Ágatha Oliveira

Antidepressant-like effects of fractions, essential oil, carnosol and betulinic acid isolated from Rosmarinus officinalis L.

The aim of this study was to investigate the antidepressant-like effect of fractions from Rosmarinus officinalis L.: ethyl acetate 1 and 2 (AcOEt1 and 2), hexane (HEX), ethanolic (ET), and essential oil-free (EOF) fractions, as well as essential oil, the isolated compounds carnosol and betulinic acid in the tail suspension test, a predictive test of antidepressant activity. Swiss mice were acutely administered by oral route (p.o.) with fractions, essential oil or isolated compounds, 60 min before the tail suspension test or open-field test. All of them produced a significant antidepressant-like effect: AcOEt1, ET, EOF fractions and essential oil (0.1-100mg/kg, p.o); HEX (0.1-10mg/kg, p.o) and AcOEt2 fraction (0.1-1mg/kg, p.o), carnosol (0.01-0.1mg/kg, p.o.) isolated from the HEX fraction and betulinic acid (10mg/kg, p.o.), isolated from the AcOEt1 and AcOEt2 fractions. No psychostimulant effect was shown in the open-field test, indicating that the effects in the tail suspension test are specific. This study suggests that carnosol and betulinic acid could be responsible for the anti-immobility effect of extracts from R. officinalis.

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

Serotonergic and noradrenergic systems are implicated in the antidepressant-like effect of ursolic acid in mice.

Ursolic acid (UA) is a natural pentacyclic triterpenoid carboxylic acid that exerts antidepressant-like effects in the tail suspension test (TST) and in the forced swimming test, and this effect was reported to be mediated by the dopaminergic system. Many studies show that currently available antidepressant agents have effects on multiple neurotransmitter systems which account for their efficacy. Therefore, this study was aimed at investigating the possible involvement of the serotonergic, noradrenergic, glutamatergic and opioid systems in the antidepressant-like effect of UA. To this end, several pharmacological agents were administered to verify their ability to influence the antidepressant-like responses elicited by UA in the TST in mice. The open-field test was used to assess the locomotor activity. The results show that the pre-treatment of mice with ρ-chlorophenylalanine (100mg/kg, i.p., 4 days) or α-methyl-ρ-tyrosine (100mg/kg, i.p.) but not with N-methyl-d-aspartate (0.1 pmol/mouse, i.c.v.) or naloxone (1mg/kg, i.p.), was able to prevent the antidepressant-like effect of UA (0.1mg/kg, p.o.). Sub-effective doses of fluoxetine (5mg/kg, p.o.) or reboxetine (2mg/kg, p.o.), but not ketamine (0.1mg/kg, i.p.) or MK-801 (0.001 mg/kg, p.o.), was capable of potentiating the effect of a sub-effective dose of UA (0.001 mg/kg, p.o.) in the TST. None of the treatments affected locomotor activity. Altogether, the results show an involvement of the serotonergic and noradrenergic systems, but not the glutamatergic or opioid systems, in the antidepressant-like effect of UA.

The activation of α1-adrenoceptors is implicated in the antidepressant-like effect of creatine in the tail suspension test.

The antidepressant-like activity of creatine in the tail suspension test (TST) was demonstrated previously by our group. In this study we investigated the involvement of the noradrenergic system in the antidepressant-like effect of creatine in the mouse TST. In the first set of experiments, creatine administered by i.c.v. route (1 μg/site) decreased the immobility time in the TST, suggesting the central effect of this compound. The anti-immobility effect of peripheral administration of creatine (1 mg/kg, p.o.) was prevented by the pretreatment of mice with α-methyl-p-tyrosine (100 mg/kg, i.p., inhibitor of tyrosine hydroxylase), prazosin (1 mg/kg, i.p., α1-adrenoceptor antagonist), but not by yohimbine (1 mg/kg, i.p., α2-adrenoceptor antagonist). Creatine (0.01 mg/kg, subeffective dose) in combination with subeffective doses of amitriptyline (1 mg/kg, p.o., tricyclic antidepressant), imipramine (0.1 mg/kg, p.o., tricyclic antidepressant), reboxetine (2 mg/kg, p.o., selective noradrenaline reuptake inhibitor) or phenylephrine (0.4 μg/site, i.c.v., α1-adrenoceptor agonist) reduced the immobility time in the TST as compared with either drug alone. These results indicate that the antidepressant-like effect of creatine is likely mediated by an activation of α1-adrenoceptor and that creatine produces synergistic effects in the TST with antidepressants that modulate noradrenaline transporter, suggesting that an improvement in the response to the antidepressant therapy may occur when creatine is combined with these antidepressants. Furthermore, the synergistic effect of creatine (0.01 mg/kg, p.o.) and reboxetine (2 mg/kg, p.o.) combination was abolished by the α1-adrenoceptor antagonist prazosin, indicating that the antidepressant-like effect of combined therapy is likely mediated by an activation of α1-adrenoceptor.

