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 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.     

Role of cortical and striatal 5-HT1A receptors in alleviating antipsychotic-induced extrapyramidal disorders

Previous studies have revealed that 5-HT_1A agonists ameliorate antipsychotic-induced extrapyramidal symptoms (EPS) through postsynaptic 5-HT_1A receptors. Here, we conducted an intracerebral microinjection study of (±)-8-hydroxy-2-(di-n-propylamino)-tetralin ((±)8-OH-DPAT) to determine the action site of the 5-HT_1A agonist in alleviating EPS. Bilateral microinjection of(±)8-OH-DPAT (5 µg/1 µL per side) either into the primary motor cortex (MC) or the dorsolateral striatum (dlST) significantly attenuated haloperidol-induced catalepsy in rats. The anticataleptic action of (±)8-OH-DPAT was more prominent with the MC injection than with the dlST injection. WAY-100135 (a selective 5-HT_1A antagonist) completely antagonized the reversal of haloperidol-induced catalepsy both by intracortical and intrastriatal (±)8-OH-DPAT. Furthermore, lesioning of dopamine neurons with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (30 mg/kg/day, i.p., for 4 days) did not alter the anti-EPS actions of (±)8-OH-DPAT in a mouse pole test. The present results strongly suggest that 5-HT_1A agonist alleviates antipsychotic-induced EPS by activating postsynaptic 5-HT_1A receptors in the MC and dlST, probably through non-dopaminergic mechanisms.     

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.     

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.     

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.     

5-HT1A agonists induce hippocampal theta activity in freely moving cats: role of presynaptic 5-HT1A receptors

Electrical activity in the dorsal hippocampus was recorded in freely moving cats in response to intravenous administration of 5-HT_1A agonist and antagonist drugs. Administration of low doses of the selective 5-HT_1A agonists 8-OH-DPAT (5–20 μg/kg) and ipsapirone (20–100 μg/kg) produced rhythmic slow activity (theta) in the hippocampal EEG within 30 s. Similar effects were observed with BMY 7378 (20 and 100 μg/kg), which acts as an agonist at presynaptic (somatodendritic) 5-HT_1A receptors and as an antagonist at postsynaptic 5-HT_1A receptors. Power spectral analyses showed that all three compounds produced a dose-dependent increase in the EEG power occurring in the theta frequency band (3.5–8.0 Hz) as a proportion of total power from 0.25 to 30.0 Hz (relative theta power). The increase in relative theta power produced by 8-OH-DPAT (20 μg/kg) was greatly attenuated by spiperone (1 mg/kg), a highly effective 5-HT_1A autoreceptor antagonist. Administration of spiperone alone had no significant effect on relative theta power. These results are discussed in relationship to the effects of these drugs on serotonergic neuronal activity. Our results suggest that preferential activation of presynaptic 5-HT_1A receptors, and subsequent inhibition of serotonin neurotransmission, facilitates the appearance of hippocampal theta activity in awake cats.     

Antidepressant properties of the 5-HT4 receptor partial agonist, SL65.0155: Behavioral and neurochemical studies in rats

This study was undertaken to investigate the potential antidepressant-like properties of SL65.0155, a serotonin 5-HT₄ receptor partial agonist, in male rats of the Wistar strain tested in the forced swim test (FST), an experimental model widely used to assess antidepressant-like activity. The expression of hippocampal neurotrophic factors, such as the brain-derived neurotrophic factor (BDNF), the phosphorilated cAMP response element-binding protein (p-CREB), the B cell lymphoma-2 (Bcl-2), the Bax and the vascular endothelium growth factor (VEGF) were also evaluated by Western Blot analysis. Different groups of rats received intraperitoneally (i.p.) injections of SL65.0155 (0.1, 0.5 and 1 mg/kg), clomipramine (50 mg/kg), citalopram (15 mg/kg) or vehicle, respectively, 24, 5 and 1 h prior to the FST. Compared to the control group, SL65.0155 (0.5 and 1 mg/kg), clomipramine or citalopram injected animals showed an increased swimming and climbing behavior and reduced immobility time in the FST. Interestingly, this effect was not due to changes in the locomotor activity since all treated groups failed to show any change in motor ability as assessed in the open field test. Western blot analysis of hippocampal homogenates showed an enhancement of p-CREB, BDNF Bcl-2 and VEGF protein levels in SL65.0155 treated groups, but not in citalopram or clomipramine treated groups, used here as positive control. No change was found in Bax expression in any treated group. These findings give further support to the hypothesis that the stimulation of serotonin 5-HT₄ receptors may be a therapeutic target for depression.     

