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In this study, we examined the ability of subchronic ascorbic acid administration to produce an antidepressant-like effect in the mouse tail suspension test (TST). Moreover, we investigated the effect of this vitamin on hippocampal and cerebrocortical brain-derived neurotrophic factor (BDNF) immunocontent, phosphorylation of protein kinase B (AKT), extracellular signal-regulated kinase (ERK), p38MAPK and c-Jun. N-terminal kinase (JNK). Fluoxetine (10 mg/kg, positive control, po) or ascorbic acid (0.1 and 1 mg/kg, po), administered once daily for 21 days, produced a significant antidepressant-like effect in the TST. The significant effects obtained in protein immunocontents were: administration of ascorbic acid at 1 mg/kg induced an increase in AKT phosphorylation in cerebral cortex of mice. Ascorbic acid treatment (1 mg/kg), similar to fluoxetine, decreased hippocampal p38MAPK but did not alter ERK or JNK phosphorylation. These results extend the data about the antidepressant-like effect of ascorbic acid by exploring, for the first time, the intracellular pathways involved in its antidepressant properties after subchronic administration. [ABSTRACT FROM AUTHOR]

Major depressive disorder is a disabling psychiatric condition that causes a significant burden on individuals and society. There is still a lack of a clear understanding of the neuropathological changes associated with this illness and the efficacy of antidepressants is still far from optimal. Research into antidepressant therapies has evolved from serendipitous observation in human trials, but more than 60 years after the first monoaminergic antidepressants emerged they remain the mainstay for treating depression. However, glutamatergic modulators such as ketamine became the forefront of antidepressant exploration, especially for treatment-resistant depression and suicidal ideation. The glutamatergic hypothesis of depression is not new, however other NMDA receptor modulators do not seem to share the rapid and sustained effects of ketamine, suggesting that a unique combination of intracellular targets might be involved in its effect. Interestingly, inflammation can impact the glutamatergic system enhancing excitotoxicity and decreasing neuroplasticity. The points of convergence between the inflammatory and glutamatergic hypotheses of depression are not completely established, especially regarding the effects of fast-acting antidepressants. In this review, we discuss the most recent research surrounding glutamatergic fast-acting antidepressants, capable of modulating cellular plasticity and synaptogenesis and the potential of anti-inflammatory compounds evaluated from a different perspective. The combination of innovative ideas plus improvements on the discoveries made so far might lead to advances in antidepressant research with the promise of finding compounds that are both effective and fast-acting, even in patients who have tried other therapies with limited success. [ABSTRACT FROM AUTHOR]

Considering that intracellular signaling pathways that modulate brain BDNF are implicated in antidepressant responses, this study investigated whether signaling pathway inhibitors upstream to BDNF might influence the antidepressant-like effect of zinc, a metal that has been shown to display antidepressant properties. To this end, the influence of i.c.v. administration of H-89 (1 μg/site, PKA inhibitor), KN-62 (1 μg/site, CAMKII inhibitor), chelerythrine (1 μg/site, PKC inhibitor), PD98059 (5 μg/site, MEK1/2 inhibitor), U0126 (5 μg/site, MEK1/2 inhibitor), LY294002 (10 nmol/site, PI3K inhibitor) on the reduction of immobility time in the tail suspension test (TST) elicited by ZnCl 2 (10 mg/kg, p.o.) was investigated. Moreover, the effect of the combination of sub-effective doses of ZnCl 2 (1 mg/kg, p.o.) and AR-A014418 (0.001 μg/site, GSK-3β inhibitor) was evaluated. The occurrence of changes in CREB phosphorylation and BDNF immunocontent in the hippocampus and prefrontal cortex of mice following ZnCl 2 treatment was also investigated. The anti-immobility effect of ZnCl 2 in the TST was prevented by treatment with PKA, PKC, CAMKII, MEK1/2 or PI3K inhibitors. Furthermore, ZnCl 2 in combination with AR-A014418 caused a synergistic anti-immobility effect in the TST. None of the treatments altered locomotor activity of mice. ZnCl 2 treatment caused no alteration in CREB phosphorylation and BDNF immunocontent. The results extend literature data regarding the mechanisms underlying the antidepressant-like action of zinc by indicating that its antidepressant-like effect may be dependent on the activation of PKA, CAMKII, PKC, ERK, and PI3K/GSK-3β pathways. However, zinc is not able to acutely increase BDNF in the hippocampus and prefrontal cortex. [ABSTRACT FROM AUTHOR]

