidepressant-like effect of lamotrigine in the FST. CONCLUSIONS: These results suggest that postsynaptic 5-HT(1A) receptors might be involved in the activity of lamotrigine. Furthermore, they demonstrate that lamotrigine more closely resembles valproate and carbamazepine than lithium, with the advantage of an anti-immobility effect in the mouse FST when administered on its own.     

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.     

Putrescine produces antidepressant-like effects in the forced swimming test and in the tail suspension test in mice

Putrescine, a polyamine present at high concentrations in the mammalian brain, was suggested to play a role in the modulation of depression. Thus, this study investigated the effect of putrescine in the mouse forced swimming test (FST) and in the tail suspension test (TST), two models predictive of antidepressant activity. Putrescine significantly reduced the immobility time both in the FST and in the TST (dose range of 1–10 mg/kg, i.p.), without changing locomotion in an open-field. I.c.v. injection of putrescine (0.1–10 nmol/site) also reduced the immobility time in the FST and in the TST. The pretreatment of mice with arcaine (1 mg/kg, i.p., an antagonist of the polyamine-site of NMDA receptor) completely blocked the anti-immobility effect of putrescine (10 mg/kg, i.p.). A subeffective dose of putrescine (0.1 mg/kg, i.p.) produced a synergistic antidepressant-like effect with agmatine (0.001 mg/kg, i.p.) in the FST. Moreover, a subeffective dose of putrescine (0.01 nmol/site, i.c.v.) produced a synergistic antidepressant-like effect with arcaine (50 μg/site, i.c.v.). The results indicate that putrescine produces antidepressant-like effects in the FST that seems to be mediated through its interaction with the polyamine-site of NMDA receptors.     

Antidepressant-like activity of S 20098 (agomelatine) in the forced swimming test in rodents: involvement of melatonin and serotonin receptors

OBJECTIVE: To study agomelatine (S 20098), a potent agonist at melatonin receptors and antagonist at serotonin-2C (5-HT(2C)) receptors, in an animal model of depression, namely, the rodent forced swimming test (FST). METHODS: The effects of acute and repeated administration of S 20098 were compared with those of melatonin (4, 8, 16, 32, 64 mg/kg intraperitoneally [IP] for mice), imipramine (64 mg/kg orally for rats, 8 mg/kg IP for mice) and fluoxetine (16 mg/kg IP for mice). The influence of the pretreatments with 5-HT(1A) or 5-HT(1B) receptor agonists (8-OH-DPAT, anpirtoline) and 5-HT(1A/1B), 5-HT(2A/2C) or 5-HT(3) antagonists (pindolol, ritanserin, ondansetron) on the effects of S 20098 or melatonin were compared with imipramine and fluoxetine in mice. RESULTS: Acute or repeated (13 days) administration of S 20098 or imipramine in rats significantly decreased the duration of immobility during the FST at all doses. A dose-dependent effect was observed after the repeated treatment with S 20098. When given for 10 days to mice in the evening, S 20098 was active on the FST at doses of 4, 16 and 32 mg/kg, whereas the acute administration of S 20098 (in the morning and evening) was without any significant effect. Acute or repeated administration of S 20098 did not modify the locomotor activity of mice. The combination of S 20098 with the above-mentioned pretreatments enhanced the effects of S 20098, given alone, on the duration of immobility. By comparison, acute melatonin was inactive in the FST and only pretreatment with 8-OH-DPAT or pindolol revealed an anti-immobility effect. A pretreatment with 8-OH-DPAT also induced anti-immobility effects with imipramine, but not fluoxetine, whereas pindolol exerted additive effects with fluoxetine but not imipramine. CONCLUSION: These results demonstrate the antidepressant-like activity of repeated administration of S 20098 in the FST. Moreover, the combination of 5-HT agonists and antagonists leads to more powerful effects with S 20098 than with melatonin, thereby emphasizing the contribution of 5-HT receptors to the antidepressant activity of S 20098. Compared with imipramine and fluoxetine, the 5-HT receptor subtypes that may be involved in the antidepressant-like activity of S 20098 are not similar. Indeed, when considering the binding properties of S 20098, the 5-HT(2C) receptor subtype appears to be the most attractive candidate. It is concluded that the antidepressant-like activity of S 20098 in this model most probably involves a combination of both its melatonin agonist and 5-HT(2C )receptor antagonist properties.     

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.     

Evidence for dual effects of nitric oxide in the forced swimming test and in the tail suspension test in mice

L-Arginine (L-Arg), a substrate for nitric oxide synthase (NOS) at a dose of 250-500 mg/kg, i.p., significantly reduced the duration of immobility both in the forced swimming test (FST) and in the tail suspension test (TST), two models of depression in mice, without changing locomotion in an open field. Paradoxically, a similar effect was observed with the administration of N(G)-nitro-L-arginine (L-NNA) (0.3-10 mg/kg, i.p.), an inhibitor of NOS. However, higher doses of L-Arg (750-1000 mg/kg) and L-NNA (30 mg/kg) did not produce any anti-immobility effect in FST and TST. The inactive isomers D-Arg (100-1000 mg/kg, i.p.) and D-NNA (0.3-30 mg/kg, i.p.) did not affect immobility duration in either the FST and TST. Preadministration of L-NNA (30 mg/kg, i.p.), but not of D-NNA completely blocked the anti-immobility effect of L-Arg (500 mg/kg, i.p.) in the FST. Similarly, L-Arg (750 mg/kg, i.p.), but not D-Arg blocked the anti-immobility effect of L-NNA (3 mg/kg, i.p.) in the FST. The results indicate that either the synthesis of NO or the inhibition of its synthesis may produce antidepressant-like effects when assessed in the FST and TST. The physiological meaning of this finding is still obscure, but it could indicate that NO has a dual role in the modulation of depression.     

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.     

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.     

Evidence for the involvement of 5-HT1A receptor in the acute antidepressant-like effect of creatine in mice

Creatine was previously shown to produce an antidepressant-like effect in the tail suspension test through a modulation of the dopaminergic system. In this study, the mechanisms underlying its antidepressant-like effect were further evaluated by investigating the involvement of the serotonergic system in its effect. The anti-immobility effect of creatine (1 mg/kg) was prevented by the pretreatment of mice with p-chlorophenylalanine methyl ester (PCPA; 100 mg/kg, i.p., for 4 consecutive days, an inhibitor of serotonin (5-HT) synthesis). Creatine (0.01 mg/kg, sub-effective dose) in combination with sub-effective doses of WAY100635 (0.1 mg/kg, s.c., a 5-HT_1A receptor antagonist), 8-OH-DPAT (0.1 mg/kg, i.p., a 5-HT_1A receptor agonist) or selective serotonin reuptake inhibitors fluoxetine (5 mg/kg, p.o.), paroxetine (0.1 mg/kg, p.o.), citalopram (0.1 mg/kg, p.o.) and sertraline (3 mg/kg, p.o.) reduced the immobility time in the tail suspension test as compared with either drug alone. These results indicate that the antidepressant-like effect of creatine is likely mediated by an interaction with 5-HT_1A receptors. Of note, the present results also indicate that creatine improves the effectiveness of the selective serotonin reuptake inhibitors, a finding that may have therapeutic implications for the treatment of depressive disorders.