Involvement of endocannabinoids in antidepressant and anti-compulsive effect of fluoxetine in mice

Endocannabinoid analogues exhibit antidepressant and anti-compulsive like effects similar to that of serotonin selective reuptake inhibitors (SSRIs) indicating a parallelism between the effects of serotonin and endocannabinoids. Therefore, the present study was designed to investigate the role of endocannabinoids in the antidepressant and anti-compulsive like effect of fluoxetine using mice model of forced swim test (FST) and marble-burying behavior (MBB). The results revealed that intracerebroventricular injections of endocannabinoid analogues, anandamide, a CB₁ agonist (AEA: 1-20 μg/mouse); AM404, an anandamide transport inhibitor (0.1-10 μg/mouse); and URB597, a fatty acid amide hydrolase inhibitor (0.05-10 μg/mouse) produced antidepressant-like effect dose-dependently, whereas influenced the MBB in a biphasic manner (produced a U-shaped dose-response curve). Fluoxetine (2.5-20 mg/kg, i.p.) dose dependently decreased the immobility time as well as burying behavior. Co-administration of sub-effective dose of fluoxetine (2.5 mg/kg, i.p.) potentiated the effect of sub-effective dose of AEA (0.5 μg/mouse, i.c.v.), AM404 (0.05 μg/mouse, i.c.v) or URB597 (0.01 μg/mouse, i.c.v) in both the paradigms. Interestingly, pretreatment with AM251, a CB₁ antagonist, blocked the effect of fluoxetine in FST and MBB at a dose (1 μg/mouse, i.c.v) that per se had no effect on either parameter. Similar effects were obtained with endocannabinoid analogues in AM251 pretreated mice. However, AM251 increased the burying behavior in MBB at a highest dose tested (5 μg/mouse). None of the treatments had any influence on locomotor activity. Thus, the study indicates an interaction between endocannabinoid and serotonergic system in regulation of depressive and compulsive-like behavior.     

The folic acid combined with 17-β estradiol produces antidepressant-like actions in ovariectomized rats forced to swim

Folic acid or 17-β estradiol produces antidepressant effects, either alone or combined with several antidepressants. However, the antidepressant-like actions of folic acid combined with 17-β estradiol in the forced swimming test (FST) have not been tested before. Thus, in the present study, ovariectomized female rats received folic acid (5.0 nmol/i.c.v., P < 0.05; 10.0 nmol/ i.c.v., P < 0.05; or 50 mg/kg, P < 0.05, p.o.; 75.0; mg/kg, P < 0.05, p.o.), or fluoxetine (20.0 mg/kg, P < 0.05; 25.0 mg/kg, P < 0.05) or 17-β estradiol (10.0 μg/rat, P < 0.05; 20.0 μg/rat, P < 0.05) and they displayed reduced immobility by increasing swimming behavior when they were tested in the FST. Combination of subthreshold doses of folic acid (2.5 nmol/i.c.v.; or 25.0 mg/kg, p.o.) with subthreshold doses of 17-β estradiol (5.0 μg/rat, P < 0.05) or with subthreshold doses of fluoxetine (15.0 mg/kg, P < 0.05) produced antidepressant-like actions. Ketanserin was used to evaluate the participation of the drugs used in the serotonergic pathway; ketanserin cancelled the antidepressant-like actions of the several combinations used. In conclusion, folic acid alone or combined with estradiol or fluoxetine in the FST reduced immobility in the FST. These antidepressant-like actions probably were due to modifications of the serotonergic system since swimming behavior was increased and these effects were cancelled by ketanserin.     

The involvement of serotonergic system in the antidepressant effect of zinc in the forced swim test

Recent preclinical data indicated the antidepressant-like activity of zinc in different tests and models of depression. The present study investigates the involvement of the serotonergic system in zinc activity in the forced swim test (FST) in mice and rats. The combined treatment of sub-effective doses of zinc (hydroaspartate, 2.5 mg Zn/kg) and citalopram (15 mg/kg), fluoxetine (5 mg/kg) but not with reboxetine (2.5 mg/kg) significantly reduces the immobility time in the FST in mice. These treatments had no influence on the spontaneous locomotor activity. Moreover, while the antidepressant-like effect of zinc (5 mg/kg) in the FST was significantly blocked by pretreatment with inhibitor of serotonin synthesis, p-chlorophenylalanine (pCPA, 3 × 200 mg/kg), 5HT-2_A/C receptor antagonist, ritanserin (4 mg/kg) or 5HT-1A receptor antagonist, WAY 1006335 (0.1 mg/kg), the zinc-induced reduction in the locomotor activity was not affected by these serotonin modulator agents. These results indicate the specific involvement of the serotonergic system in antidepressant but not the motion behavior of zinc in mice. Also, an increase in the swimming but not climbing parameter of the rat FST observed following zinc administration (2.5 and 5 mg Zn/kg) indicates the serotonin pathway participation. This present data indicates that the antidepressant-like activity of zinc observed in the FST involves interaction with the serotonergic system.     

