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

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

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

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

Involvement of NMDA receptors and l-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effects of escitalopram in the forced swimming test

Escitalopram is a serotonin reuptake inhibitor used in the treatment of depression and anxiety disorders. This study investigated the effect of escitalopram in forced swimming test (FST) and in the tail suspension test (TST) in mice, and tested the hypothesis that the inhibition of NMDA receptors and NO-cGMP synthesis is implicated in its mechanism of action in the FST. Escitalopram administered by i.p. route reduced the immobility time both in the FST (0.3–10 mg/kg) and in the TST (0.1–10 mg/kg). Administration of escitalopram by p.o route (0.3–10 mg/kg) also reduced the immobility time in the FST. The antidepressant-like effect of escitalopram (3 mg/kg, p.o.) in the FST was prevented by the pretreatment 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 7-nitroindazole (50 mg/kg, i.p., a neuronal nitric oxide synthase inhibitor), methylene blue (20 mg/kg, i.p., an inhibitor of both nitric oxide synthase and soluble guanylate cyclase) or ODQ (30 pmol/site i.c.v., a soluble guanylate cyclase inhibitor) in combination with a subeffective dose of escitalopram (0.1 mg/kg, p.o.) reduced the immobility time in the FST as compared with either drug alone. None of the drugs produced significant effects on the locomotor activity in the open-field test. Altogether, our data suggest that the antidepressant-like effect of escitalopram is dependent on inhibition of either NMDA receptors or NO-cGMP synthesis. The results contribute to the understanding of the mechanisms underlying the antidepressant-like effect of escitalopram and reinforce the role of NMDA receptors and l-arginine-NO-GMP pathway in the mechanism of action of antidepressant agents.     

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

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

Involvement of serotonin receptor subtypes in the antidepressant-like effect of trim in the rat forced swimming test

Depression is a common illness with severe morbidity and mortality. Nitric oxide synthase (NOS) inhibitors are shown to elicit antidepressant-like effect in various animals models. It is widely known that serotonin plays an important role in the antidepressant-like effect of drugs. The aim of this study is to investigate the involvement of 5-HT₁ and 5-HT₂ receptor subtypes in the antidepressant-like effect of TRIM, a nNOS inhibitor, in the rat forced swimming test (FST). TRIM displays an antidepressant-like activity in FST which is blocked by pretreatment with the NOS substrate l-arginine. Depletion of endogenous serotonin using para-chlorophenylalanine (pCPA; 3 × 150 mg/kg, i.p.) partially attenuated TRIM (50 mg/kg)-induced reductions in immobility time in FST. Pretreatment with methiothepin (0.1 mg/kg, i.p, a non-selective 5-HT receptor antagonist), cyproheptadine (3 mg/kg i.p, a 5-HT₂ receptor antagonist) or ketanserin (5 mg/kg i.p, a 5HT_2A/2C receptor antagonist) prevented the effect of TRIM (50 mg/kg) in the FST. WAY 100635 (0.1 mg/kg i.p, a selective 5-HT_1A receptor antagonist) and GR 127935 (3 mg/kg i.p, a selective 5-HT_1B/1D receptor antagonist) slightly reversed the immobility-reducing effect of TRIM in the FST, but this failed to reach a statistically significant level. The results of this study demonstrate that antidepressant-like effect of TRIM in the FST seems to be mediated, at least in part, by an interaction with 5-HT₂ receptors while non-significant effects were obtained with 5-HT₁ receptors.     

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

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

Antidepressant and anxiolytic effects of amentoflavone isolated from Cnestis ferruginea in mice