Agmatine, an endogenous guanidine amine, has been shown to produce antidepressant-like effects in animal studies. This study investigated the effects of the combined administration of agmatine with either conventional monoaminergic antidepressants or the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 in the tail suspension test (TST) in mice. The aim was to evaluate the extent of the antidepressant synergism by examining the ability of a fixed dose of agmatine to shift the antidepressant potency of fluoxetine, imipramine, bupropion and MK-801. A sub-effective dose of agmatine (0.0001 mg/kg, p.o.) significantly increased the potency by which fluoxetine, imipramine, bupropion and MK-801 decreased immobility time in the TST by 2-fold (fluoxetine), 10-fold (imipramine and bupropion) and 100-fold (MK-801). Combined with previous evidence indicating a role of monoaminergic systems in the effect of agmatine, the current data suggest that agmatine may modulate monoaminergic neurotransmission and augment the activity of conventional antidepressants. Moreover, this study found that agmatine substantially augmented the antidepressant-like effect of MK-801, reinforcing the notion that this compound modulates NMDA receptor activation. These preclinical data may stimulate future clinical studies testing the effects of augmentation therapy with agmatine for the management of depressive disorders. [ABSTRACT FROM AUTHOR]

Abstract: The present study investigated the involvement of the PI3K, GSK-3β, heme oxygenase-1 (HO-1) and mTOR in the antidepressant-like effect of ascorbic acid in the tail suspension test (TST). Male Swiss mice were pretreated with ascorbic acid (1 mg/kg, p.o.) or vehicle and 45 min after, LY294002 (10 μg/site, i.c.v., reversible PI3K inhibitor), rapamycin (0.2 nmol/site, i.c.v., selective mTOR inhibitor), zinc protoporphyrin (ZnPP – 10 ng/site, i.c.v., HO-1 inhibitor) or vehicle was administered. We also investigated the synergistic effect of ascorbic acid (0.1 mg/kg, p.o., sub-effective dose in the TST) with lithium chloride (10 mg/kg, p.o., non-selective GSK-3β inhibitor), AR-A014418 (0.01 μg/site, i.c.v., selective GSK-3β inhibitor) or cobalt protoporphyrin (CoPP – 0.01 μg/site, i.c.v., HO-1 inducer) in the TST. The antidepressant-like effect of ascorbic acid (1 mg/kg, p.o.) was prevented by the treatment of mice with LY294002, rapamycin or ZnPP. In addition, sub-effective doses of lithium chloride, AR-A014418 or CoPP, combined with a sub-effective dose of ascorbic acid produced a synergistic antidepressant-like effect. We also demonstrated that 1 h after its administration, ascorbic acid increased the phosphorylation of p70S6K and the immunocontent of PSD-95 in the hippocampus of mice. These results indicate that the antidepressant-like effect of ascorbic acid in the TST might be dependent on the activation of PI3K and mTOR, inhibition of GSK-3β as well as induction of HO-1, reinforcing the notion that these are important targets for antidepressant activity and contributing to better elucidate the mechanisms underlying the antidepressant-like effect of ascorbic acid. [Copyright &y& Elsevier]

Abstract: Considering that the administration of ascorbic acid elicits an antidepressant-effect in mice by a mechanism which involves an interaction with N-methyl-d-aspartate receptors and the l-arginine-nitric oxide-cGMP pathway and taking into account that the stimulation of this pathway is associated with the activation of potassium (K+) channels, this study investigated the involvement of different types of K+ channels on the effect of ascorbic acid in the mouse tail suspension test (TST). Intracerebroventricular administration of tetraethylammonium (TEA, a non-specific blocker of K+ channels, 25pg/site), glibenclamide (an ATP-sensitive K+ channel blocker, 0.5pg/site), charybdotoxin (a large- and intermediate conductance calcium-activated K+ channel blocker, 25pg/site) or apamin (a small-conductance calcium-activated K+ channel blocker, 10pg/site) was able to produce a synergistic effect with a sub-effective dose of ascorbic acid (0.1mg/kg) given orally (p.o.). The antidepressant-like effect of ascorbic acid (1mg/kg, p.o.) in the TST was prevented by the pre-treatment of mice with cromakalim (a K+ channel opener, 10μg/site, i.c.v.) and minoxidil (10μg/site, i.c.v.). Moreover, cromakalim abolished the synergistic effect elicited by the combined treatment with sub-effective doses of ascorbic acid and 7-nitroindazole. The administration of the K+ channel modulators alone or in combination with ascorbic acid did not affect the locomotion of mice. Together, our results show that the antidepressant-like effect of ascorbic acid in the TST may involve, at least in part, the modulation of neuronal excitability, via inhibition of K+ channels. [Copyright &y& Elsevier]