The antidepressant-like effect of physical activity on a voluntary running wheel.

PURPOSE Physical activity is currently being considered an effective alternative in the treatment of depression. At the preclinical level, the voluntary running wheel is a useful method of increasing physical activity in rodents and induces an antidepressant-like effect in some behavioral paradigms. METHODS This study investigated the effect of physical activity on a voluntary running wheel in mice submitted to the forced swimming test (FST) and tail suspension test, two predictive tests of antidepressant properties. Moreover, the influence of the inhibition of serotonin and noradrenaline synthesis as well as the inhibition of protein kinase A (PKA) and calcium/calmodulin-dependent protein kinase II (CAMK-II) activity by pharmacological agents in the antidepressant-like action of physical activity was investigated. RESULTS Physical activity on a voluntary running wheel by 21 d produced a reduction in the immobility time in the FST and tail suspension test, without producing alteration on locomotor activity in the open-field test. The antidepressant-like effect in the FST elicited by physical activity lasted for 7 d after removal of the running wheel. The anti-immobility effect of physical activity was prevented by the pretreatment of mice with p-chlorophenylalanine methyl ester (100 mg·kg, i.p., once a day, for four consecutive days, inhibitor of serotonin synthesis), α-methyl-p-tyrosine (100 mg·kg, i.p., an inhibitor of noradrenaline and dopamine synthesis), H-89 (1 μg per site, i.c.v., a PKA inhibitor), and KN-62 (1 μg per site, i.c.v., a CAMK-II inhibitor). CONCLUSIONS Taken together, these results first suggest that the effect of physical activity on the FST is dependent on either the increase in the bioavailability of monoamines in the synaptic cleft or an activation of intracellular signaling pathways mediated by PKA and CAMK-II.

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 (1mg/kg) was prevented by the pretreatment of mice with p-chlorophenylalanine methyl ester (PCPA; 100mg/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 (0.1mg/kg, s.c., a 5-HT1A receptor antagonist), 8-OH-DPAT (0.1mg/kg, i.p., a 5-HT1A receptor agonist) or selective serotonin reuptake inhibitors fluoxetine (5mg/kg, p.o.), paroxetine (0.1mg/kg, p.o.), citalopram (0.1mg/kg, p.o.) and sertraline (3mg/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-HT1A 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.

Involvement of PKA, PKC, CAMK-II and MEK1/2 in the acute antidepressant-like effect of creatine in mice

BACKGROUND The aim of this study was to investigate the involvement of signaling pathways on the creatine antidepressant-like effect in the tail suspension test (TST) in mice. METHODS The TST was used to assess the antidepressant-like properties of creatine. RESULTS The anti-immobility effect of creatine (1mg/kg, p.o.) in the TST was blocked by i.c.v. pretreatment with H-89 (1μg/site, PKA inhibitor), KN-62 (1μg/site, CAMK-II inhibitor), chelerythrine (1μg/site, PKC inhibitor), U0126 (5μg/site, MEK1/2 inhibitor) or PD09058 (5μg/site, MEK1/2 inhibitor). CONCLUSION These results suggest that the antidepressant-like effect of creatine is dependent on PKA, CaMK-II, PKC and MEK 1/2 activation.