The root decoction of Cnestis ferruginea (CF) Vahl DC (Connaraceae) is used in traditional African medicine in the management of psychiatric disorders. This study presents the antidepressant and anxiolytic effects of amentoflavone (CF-2) isolated from the root extract of C. ferruginea.The antidepressant effect was studied using the forced swimming (FST) and tail suspension tests (TST) while the hole-board, elevated plus maze (EPM) and light/dark tests were used to evaluate the anxiolytic effect. Acute treatment with CF extract and amentoflavone significantly (p < 0.001) reduced the duration of immobility in FST and TST with peak effects observed at 100 and 50 mg/kg respectively in comparison to control treated. Antidepressant effects of CF and amentoflavone were significantly higher (p < 0.05) when compared to imipramine in FST but comparable to the fluoxetine treated group in TST.The pretreatment of mice with metergoline (4 mg/kg, i.p., a 5-HT2 receptor antagonist), prazosin (62.5 μg/kg, i.p., an α1-adrenoceptor antagonist), and yohimbine (1 mg/kg, i.p., an α2-adrenoceptor antagonist), but not sulpiride (50 mg/kg, i.p., a dopamine D2 receptor antagonist), cyproheptadine (3 mg/kg, i.p., a 5-HT2 receptor antagonist), atropine (1 mg/kg, i.p., a muscarinic receptor antagonist) 15 mins before the administration of amentoflavone (50 mg/kg; p.o.) significantly prevented its antiimmobility effect in the FST.CF extract and CF-2 significantly (p < 0.05) attenuated anxiety by increasing the number of head-dips in the hole-board test, the time spent on the open arms in the EPM, and the exploration of the light chamber in the light/dark test. Pretreatment with flumazenil (3 mg/kg, i.p., ionotropic GABA receptor antagonist) 15 min before oral administration of amentoflavone (25 mg/kg) significantly reduced the time spent in the open arms in EPM. It is concluded from the results obtained that amentoflavone produces its antidepressant effect through interaction with 5-HT2 receptor and α1-, and α2-adrenoceptors while the anxiolytic effect involved the ionotropic GABA receptor.     

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

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

Antidepressant-like effects of the nociceptin/orphanin FQ receptor antagonist UFP-101: new evidence from rats and mice

Receptor antagonist and knockout studies have demonstrated that blockade of signalling via nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) has antidepressant-like effects in mice submitted to the forced swimming test (FST). The aim of the present study was to explore further the antidepressant-like properties of the NOP antagonist UFP-101 in different species (mouse and rat) and using different assays [FST and tail suspension test (TST)], and to investigate the mechanism(s) involved in its actions.UFP-101 (10 nmol i.c.v.) reduced immobility time of Swiss mice in the TST (mean±SEM) from 179±11 to 111±10 s. N/OFQ (1 nmol i.c.v.) was without effect per se, but fully prevented the effect of UFP-101. The spontaneous immobility time of NOP^–/– CD1-C57BL/6J-129 mice in the TST was much lower than that of wild-type (NOP^+/+) littermates (75±11 vs. 144±17 s) or of Swiss mice. UFP-101 (10 nmol i.c.v.) decreased immobility time (–65%) and increased climbing time (71%) in rats submitted to the FST. In rat brain slices, N/OFQ (100 nM) triggered robust K⁺-dependent hyperpolarizing currents in locus coeruleus and dorsal raphe neurons. UFP-101 (3 µM) fully prevented N/OFQ-induced currents, but was inactive per se. Fluoxetine, desipramine (both 30 mg/kg i.p.) and UFP-101 (10 nmol i.c.v.) reduced immobility time of mice in the FST. The serotonin synthesis inhibitor p-chlorophenylalanine methylester (PCPA, 4×100 mg/kg per day i.p.) prevented the antidepressant-like effects of fluoxetine and UFP-101 (but not desipramine), whereas N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, neurotoxic for noradrenergic neurons; 50 mg/kg i.p., 7 days beforehand), suppressed only the effect of desipramine. Neither pretreatment affected spontaneous immobility time per se.Thus, UFP-101 exhibits pronounced antidepressant-like effects in different species and animal models, possibly by preventing the inhibitory effects of endogenous N/OFQ on brain monoaminergic (in particular serotonergic) neurotransmission. Participation of the N/OFQ-NOP receptor system in mood modulation sets new potential targets for antidepressant drug development.     

Acute atorvastatin treatment exerts antidepressant-like effect in mice via the l-arginine–nitric oxide–cyclic guanosine monophosphate pathway and increases BDNF levels