Abstract: Reactive oxygen species (ROS) have been shown to play a role in the pathophysiology of depression. Taking into account that experimental chronic unpredictable stress (CUS) induces depressive-like behavior and that ascorbic acid has antidepressant-like effect in animals, the objective of this study was to investigate the influence of ascorbic acid on depressive-like behavior induced by CUS paradigm, serum corticosterone levels and markers of oxidative stress in cerebral cortex and hippocampus of mice. Animals were submitted to CUS procedure during 14 days. From the 8th to the 14th day mice received ascorbic acid (10 mg/kg) or fluoxetine (10 mg/kg, conventional antidepressant, positive control) once a day by oral route. On 15th day behavioral and biochemical parameters were analyzed. CUS exposure caused a depressive-like behavior evidenced by the increased immobility time in the tail suspension test and decreased time in which mice spent grooming in the splash test. Depressive-like behavior induced by CUS was accompanied by a significant increased lipid peroxidation (cerebral cortex and hippocampus), decreased catalase (CAT) (cerebral cortex and hippocampus) and glutathione reductase (GR) (hippocampus) activities and reduced levels of glutathione (cerebral cortex). Repeated ascorbic acid or fluoxetine administration significantly reversed CUS-induced depressive-like behavior and oxidative damage. No alteration was observed in locomotor activity, corticosterone levels and glutathione peroxidase (GPx) activity. These findings indicate a rapid and robust effect of ascorbic acid in reversing behavioral and biochemical alterations induced by CUS in mice, suggesting that this vitamin may be an alternative approach for the management of depressive symptoms. [Copyright &y& Elsevier]

Abstract: Clinical and preclinical data reported that ascorbic acid has antidepressant properties. The present study was designed to investigate the participation of l-arginine–NO–cGMP pathway in the antidepressant-like effect of ascorbic acid in the tail suspension test (TST) in mice. The antidepressant-like effect of ascorbic acid (1mg/kg, p.o.) in the TST was prevented by the pre-treatment of mice with NMDA (0.1pmol/site, i.c.v.), l-arginine (750mg/kg, i.p., a substrate for nitric oxide synthase) or sildenafil (5mg/kg, i.p., a phosphodiesterase 5 inhibitor). The administration of MK-801 (0.001mg/kg, i.p), 7-nitroindazole (25mg/kg, i.p., a neuronal nitric oxide synthase inhibitor) or ODQ (30pmol/site i.c.v., a soluble guanylate cyclase inhibitor) in combination with a sub-effective dose of ascorbic acid (0.1mg/kg, p.o.) reduced the immobility time in the TST test when compared with either drug alone. None of the results in the TST appears to be due to a nonspecific locomotor effect. Our findings provide evidence that the effect of ascorbic acid in the TST involve an interaction with NMDA receptors and l-arginine–NO–cGMP pathway, contributing to the understanding of the mechanisms underlying the antidepressant-like effect of this vitamin. [Copyright &y& Elsevier]

Abstract: The present study aimed to investigate the effects of tamoxifen (TMX) on locomotor behavior and on the activities of mitochondrial respiratory chain complexes and creatine kinase (CK) in the brain of rats subjected to an animal model of mania induced by d-amphetamine (d-AMPH)—reversion and prevention protocols. The d-AMPH administration increased locomotor activity in saline-treated rats under prevention and reversion treatment; furthermore, there was evident reduction in the locomotion in the d-amphetamine group treated with TMX. d-AMPH significantly decreased the activity of mitochondrial respiratory chain complexes in saline-treated rats in prefrontal cortex, hippocampus, striatum and amygdala in both prevention and reversion treatment. Depending on the cerebral area and evaluated complex, TMX was able to prevent and reverse this impairment. A decrease in CK activity was also verified in the brain of rats when d-AMPH was administrated in both experiments; the administration of TMX reversed but not prevented the decrease in CK activity induced by d-AMPH. The present study demonstrated that TMX reversed and prevented the alterations in behavioral and energy metabolism induced by d-AMPH (alterations were also observed in bipolar disorder), reinforcing the need for more studies about inhibitors of PKC as possible targets for new medications in the treatment of bipolar disorder. [Copyright &y& Elsevier]

