The effect of voluntary wheel running on the antioxidant status is dependent on sociability conditions.

Voluntary wheel running is widely used as a physical activity (PA) model in rodents, but most studies investigate the beneficial effects of this intervention in socially isolated mice. Social isolation stress (SIS) is associated with vulnerability to oxidative stress and reduced mitochondrial activity. Thus, the aim of this study was to investigate the effects of free access to a running wheel for 21 days on the various markers of the cellular redox/antioxidant status as well as mitochondrial function of mice subjected to SIS or maintained in groups of 3 in the homecage. SIS increased thiobarbituric acid reactive substance (TBARS) levels in the cerebral cortex, and PA intervention was not able to reverse such alteration. PA reduced TBARS levels in the liver of grouped mice and gastrocnemius of socially isolated mice. PA increased nonprotein thiol (NPSH) levels in the cerebral cortex of grouped mice. Furthermore, socially isolated mice presented lower glutathione peroxidase (GPx) activity in the cerebellum and gastrocnemius, and glutathione reductase (GR) activity in the cerebral cortex and liver. By contrast, SIS induced higher GPx activity in the cerebral cortex and heart. PA reduced GPx (cerebral cortex) and GR (cerebral cortex and liver) activities of socially isolated mice. SIS caused higher activity of mitochondrial complexes I and II in the cerebral cortex, and the PA paradigm was not able to alter this effect. Interestingly, the PA produced antidepressant-like effect at both SIS and control groups. In conclusion, the results showed the influence of SIS for the effects of PA on the antioxidant status, but not on the mitochondrial function and emotionality.

Increased susceptibility of brain acetylcholinesterase activity to methylmalonate in young rats with renal failure.

Tissue methylmalonic acid (MMA) accumulation is the biochemical hallmark of methylmalonic acidemia. Clinically, the disease is characterized by progressive neurological deterioration and renal failure, whose pathophysiology is still undefined. In the present study we investigated the effect of acute MMA administration on some important parameters of brain neurotransmission in cerebral cortex of rats, namely Na(+), K(+)-ATPase, ouabain-insensitive ATPases and acetylcholinesterase activities, in the presence or absence of kidney injury induced by gentamicin administration. Initially, thirty-day old Wistar rats received one intraperitoneal injection of saline or gentamicin (70 mg/kg). One hour after, the animals received three consecutive subcutaneous injections of MMA (1.67 µmol/g) or saline, with an 11 h interval between each injection. One hour after the last injection the animals were killed and the cerebral cortex isolated. MMA administration by itself was not able to modify Na(+), K(+)-ATPase, ATPases ouabain-insensitive or acetylcholinesterase activities in cerebral cortex of young rats. In rats receiving gentamicin simultaneously with MMA, it was observed an increase in the activity of acetylcholinesterase activity in cerebral cortex, without any alteration in the activity of the other studied enzymes. Therefore, it may be speculated that cholinergic imbalance may play a role in the pathogenesis of the brain damage. Furthermore, the pathophysiology of tissue damage cannot be exclusively attributed to MMA toxicity, and control of kidney function should be considered as a priority in the management of these patients, specifically during episodes of metabolic decompensation when MMA levels are higher.

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.

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.

Fluoxetine modulates hippocampal cell signaling pathways implicated in neuroplasticity in olfactory bulbectomized mice.