Atorvastatin is a synthetic and lipophilic statin that presents a good effect in decreasing cholesterol levels and is safe and well tolerated. Population-based studies have suggested a positive role of statins in reducing depression risk. This study aimed at investigating the atorvastatin effect in the tail suspension test (TST) and in the forced swimming test (FST). The participation of NMDA receptors and l–arginine–NO–cGMP in an atorvastatin antidepressant-like effect in the TST was evaluated. Acute atorvastatin administration (0.1–30 mg/kg) reduced the immobility time both in TST and FST. A similar effect was observed by using imipramine as a positive control in the TST and FST (1 and 0.1–1 mg/kg, p.o., respectively). An atorvastatin (0.1 mg/kg) antidepressant-like effect was prevented by the pretreatment of mice with NMDA (0.1 pmol/site, i.c.v.), l-arginine (750 mg/kg, i.p.) or sildenafil (5 mg/kg, i.p.). The administration of MK-801 (0.001 mg/kg, i.p.), ketamine (0.1 mg/kg, i.p.), 7-nitroindazole (50 mg/kg, i.p.), methylene blue (20 mg/kg, i.p.), or ODQ (30 pmol/site i.c.v.) in combination with a subeffective dose of atorvastatin (0.01 mg/kg, p.o.) reduced the immobility time in the TST compared to drugs alone, showing the participation of the pathway l-arginine–NO–cGMP. The administration of drugs did not produce any significant alteration in locomotor activity in the open-field test. Acute atorvastatin treatment (0.1–10.0 mg/kg, v.o.) increased the hippocampal BDNF levels, which is an effect that has not been observed in imipramine-treated mice. These results demonstrate that atorvastatin exerts an antidepressant-like effect and point to dependence on the inhibition of NMDA receptors and NO–cGMP synthesis, and on the increase of hippocampal BDNF levels.     

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

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

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

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

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

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

Blockade of 5-HT1A receptors by (+/-)-pindolol potentiates cortical 5-HT outflow, but not antidepressant-like activity of paroxetine: microdialysis and behavioral approaches in 5-HT1A receptor knockout mice.

Selective serotonin reuptake inhibitors like paroxetine (Prx) often requires 4-6 weeks to achieve clinical benefits in depressed patients. Pindolol shortens this delay and it has been suggested that this effect is mediated by somatodendritic 5-hydroxytryptamine (5-HT) 1A autoreceptors. However clinical data on the beneficial effects of pindolol are conflicting. To study the effects of (+/-)-pindolol-paroxetine administration, we used genetical and pharmacological approaches in 5-HT1A knockout mice (5-HT1A-/-). Two assays, in vivo intracerebral microdialysis in awake mice and the forced swimming test (FST), were used to assess the antidepressant-like effects of this drug combination. Basal levels of extracellular serotonin, 5-HT ([5-HT]ext) in the frontal cortex (FCX) and the dorsal raphe nucleus (DRN) did not differ between the two strains of mice, suggesting a lack of tonic control of 5-HT1A autoreceptors on nerve terminal 5-HT release. Prx (1 and 4 mg/kg) dose-dependently increased cortical [5-HT]ext in both genotypes, but the effects were greater in mutants. The selective 5-HT1A receptor antagonist, WAY-100635 (0.5 mg/kg), or (+/-)-pindolol (5 and 10 mg/kg) potentiated the effects of Prx (4 mg/kg) on cortical [5-HT]ext in 5-HT1A+/+, but not in 5-HT1A-/- mice. Similar responses were obtained following local intra-raphe perfusion by reverse microdialysis of either WAY-100635 or (+/-)-pindolol (100 microM each). In the FST, Prx administration dose-dependently decreased the immobility time in both strains of mice, but the response was much greater in 5HT1A-/- mice. In contrast, (+/-)-pindolol blocked Prx-induced decreases in the immobility time while WAY-100635 had no effect in both genotypes. These findings using 5-HT1A-/- mice confirm that (+/-)-pindolol behaves as an antagonist of 5-HT1A autoreceptor in mice, but its blockade of paroxetine-induced antidepressant-like effects in the FST may be due to its binding to other neurotransmitter receptors.     

N-palmitoylethanolamide, an endocannabinoid, exhibits antidepressant effects in the forced swim test and the tail suspension test in mice

The antidepressant-like effects of N-palmitoylethanolamide (PEA), a putative endocannabinoid, was investigated in mice using the tail suspension test (TST) and the forced swimming test (FST). In TST, PEA (10, 20, and 40 mg/kg) produced a statistically significant reduction in immobility (50, 32, and 34%, respectively, vs. the control group), whereas fluoxetine (20 mg/kg) reduced immobility by 38%. In FST, PEA (5, 10, and 20 mg/kg) produced a statistically significant reduction in immobility (15, 21, and 36%, respectively), whereas fluoxetine (20 mg/kg) reduced immobility by 18%. Moreover, PEA (20 mg/kg) did not significantly change motor activity in a spontaneous behavioral test. In conclusion, PEA (dose range of 5-40 mg/kg) administered orally reduced immobility in TST and FST, comparable to the antidepressant effect of fluoxetine, and had no effect on spontaneous activity in mice.     