Abstract: There is a body of evidence suggesting that BDNF is involved in bipolar disorder (BD) pathogenesis. Intracerebroventricular (ICV) injection of ouabain (OUA), a specific Na+/K+ ATPase inhibitor, induces hyperlocomotion in rats, and has been used as an animal model of mania. The present study aims to investigate the effects of the lithium (Li) and valproate (VPT) in an animal model of mania induced by ouabain. In the reversal model, animals received a single ICV injection of OUA or cerebrospinal fluid (aCSF). From the day following the ICV injection, the rats were treated for 6days with intraperitoneal (IP) injections of saline (SAL), Li or VPT twice a day. In the maintenance treatment (prevention model), the rats received IP injections of Li, VPT, or SAL twice a day for 12days. In the 7th day of treatment the animals received a single ICV injection of either OUA or aCSF. After the ICV injection, the treatment with the mood stabilizers continued for more 6days. Locomotor activity was measured using the open-field test and BDNF levels were measured in rat hippocampus and amygdala by sandwich-ELISA. Li and VPT reversed OUA-related hyperactive behavior in the open-field test in both experiments. OUA decreased BDNF levels in first and second experiments in hippocampus and amygdala and Li treatment, but not VPT reversed and prevented the impairment in BDNF expression after OUA administration in these cerebral areas. Our results suggest that the present model fulfills adequate face, construct and predictive validity as an animal model of mania. [Copyright &y& Elsevier]

• Folic acid abrogates the depressive-like behavior induced by TNF-α in mice. • Folic acid and antidepressants have a synergistic effect in the TST. • The antidepressant-like effect of folic acid involves inhibition of NMDA receptors. • The antidepressant-like effect of folic acid depends on reduced NO synthesis. • Akt modulation may be involved in the antidepressant-like action of folic acid. Folic acid has been reported to exert antidepressant effects, but its ability to abrogate the depressive-like behavior and signaling pathways alterations elicited by an inflammatory model of depression remains to be established. This study examined: a) the efficacy of folic acid in a mouse model of depression induced by tumor necrosis factor (TNF-α); b) whether the administration of subthreshold doses of folic acid and antidepressants (fluoxetine, imipramine, and bupropion), MK-801, or 7-nitroindazole cause antidepressant-like effects; c) the effects of TNF-α and/or folic acid on hippocampal p38MAPK, Akt, ERK, and JNK phosphorylation. Folic acid reduced the immobility time in the tail suspension test (TST) in control mice (10–50 mg/kg, p.o) and abolished the depressive-like behavior elicited by TNF-α (0.001 fg/site, i.c.v.) in this test (1–50 mg/kg, p.o). Coadministration of subthreshold doses of folic acid (1 mg/kg, p.o.) and fluoxetine, imipramine, bupropion, MK-801, or 7-nitroindazole produced an antidepressant-like effect in mice exposed or not to TNF-α. TNF-α-treated mice presented increased p38MAPK phosphorylation and decreased Akt phosphorylation, and the later effect was prevented by folic acid (10 mg/kg, p.o.). Additionally, ERK1 phosphorylation was increased in mice treated with TNF-α + folic acid (1 mg/kg), but no effects on ERK2 or JNK1/2/3 phosphorylation were found in any group. The results indicate the efficacy of folic acid to counteract the depressive-like behavior induced by a pro-inflammatory cytokine, an effect that might be associated with the activation of monoaminergic systems, inhibition of N-methyl- d -aspartate (NMDA) receptors and nitric oxide (NO) synthesis, as well as Akt modulation. [ABSTRACT FROM AUTHOR]