The olfactory bulbectomy (OB) animal model of depression is a well-established model that is capable of detecting antidepressant activity following chronic drug therapy, and the surgery results in behavioral and biochemical changes that are reminiscent of various symptoms of depression. In the present study, we investigated the degree to which 14 days of p.o. administration of the classic antidepressant fluoxetine (10mg/kg) were able to reverse OB-induced changes in behavior (namely, hyperactivity in the open-field test and reduced motivational and self-care behaviors in the splash test) and in the activation of hippocampal cell signaling pathways that are thought to be involved in synaptic plasticity. OB caused significant increases in ERK1 and CREB (Ser(133)) phosphorylation and in the expression of BDNF immunocontent, all of which were prevented by fluoxetine administration. Moreover, fluoxetine administration also caused a significant decrease in ERK2 phosphorylation in mice that had undergone OB. Neither Akt nor GSK-3ß phosphorylation was altered in any experimental condition. In conclusion, the present study shows that OB can induce significant behavioral changes that are accompanied by the activation of hippocampal signaling pathways, namely the ERK1/CREB/BDNF pathway, which is involved in the synaptic plasticity. Conversely, fluoxetine prevented these OB-induced behavioral changes and avoided the activation of ERK1/CREB/BDNF in the hippocampus. Taken together, our results extend the data from the existing literature regarding OB-induced behavioral and neurochemical changes, and suggest a possible underlying mechanism that can account for the antidepressant effect of fluoxetine in this model.

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.

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.

Antidepressant-like action of the bark ethanolic extract from Tabebuia avellanedae in the olfactory bulbectomized mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Tabebuia avellanedae Lorentz ex Griseb is a plant employed in tropical America folk medicine for the treatment of several diseases, including depressive disorders. AIM OF THE STUDY: To investigate the ability of Tabebuia avellanedae ethanolic extract (EET) administered chronically to cause an antidepressant-like effect in the tail suspension test (TST), a predictive test of antidepressant activity, and to reverse behavioral (hyperactivity, anhedonic-like behavior and increased immobility time in the TST) and biochemical changes induced by olfactory bulbectomy (OB), a model of depression, in mice. MATERIALS AND METHODS: Mice were submitted to OB to induce depressive-related behaviors, which were evaluated in the open-field test (hyperactivity), splash test (loss of motivational and self-care behavior indicative of an anhedonic-like behavior) and TST (increased immobility time). Phosphorylation levels of Akt, GSK-3ß, ERK1/2 and CREB, as well as BDNF immunocontent, were evaluated in the hippocampus of bulbectomized mice or sham-operated mice treated for 14 days by p.o. route with EET or vehicle. RESULTS: EET (10 and 30mg/kg) given 14 days by p.o route to mice reduced the immobility time in the TST without altering locomotor activity, an indicative of an antidepressant-like effect. EET per se increased both CREB (Ser(133)) and GSK-3ß (Ser(9)) phosphorylation (at doses of 10-30 and 30mg/kg, respectively) in sham-operated mice. OB caused hyperactivity, loss of motivational and self-care behavior, increased immobility time in the TST and an increase in CREB and ERK1 phosphorylation, as well as BDNF immunocontent. EET abolished all these OB-induced alterations except the increment of CREB phosphorylation. Akt (Ser(473)) and ERK2 phosphorylation levels were not altered in any group. CONCLUSIONS: EET ability to abolish the behavioral changes induced by OB was accompanied by modulation of ERK1 and BDNF signaling pathways, being a promising target of EET. Results indicate that this plant could constitute an attractive strategy for the management of depressive disorders, once more validating the traditional use of this plant.

Fluoxetine reverses depressive-like behaviors and increases hippocampal acetylcholinesterase activity induced by olfactory bulbectomy.

The olfactory bulbectomy (OB) is an animal model of depression that results in behavioral, neurochemical and neuroendocrinological changes, features comparable to those seen in depressive patients. This study investigated OB-induced alterations in locomotor activity and exploratory behavior in the open-field test, self-care and motivational behavior in the splash test, hyperactivity in the novel object test and novel cage test, and the influence of chronic treatment with fluoxetine (10mg/kg, p.o., once daily for 14days) on these parameters. Fluoxetine reversed OB-induced hyperactivity in the open-field test, locomotor hyperactivity and the increase in exploratory behavior induced by novelty in the novel object and novel cage tests, and the loss of self-care and motivational behavior in the splash test. Moreover, OB decreased the number of grooming and fecal boli in the open-field and novel cage tests, alterations that were not reversed by fluoxetine. OB caused an increase in hippocampal, but not in prefrontal acetylcholinesterase (AChE) activity. Fluoxetine was able to reverse the increase in hippocampal AChE activity induced by OB. Serum corticosterone was increased in SHAM and bulbectomized mice treated with fluoxetine. In conclusion, OB mice exhibited depressive-like behaviors associated with an increase in hippocampal AChE activity, effects that were reversed by chronic treatment with fluoxetine.