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

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

Antidepressant-like effects of paroxetine are produced by lower doses than those which produce nausea

Paroxetine is prescribed to treat depression, but it also produces nausea. The potential of animal models to detect nauseating, antidepressant-like, and rewarding/aversive effects of paroxetine were assessed. In Experiments 1 (spaced conditioning trials) and 3 (massed conditioning trials), a dose of 30 mg/kg, but not lower doses (3 and 10 mg/kg) of paroxetine produced conditioned gaping reactions (reflective of nausea) in the Taste Reactivity (TR) test. In Experiment 2, when administered 23.5, 5 and 1 h prior to a 5 min forced swim test (FST) a dose as low as 3 mg/kg of paroxetine increased swimming and decreased immobility (reflective of antidepression) compared to controls. In Experiment 3, neither 10 nor 30 mg/kg of paroxetine produced a conditioned floor preference/aversion, but both doses decreased activity during conditioning trials. These results suggest that paroxetine produced an antidepressant-like effect at a lower dose (3 mg/kg) than that necessary to produce nausea (30 mg/kg). The TR test may be beneficial for assessing the side effect of nausea in preclinical tests of new compounds.     

Augmentation effect of combination therapy of aripiprazole and antidepressants on forced swimming test in mice

Rationale  A deficiency in brain monoamine systems (serotonin, dopamine, and/or norepinephrine) have long been hypothesized for the pathogenesis of depression. Drugs enhancing neurotransmission of those monoamines have been proven to have antidepressant effects. We hypothesized that aripiprazole, a partial D₂ agonist, could increase the activity of various antidepressants in the mice forced swimming test (FST), an animal model of depression. Objectives  The scope of this study was to investigate the antidepressant-like effect of aripiprazole, when combined with conventional antidepressants drugs. Materials and methods  This study assessed the effects of co-administration of aripiprazole with selective serotonin reuptake inhibitors (SSRIs; sertraline, paroxetine, and citalopram), selective serotonin–norepinephrine reuptake inhibitors (SNRIs; venlafaxine and minalcipran), selective norepinephrine reuptake inhibitor (NRI; desipramine), and the dual dopamine and norepinephrine reuptake inhibitor (bupropion), using the FST in mice. Subactive doses of aripiprazole and antidepressants sertraline, paroxetine, citalopram, venlafaxine, minalcipran, bupropion (4 and 8 mg/kg), and desipramine (2 and 4 mg/kg) were given i.p. 30 and 45 min, respectively, before the test. Results  Aripiprazole (0.03 and 0.06 mg/kg) combined with inactive doses of antidepressants, increased the activity of all antidepressants with the exception of bupropion and desipramine. Conclusion  The augmentation effects of aripiprazole, in the present study, are in agreement with clinical evidence suggesting that aripiprazole may enhance the efficacy of therapeutic effect of SSRIs and SNRIs but not of NRI. These results suggest that augmentation effect of aripiprazole only appears when 5-HT system is activated and might implicate complex regulation between dopamine and 5-HT_1A and 5-HT_2A receptors.     