AZD6765 (lanicemine) is a non-competitive NMDA receptor antagonist that induces a fast-acting antidepressant effect without presenting psychotomimetic effects. However, the mechanisms underlying its effects remain to be established. In this context, we demonstrated that a single administration of AZD6765 (1 mg/kg, i.p.) was able to induce an antidepressant-like effect in mice submitted to tail suspension test (TST), an effect reversed by LY294002 (a reversible PI3K inhibitor, 10 nmol/site, i.c.v.), wortmannin (an irreversible PI3K inhibitor, 0.1 μg/site, i.c.v.) and rapamycin (a selective mTOR inhibitor, 0.2 nmol/site, i.c.v.). In addition, the administration of sub-effective doses of AZD6765 (0.1 mg/kg, i.p.) in combination with lithium chloride (non-selective GSK-3β inhibitor, 10 mg/kg, p.o.) or AR-A014418 (selective GSK-3β inhibitor, (0.01 μg/site, i.c.v.) caused a synergistic antidepressant-like effect. These results suggest the involvement of PI3K/Akt/mTOR/GSK3β signaling in the AZD6765 antidepressant-like effect. In addition, western blotting analysis showed an increased immunocontent of synapsin in the prefrontal cortex and a tendency to an increased immunocontent of this protein in the hippocampus 30 min after AZD6765 administration, but no significant effect of AZD6765 was observed in P70S6K (Thr389) phosphorylation and GluA1 immunocontent. A single dose of AZD6765 (3 mg/kg, i.p.), similarly to ketamine (1 mg/kg, i.p.), decreased the latency to feed in the novelty suppressed feeding (NSF) test, a behavioral paradigm that evaluates depression/anxiety-related behavior. This effect was reversed by rapamycin administration, suggesting the activation of mTOR signaling in the effect of AZD in the NSF test. In addition, a single administration of AZD6765 (1 mg/kg, i.p.) or ketamine (1 mg/kg, i.p.) reversed the depressive-like behavior induced by chronic unpredictable stress (CUS). Altogether, the results provide evidence for the fast-acting antidepressant profile of AZD6765, by a mechanism likely dependent on PI3K/Akt/mTOR/GSK3β. • AZD6765 induced an antidepressant-like effect in mice submitted to TST. • There is an involvement of PI3K/Akt/mTOR/GSK3β signaling in AZD6765 effects. • AZD6765 decreased the latency to feed in the NFT, similarly to ketamine. • The effects of AZD6765 in NFT were dependent on mTOR signaling. • AZD6765 reversed the depressive-like behavior induced by CUS. [ABSTRACT FROM AUTHOR]

In this study, we investigated the ability of a single coadministration of subeffective doses of ascorbic acid and ketamine to reverse the depressive-like behavior induced by chronic unpredictable stress (CUS) in mice. Moreover, we examined the effect of combined administration of ascorbic acid and ketamine on hippocampal phosphorylation of p70S6K and immunocontents of GLUA1 and PSD-95 in mice submitted to the CUS procedure. CUS procedure was applied for 21 days. Animals received a single coadministration of subeffective doses of ascorbic acid (0.1 mg/kg) and ketamine (0.1 mg/kg) and were subjected to behavioral evaluation 24 h after the treatments. Immediately after the behavioral observations the hippocampi were dissected for Western blotting analyses. Our results revealed that a single administration of subeffective doses of ascorbic acid and ketamine completely reversed the depressive-like behavior induced by CUS, however, this effect was not accompanied by changes in the phosphorylation of p70S6K and immunocontent of GLUA1 or PSD95 in the hippocampus. These findings point to a synergistic antidepressant-like effect of ascorbic acid and ketamine, paving the way for additional studies on the combined use of these compounds for the management of major depressive disorder (MDD). • Chronic stress elicits a depressive-like behavior in the mouse TST. • Combined administration of ascorbic acid and ketamine has antidepressant-like effect. • Hippocampal phosphorylation of p70S6K is not affected by stress and/or treatments. • Hippocampal GLUA1 or PSD95 immunocontents are not altered by stress and/or treatments. [ABSTRACT FROM AUTHOR]

Abstract Agmatine is a neuromodulator that has been proposed as a therapeutic strategy for the treatment of major depressive disorder (MDD). A previous study reported that agmatine caused a fast-acting effect in mice subjected to chronic mild stress without causing changes in the levels of synaptic proteins in the prefrontal cortex. We examined whether a single administration of agmatine is able to counteract the depressive-like behavior induced by chronic administration of corticosterone, a pharmacological model of stress, paralleled with the modulation of synaptic protein levels in the prefrontal cortex and hippocampus. Female mice received corticosterone (20 mg/kg, p.o.) for 21 days and, in the last day of treatment, were administered with a single dose of agmatine (0.1 mg/kg, p.o.), fluoxetine (10 mg/kg, p.o.; control for a conventional antidepressant) or ketamine (1 mg/kg, i.p.; control for a fast-acting antidepressant). Agmatine, similar to ketamine, reversed the depressive-like behavior induced by corticosterone in the tail suspension test (TST), an effect that was not observed in mice treated with fluoxetine. The immunocontent of GluA1 was increased by all the treatments in the hippocampus of control mice, whereas PSD95 was not significantly altered by treatments in any brain structure. Although the levels of synaptic proteins do not seem to account for the behavioral findings reported here, the present study provides clear evidence for the fast-acting antidepressant profile of agmatine in the TST, similar to ketamine. Highlights • Corticosterone induced depressive-like behavior in the TST. • Agmatine reversed the depressive-like behavior induced by corticosterone. • Agmatine exhibits a behavioral profile similar to ketamine. • GluA1 and PSD95 levels seem to be unrelated to the behavioral effects of agmatine. [ABSTRACT FROM AUTHOR]