Involvement of monoaminergic systems in the antidepressant-like effect of Eugenia brasiliensis Lam. (Myrtaceae) in the tail suspension test in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Several species of Eugenia L. are used in folk medicine for the treatment of various diseases. Eugenia brasiliensis is used for the treatment of inflammatory diseases, whereas Eugenia. uniflora is used for the treatment of symptoms related to depression and mood disorders, and is used in Brazil by the Guarani Indians as a tonic stimulant. AIM OF THE STUDY: To investigate the antidepressant-like effect of hydroalcoholic extracts of different plant species of genus Eugenia and to characterize the participation of the monoaminergic systems in the mechanism of action of the specie that afforded the most prominent antidepressant-like efficacy. MATERIALS AND METHODS: In the first set of experiments, the effects of hydroalcoholic extracts of Eugenia beaurepaireana, Eugenia brasiliensis, Eugenia catharinae, Eugenia umbelliflora and Eugenia uniflora and the antidepressant fluoxetine (positive control) administered acutely by p.o. route were evaluated in the tail suspension test (TST) and locomotor activity was assessed in the open-field test in mice. In the second set of experiments, the involvement of the monoaminergic systems in the antidepressant-like activity of Eugenia brasiliensis was evaluated by treating mice with several pharmacological agonists and antagonists. The effects of the combined administration of sub-effective doses of Eugenia brasiliensis and the antidepressants fluoxetine, imipramine and bupropion were also evaluated. RESULTS: The administration of the extracts from Eugenia brasiliensis, Eugenia catharinae and Eugenia umbelliflora, but not Eugenia beaurepaireana and Eugenia uniflora, exerted a significant antidepressant-like effect, without altering locomotor activity. The behavioral profile was similar to fluoxetine. Pre-treatment of mice with ketanserin, haloperidol, SCH23390, sulpiride, prazosin and yohimbine prevented the reduction of immobility time induced by Eugenia brasiliensis. Treatment with sub-effective doses of WAY100635, SKF38393, apomorphine, phenylephrine, but not clonidine, combined with a sub-effective dose of Eugenia brasiliensis decreased the immobility time in the TST. Furthermore, the combined administration of sub-effectives doses of Eugenia brasiliensis with fluoxetine, imipramine and bupropion produced an antidepressant-like effect. CONCLUSIONS: This study show, for the first time, the antidepressant-like effect of species of the genus Eugenia, especially Eugenia brasiliensis, whose effects in the TST seem to be mediated by serotoninergic (5-HT(1A) and 5-HT(2) receptors), noradrenergic (α(1)-adrenoceptor) and dopaminergic (dopamine D(1) and D(2) receptors) systems.

Involvement of NMDA receptors in the antidepressant-like action of adenosine.

BACKGROUND AND METHOD: In this work, the contribution of NMDA receptors to the antidepressant-like effect of adenosine in the forced swimming test (FST) was investigated. RESULTS: The pretreatment of mice with NMDA or D-serine was able to prevent the anti-immobility effect of either adenosine or MK-801 in the FST. In addition, the administration of a sub-effective dose of adenosine produced a synergistic effect with sub-effective doses of MK-801, ketamine and zinc chloride. Moreover, the immobility time of the mice treated with active doses of adenosine or N(6)-cyclohexyladenosine (CHA) plus MK-801 was not significantly different from that obtained with adenosine, CHA and MK-801 alone; by contrast, the combination between active doses of adenosine and CHA plus an active dose of the tricyclic antidepressant imipramine produced a greater effect in the FST than the administration of either drug alone. CONCLUSION: Together, the results suggest that the effect of adenosine in the FST is likely dependent on the inhibition of NMDA receptors mediated by the activation of adenosine A(1) receptors.