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.     

Intra-lateral septal infusions of folic acid alone or combined with various antidepressant drugs produce antidepressant-like actions in male Wistar rats forced to swim

Intra-cerebral administrations of folic acid produce antidepressant-like effects; either alone or combined with several antidepressant drugs. However, the specific limbic structures implied in the antidepressant-like actions of folic acid are un-known. Thus, intra-lateral septal infusions of folic acid (5.0 nmol, P < 0.05; 10.0 nmol, P < 0.05) or oral administrations of folic acid (50 mg/kg, P < 0.05, p.o.; 75.0; mg/kg, P < 0.05, p.o.) or systemic administrations of fluoxetine (20.0 mg/kg, P < 0.05; 25.0 mg/kg, P < 0.05) reduced immobility by increasing swimming behavior in the forced swimming test (FST) of male Wistar rats. Conversely, desipramine (10.0 mg/kg, P < 0.05; 15.0 mg/kg, P < 0.05) reduced immobility by increasing climbing behavior. Subthreshold doses of folic acid (2.5 nmol/intra-LSN) combined with subthreshold doses of folic acid (25.0 mg/kg, p.o., P < 0.05) or with subthreshold doses of fluoxetine (15.0 mg/kg, P < 0.05) and they produced antidepressant-like effects which were canceled by ketanserin. In conclusion, intra-lateral septal infusions of folic acid alone or combined with systemic doses of folic acid or fluoxetine reduced immobility in the FST. These antidepressant-like actions, probably, were due to modifications of the serotonergic system since swimming behavior was increased and these effects were canceled by ketanserin.     

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.     

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.     

Evidence for 5-HT4 receptor involvement in the enhancement of acetylcholine release by p-chloroamphetamine in rat frontal cortex

The roles of endogenous serotonin (5-HT) and 5-HT receptor subtypes in regulation of acetylcholine (ACh) release in frontal cortex of conscious rats were examined using a microdialysis technique. Systemic administration (1 and 3 mg/kg, i.p.) of the 5-HT-releasing agent p-chloroamphetamine (PCA) elevated ACh output in a dose-dependent manner. Depletion of endogenous 5-HT by p-chlorophenylalanine significantly attenuated the facilitatory effect of PCA on ACh release. The PCA (3 mg/kg)-induced increase in ACh release was significantly inhibited by local application of the 5-HT₄ receptor antagonists RS23597 (50 μM) and GR113803 (1 μM), while the 5-HT_1A antagonist WAY-100135 (10 mg/kg, i.p.; 100 μM), 5-HT_1A/1B/β-adrenoceptor antagonists (−)-pindolol (8 mg/kg, i.p.) and (−)-propranolol (150 μM), 5-HT_2A/2C antagonist ritanserin (1 mg/kg, i.p.; 10 μM) and 5-HT₃ antagonist ondansetron (1 mg/kg, i.p.; 10 μM) failed to significantly modify the effect of PCA. These results suggest that PCA-induced enhancement of 5-HT transmission facilitates ACh release from rat frontal cortex at least in part through 5-HT₄ receptors.     

Dose- and time-dependent effects of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a serotonergic 5-HT2 receptor agonist, on local cerebral glucose metabolism in awake rats

The time course and the relation to dose of regional cerebral metabolic rates for glucose (rCMRglc) were measured in awake male Fischer-344 rats after administration of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a selective serotonergic 5-HT₂ agonist. rCMRglc was determined, using the quantitative autoradiographic [¹⁴C]2-deoxyglucose technique, in 75 brain regions at 5, 15, 30, 60 and 90 min after administration of DOI 10 mg/kg i.p., and at 15 min after DOI 2.5, 25 or 50 mg/kg i.p. In non-hippocampal regions, peak effects were observed at 15–30 min, when rCMRglc in 12% of the regions was significantly different from control. In hippocampal regions rCMRglc effects peaked at 30 min (average rCMRglc reduction 21%) and were sustained for at least 60 min. Higher doses of DOI reduced rCMRglc in most prosencephalic regions (25 mg/kg, 35% of all regions studied; 50 mg/kg, 32%), where 5-HT₂ receptors are present in high density. These data suggest that selective 5-HT₂ receptor stimulation leads to rCMRglc reduction in areas with high densities of 5-HT₂ receptors.