Some studies have demonstrated that ascorbic acid, similarly to ketamine, exhibits antidepressant-like effects mediated, at least in part, by modulation of the glutamatergic system. Despite the involvement of glutamatergic system in the pathophysiology of anxiety disorders, the ability of ascorbic acid and ketamine to elicit anxiolytic effects in animal models remains to be established. Therefore, this study investigated the effects of a single administration of ascorbic acid, ketamine or diazepam (positive control) in different animal models of anxiety. Mice were treated with ascorbic acid (1, 3 and 10 mg∕kg, p.o.), ketamine (1 and 10 mg∕kg, i.p.) or diazepam (2 mg∕kg, p.o) and their behavioral responses were assessed in the elevated plus maze, open field test (OFT), ligh∕dark preference test and marble burying test. Ascorbic acid increased total time spent in the open arms of elevated plus maze, increased total time in the center of the OFT, decreased rearing responses, increased the latency to grooming, decreased the rostral grooming, but did not affect body grooming. Furthermore, ascorbic acid increased the latency time and total time in light area in the ligh∕dark preference test, but did not affect the performance of mice in the marble burying test. Ketamine demonstrated an anxiolytic-like effect in elevated plus maze, OFT, and ligh∕dark preference test. Diazepam exhibited an anxiolytic-like effect in all the behavioral tests. Altogether, the results indicate the potential anxiolytic effect of ascorbic acid and ketamine, providing a possible new avenue for the management of anxiety-related disorders. [ABSTRACT FROM AUTHOR]

Agmatine is an endogenous neuromodulator that has been shown to have antidepressant-like properties. We have previously demonstrated that it can induce a rapid increase in BDNF levels after acute administration, suggesting that agmatine may be a fast-acting antidepressant. To investigate this hypothesis, the present study evaluated the effects of a single administration of agmatine in mice subjected to chronic unpredictable stress (CUS), a model of depression responsive only to chronic treatment with conventional antidepressants. The ability of agmatine to reverse CUS-induced behavioral and biochemical alterations was evaluated and compared with those elicited by the fast-acting antidepressant (ketamine) and the conventional antidepressant (fluoxetine). After exposed to CUS for 14 days, mice received a single oral dose of agmatine (0.1 mg/kg), ketamine (1 mg/kg) or fluoxetine (10 mg/kg), and were submitted to behavioral evaluation after 24 h. The exposure to CUS caused an increased immobility time in the tail suspension test (TST) but did not change anhedonic-related parameters in the splash test. Our findings provided evidence that, similarly to ketamine, agmatine is able to reverse CUS-induced depressive-like behavior in the TST. Western blot analyses of prefrontal cortex (PFC) demonstrated that mice exposed to CUS and/or treated with agmatine, fluoxetine or ketamine did not present alterations in the immunocontent of synaptic proteins [i.e. GluA1, postsynaptic density protein 95 (PSD-95) and synapsin]. Altogether, our findings indicate that a single administration of agmatine is able to reverse behavioral alterations induced by CUS in the TST, suggesting that this compound may have fast-acting antidepressant-like properties. However, there was no alteration in the levels of synaptic proteins in the PFC, a result that need to be further investigated in other time points. [ABSTRACT FROM AUTHOR]