Rosmarinus officinalis L. hydroalcoholic extract, similar to fluoxetine, reverses depressive-like behavior without altering learning deficit in olfactory bulbectomized mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Rosemary, Rosmarinus officinalis L., has several therapeutic applications in folk medicine for the treatment of a wide range of diseases, including depression. AIM OF THE STUDY: To evaluate the ability of Rosmarinus officinalis hydroalcoholic extract (ROHE), as compared to the positive control fluoxetine, to reverse behavioral (hyperactivity, anhedonic behavior and learning deficit in water maze) and biochemical alterations (serum glucose level and acetylcholinesterase, AChE, activity) induced by an animal model of depression, the olfactory bulbectomy (OB) in mice. MATERIALS AND METHODS: Locomotor and exploratory behavior was assessed in the open-field, novel object and novel cage tests, anhedonic behavior was assessed in the splash test; cognitive deficits were evaluated in the water maze task. For the first set of experiments, ROHE (10-300 mg/kg) or fluoxetine (10mg/kg) was administered once daily (p.o.) for 14 days after OB and the behavioral tests were performed. For the second set of experiments, serum glucose and hippocampal and cerebrocortical AChE activity were determined in OB and SHAM-operated mice treated orally with ROHE (10mg/kg), fluoxetine (10mg/kg) or vehicle. RESULTS: ROHE (10-300 mg/kg), similar to fluoxetine, reversed OB-induced hyperactivity, increased exploratory and anhedonic behavior. OB needed significantly more trials in the training session to acquire the spatial information, but they displayed a similar profile to that of SHAM mice in the test session (24h later), demonstrating a selective deficit in spatial learning, which was not reversed by ROHE or fluoxetine. A reduced serum glucose level and an increased hippocampal AChE activity were observed in bulbectomized mice; only the latter effect was reversed by fluoxetine, while both effects were reversed by ROHE. CONCLUSIONS: ROHE exerted an antidepressant-like effect in bulbectomized mice and was able to abolish AchE alterations and hypoglycemia, but not spatial learning deficit induced by OB. Overall, results suggest the potential of Rosmarinus officinalis for the treatment of depression, validating the traditional use of this plant.

Antidepressant-like effect of creatine in mice involves dopaminergic activation.

Creatine has been shown to play a significant role in health and disease. However, studies concerning its effect on mood are scarce. This study investigated the effect of creatine (p.o.) in the tail suspension test, a predictive test of antidepressant activity. Creatine reduced the immobility time in the tail suspension test (0.1-1000 mg/kg, male and female mice), without affecting locomotor activity. Furthermore, the involvement of the dopaminergic system in creatine-induced antidepressant-like effect in male mice in the tail suspension test was investigated. The anti-immobility effect of creatine (1 mg/kg) was prevented by the pre-treatment of mice with haloperidol (0.2 mg/kg, intraperitoneal (i.p.) route, non-selective dopamine receptor antagonist), (R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390; 0.05 mg/kg, subcutaneous (s.c.) route, dopamine D1 receptor antagonist) and sulpiride (50 mg/kg, i.p., dopamine D2 receptor antagonist). Creatine (0.01 mg/kg, sub-effective dose) in combination with sub-effective doses of (1-phenyl-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine) hydrochloride (SKF38393; 0.1 mg/kg, s.c., dopamine D1 receptor agonist), apomorphine (0.5 µg/kg, i.p., preferential dopamine D2 receptor agonist) or bupropion (1 mg/kg, p.o., dopamine reuptake inhibitor with subtle activity on noradrenergic reuptake) 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 activation of dopamine D1 and D2 receptors.