Antidepressant-like effects in various mice strains in the forced swimming test

Rationale. Strain differences in mice have been reported in response to drugs in the mouse forced swimming test (FST), even if few antidepressants were examined. Objectives. The aim of the present study was to investigate the influence of genetic factors, using five antidepressants (imipramine, desipramine, citalopram, paroxetine and bupropion) in the mouse FST, in outbred strains (Swiss, NMRI) and inbred strains (DBA/2, C57BL/6J Rj). Moreover, whole brain levels of dopamine (DA), noradrenaline (NA), serotonin (5-HT) in vehicle treated animals, which were or were not subjected to the FST, were measured by HPLC analysis in an attempt to explain behavioural differences. Methods. For each antidepressant, a dose range (1–16 mg/kg) was tested in the locomotor apparatus and only non-psychostimulant doses were then tested in the FST in order to detect antidepressant-like activity. Results. No baseline differences among Swiss, NMRI, DBA/2 and C57BL/6J Rj strains were observed in our experiments, allowing the comparison of different antidepressants in each strain. Imipramine (16 mg/kg), desipramine, citalopram (4–16 mg/kg) and paroxetine (8 and 16 mg/kg) treatment decreased the immobility time in the Swiss strain and the size of the effect reached more than 20% for each of these antidepressants. C57BL/6J Rj was the only strain sensitive to bupropion (2 and 4 mg/kg). In the NMRI strain, only paroxetine treatment decreased the immobility time (16 mg/kg). Conclusion. Our study showed that drug sensitivity is genotype dependent. FST results have shown that Swiss mice are the most sensitive strain to detect 5-HT and/or NA treatment. The use of DBA/2 inbred mice may be limited, as an absence of antidepressant-like response was observed in the FST. The lack of sensitivity to antidepressant treatment in DBA/2 strains could be due to high DA, NA and 5-HT whole brain concentrations. Electronic Publication     

In-vivo modulation of central 5-hydroxytryptamine (5-HT1A) receptor-mediated responses by the cholinergic system

The aim of the present study was to investigate a putative modulation of rat 5-HT system by the muscarinic receptor antagonist atropine using in-vivo electrophysiological and behavioural techniques. In the dorsal raphe nucleus, administration of atropine (1 mg/kg i.v.) prevented the suppressant effect of the selective serotonin reuptake inhibitor paroxetine (0.5 mg/kg i.v.) on the spontaneous firing activity of 5-HT neurons, suggesting that atropine could induce an attenuation of somatodendritic 5-HT1A autoreceptors responsiveness. The 5-HT1A receptor agonist 8-OH-DPAT decreased both immobility in the forced swim test and the body core temperature. Pre-treatment with atropine (5 and 10 mg/kg i.p.) enhanced antidepressant-like effect of 8-OH-DPAT (1 mg/kg s.c.) and reduced 8-OH-DPAT (0.1 mg/kg s.c.)-induced hypothermia. In conclusion, the present study reports a functional role of muscarinic receptors in the modulation of pre- and post-synaptic 5-HT1A receptors mediated responses.     

Effects of combined administration of 5-HT1A and/or 5-HT1B receptor antagonists and paroxetine or fluoxetine in the forced swimming test in rats

Clinical data suggest that coadministration of pindolol, a 5-HT1A/5-HT1B/beta-adrenoceptor antagonist, and selective serotonin reuptake inhibitors (SSRIs) may shorten the time of onset of a clinical action and may increase beneficial effects of the therapy of drug-resistant depression. Effects of combined administration of SSRIs and 5-HT receptor ligands are currently evaluated in animal models for the detection of an antidepressant-like activity; however, the obtained results turned out to be inconsistent. The aim of the present study was to investigate effects of a 5-HT1A antagonist (WAY 100635), 5-HT1B antagonists (SB 216641 and GR 127935) or pindolol, given in combination with paroxetine or fluoxetine (SSRIs), in the forced swimming test in rats (Porsolt test). When given alone, paroxetine (10 and 20 mg/kg), fluoxetine (10 and 20 mg/kg), WAY 100635 (0.1 and 1 mg/kg), SB 216641 (2 mg/kg), GR 127935 (10 and 20 mg/kg) and pindolol (4 and 8 mg/kg) did not shorten the immobility time of rats in that test. Interestingly, SB 216641 administered alone at a dose of 4 mg/kg produced a significant reduction of the immobility time in that test. A combination of paroxetine (20 mg/kg) and WAY 100635 or pindolol failed to reveal a significant interaction; on the other hand, when paroxetine was given jointly with SB 216641 (2 mg/kg) or GR 127935 (10 and 20 mg/kg), that combination showed a significant antiimmobility action in the forced swimming test in rats. The active behaviors in that test did not reflect increased general activity because combined administration of both the 5-HT1B antagonists and paroxetine failed to alter the locomotor activity of rats, measured in the open field test. Coadministration of fluoxetine and all the antagonists used did not affect the behavior of rats in the forced swimming test. The obtained results seem to indicate that blockade of 5-HT1B receptors, but not 5-HT1A ones, can facilitate the antidepressant-like effect of paroxetine in the forced swimming test in rats. No interaction was observed between fluoxetine and 5-HT1A/5-HT1B receptor antagonists.     

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

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