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., ß-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-HT2A receptors), noradrenergic (α2 and ß-receptor) and dopaminergic (D1 and D2 receptors) systems.

Antidepressant-like effect of scopoletin, a coumarin isolated from Polygala sabulosa (Polygalaceae) in mice: evidence for the involvement of monoaminergic systems.

The relationship between depression and monoaminergic systems has been hypothesized for many years. In this study, we have investigated the possible antidepressant-like effect of scopoletin, a coumarin from Polygala sabulosa in the tail suspension test and forced swimming test. Moreover, the ability of scopoletin to reverse the depression-like behavior in the forced swimming test induced by immobility stress in mice was evaluated. Scopoletin reduced the immobility time in the tail suspension test (10-100mg/kg, p.o.), but not in the forced swimming test. Fluoxetine (positive control) decreased the immobility time in the forced swimming and tail suspension tests (20mg/kg, p.o. and 10mg/kg. p.o., respectively). Immobility stress caused an increase in the immobility time in the forced swimming test (depression-like behavior), which was reversed by scopoletin (1-100mg/kg, p.o.) and fluoxetine (10mg/kg, p.o.). Scopoletin produced no psychostimulant effect in the open-field test. The pretreatment of mice with ketanserin (5mg/kg, i.p., a preferential 5-HT(2A) receptor antagonist), prazosin (1mg/kg, i.p., an alpha(1)-adrenoceptor antagonist), yohimbine (1mg/kg, i.p., an alpha(2)-adrenoceptor antagonist), haloperidol (0.2mg/kg, i.p., a dopaminergic receptor antagonist), SCH23390 (0.05 mg/kg, s.c., a dopamine D(1) receptor antagonist) or sulpiride (50mg/kg, i.p., a dopamine D(2) receptor antagonist), but not WAY100635 (0.1mg/kg, s.c., a selective 5-HT(1A) receptor antagonist) prevented the antidepressant-like effect of scopoletin (10mg/kg, p.o.) in the tail suspension test. The results indicate that its antidepressant-like effect is dependent on the serotonergic (5-HT(2A) receptors), noradrenergic (alpha(1)- and alpha(2)-adrenoceptors) and dopaminergic (dopamine D(1) and D(2) receptors) systems.

Effects of traumatic brain injury of different severities on emotional, cognitive, and oxidative stress-related parameters in mice.

Cognitive deficits and psychiatric disorders are significant sequelae of traumatic brain injury (TBI). Animal models have been widely employed in TBI research, but few studies have addressed the effects of experimental TBI of different severities on emotional and cognitive parameters. In this study, mice were subjected to weight-drop TBI to induce mild, intermediate, or severe TBI. After neurological assessment, the mice recovered for 10 days, and were then subjected to a battery of behavioral tests, which included open-field, elevated plus-maze, forced swimming, tail suspension, and step-down inhibitory avoidance tests. Oxidative stress-related parameters (nonprotein thiols [NPSH], glutathione peroxidase [GPx], glutathione reductase [GR], and thiobarbituric acid reactive species [TBARS]) were quantified in the cortex and hippocampus at 2 and 24 h and 14 days after TBI, and histopathological analysis was performed 15 days after TBI. Mice subjected to mild TBI showed increased anxiety and depressive-like behaviors, while intermediate and severe TBI induced robust memory deficits. The severe TBI group also displayed increased locomotor activity. Intermediate and severe TBI caused extensive macroscopic and microscopic brain damage, while mild TBI typically had no histological abnormalities. Moreover, a significant increase in TBARS in the ipsilateral cortex and GPx in the ipsilateral hippocampus was observed at 24 h and 14 days, respectively, following intermediate TBI. The current experimental TBI model induced emotional and cognitive changes comparable to sequelae seen in human TBI, and it might therefore represent a useful approach to the study of mechanisms of and new treatments for TBI and related disorders.

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 alpha(1)-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an alpha(2)-adrenoceptor antagonist), propranolol (2 mg/kg, i.p., a beta-adrenoceptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D(2) receptor antagonist) and SCH23390 (0.05 mg/kg, s.c., a dopamine D(1) 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-HT(3) receptor agonist), prazosin (1 mg/kg, i.p., an alpha(1-)adrenoceptor antagonist), SCH23390 (0.05 mg/kg, s.c., a dopamine D(1) receptor antagonist) or sulpiride (50 mg/kg, i.p., a dopamine D(2) receptor antagonist), but not yohimbine (1 mg/kg, i.p., an alpha(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-HT(3) 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.

Interaction of zinc with antidepressants in the tail suspension test.

The antidepressant-like effect of zinc has been shown in several animal models of depression. In this study, zinc chloride (ZnCl2) was given alone or in combination with different classes of antidepressants by oral route (p.o.) to mice and the behavioral response in the tail suspension test (TST), a predictive test of antidepressant action, was investigated. ZnCl2 at a dose of 10 and 30 mg/kg, p.o., reduced the immobility time in the TST, without affecting the locomotor activity in open-field test. The antidepressants fluoxetine, paroxetine, imipramine, desipramine and bupropion produced a significant reduction in the immobility time in TST at the doses of 10, 1, 1, 1 and 10 mg/kg, p.o., respectively. The combined treatment of sub-effective doses of ZnCl2 (1 mg/kg) with sub-effective doses of fluoxetine (5 mg/kg), paroxetine (0.1 mg/kg), desipramine (0.1 mg/kg), imipramine (0.1 mg/kg) or bupropion (1 mg/kg) induced a significant reduction in the immobility time in the TST when compared with the groups treated with ZnCl2 or with antidepressants alone. The treatment with sub-effective doses of ZnCl2 and antidepressants alone or in combination did not affect the locomotion in open-field test, except that desipramine alone reduced the ambulation. The results first indicate that ZnCl2 administered by p.o. route produces an antidepressant-like effect in the TST. Moreover, synergistic effects of zinc with antidepressants were shown in the TST, suggesting that an improvement in the response to the antidepressant therapy occurs when zinc is combined with different classes of antidepressants.

Antidepressant-like effect of rutin isolated from the ethanolic extract from Schinus molle L. in mice: evidence for the involvement of the serotonergic and noradrenergic systems.

We have recently shown that the hexanic extract from leaves of Schinus molle produces antidepressant-like effects in the tail suspension test in mice. This study investigated the antidepressant-like effect of the ethanolic extract from aerial part of S. molle in the forced swimming test and tail suspension test in mice, two predictive models of depression. Moreover, we investigated the antidepressant potential of rutin, a flavonoid isolated from the ethanolic extract of this plant and the influence of the pretreatment with the inhibitors of serotonin or noradrenaline synthesis, p-chlorophenylalanine methyl ester (PCPA) and alpha-methyl-p-tyrosine (AMPT), respectively in the antidepressant-like effect of this flavonoid. The administration of the ethanolic extract produced a reduction in the immobility time in the tail suspension test (dose range 600-1000 mg/kg, p.o.), but not in the forced swimming test. It also produced a reduction in the ambulation in the open-field test in mice not previously habituated to the arena, but no effect in the locomotor activity in mice previously habituated to the open-field. The administration of rutin reduced the immobility time in the tail suspension test (0.3-3 mg/kg, p.o.), but not in the forced swimming test, without producing alteration in the locomotor activity. In addition, pretreatment of mice with PCPA (100 mg/kg, i.p., for 4 consecutive days) or AMPT (100 mg/kg, i.p.) prevented the anti-immobility effect of rutin (0.3 mg/kg, p.o.) in the tail suspension test. The results firstly indicated the antidepressant-like effect of the ethanolic extract of S. molle in the tail suspension test may be dependent on the presence of rutin that likely exerts its antidepressant-like effect by increasing the availability of serotonin and noradrenaline in the synaptic cleft.