Dyskinesia consists in a series of trunk, limbs and orofacial involuntary movements that can be observed following long-term pharmacological treatment in some psychotic and neurological disorders such as schizophrenia and Parkinson’s disease, respectively. Agmatine is an endogenous arginine metabolite that emerges as neuromodulator and a promising agent to manage diverse central nervous system disorders by modulating nitric oxide (NO) pathway, glutamate NMDA receptors and oxidative stress. Herein, we investigated the effects of a single intraperitoneal (i.p.) administration of different agmatine doses (10, 30 or 100 mg/kg) against the orofacial dyskinesia induced by reserpine (1 mg/kg, s.c.) in mice by measuring the vacuous chewing movements and tongue protusion frequencies, and the duration of facial twitching. The results showed an orofacial antidyskinetic effect of agmatine (30 mg/kg, i.p.) or the combined administration of sub-effective doses of agmatine (10 mg/kg, i.p.) with the NMDA receptor antagonists amantadine (1 mg/kg, i.p.) and MK801 (0.01 mg/kg, i.p.) or the neuronal nitric oxide synthase (NOS) inhibitor 7-nitroindazole (7-NI; 0.1 mg/kg, i.p.). Reserpine-treated mice displayed locomotor activity deficits in the open field and agmatine had no effect on this response. Reserpine increased nitrite and nitrate levels in cerebral cortex, but agmatine did not reverse it. Remarkably, agmatine reversed the decrease of dopamine and non-protein thiols (NPSH) levels caused by reserpine in the striatum. However, no changes were observed in striatal immunocontent of proteins related to the dopaminergic system including tyrosine hydroxylase, dopamine transporter, vesicular monoamine transporter type 2, pDARPP-32[Thr75], dopamine D 1 and D 2 receptors. These results indicate that the blockade of NO pathway, NMDAR and oxidative stress are possible mechanisms associated with the protective effects of agmatine against the orofacial dyskinesia induced by reserpine in mice. [ABSTRACT FROM AUTHOR]

Highlights: [•] Agmatine at low doses produces an antidepressant-like effect in TST. [•] TNF-α increases immobility time in TST, indicative of a depressive-like behavior. [•] Agmatine abolishes the depressive-like behavior induced by TNF-α. [•] Agmatine produces synergistic effect with classical antidepressants in the TST. [•] Agmatine modulates monoaminergic systems, NMDAr and L-arg-NO pathway. [Copyright &y& Elsevier]

Abstract: Taking into account that pro-inflammatory cytokines and oxidative and nitrosative stress are implicated in the pathogenesis of depression and that α-tocopherol has antidepressant, anti-inflammatory and antioxidant properties, this study investigated the ability of α-tocopherol to abolish the depressive-like behavior induced by i.c.v. administration of TNF-α in the mouse TST. Additionally, we investigated the occurrence of changes in the levels of Bcl2 and Bax and phosphorylation of GSK-3β (Ser9) in the hippocampus of mice. The administration of TNF-α (0.001fg/site, i.c.v.) increased the immobility time in the TST, which was prevented by the administration of α-tocopherol at the doses of 10, 30 and 100mg/kg (p.o.). Subeffective doses of α-tocopherol (10mg/kg, p.o.) and/or the antidepressants fluoxetine (5mg/kg, p.o.), imipramine (0.1mg/kg, p.o.) and bupropion (1mg/kg, p.o.), the NMDA receptor antagonist MK-801 (0.001mg/kg, p.o.) or the neuronal nitric oxide synthase inhibitor 7-nitroindazole (25mg/kg, i.p.) prevented the depressive-like effect induced by TNF-α. None of the treatments altered the locomotor activity of mice. Treatment with TNF-α and/or α-tocopherol did not alter the levels of Bax and Bcl2 or the phosphorylation of GSK-3β in the hippocampus of mice. Together, our results show a synergistic antidepressant-like effect of α-tocopherol with antidepressants against the depressive-like behavior induced by an inflammatory insult, suggesting that this vitamin may be useful to optimize conventional pharmacotherapy of depression, including depressive states associated with inflammatory conditions. [Copyright &y& Elsevier]

The ketamine's potential for the treatment of refractory depression and anxiety has been considered one the most important discoveries in the last years, however, repeated use of ketamine is limited due to its side/adverse effects. Therefore, the search for effective augmentation strategies that may reduce ketamine doses is welcome. Therefore, this study sought to augment the effect of ketamine by guanosine in the novelty-suppressed feeding (NSF) test, a behavioral paradigm able to detect depression/anxiety-related behavior. Acute administration of guanosine (0.05 mg/kg, p.o.), similar to ketamine (1 mg/kg, i.p.), produced a rapid behavioral response in mice submitted to NSF test. Moreover, the coadministration of sub-effective doses of guanosine (0.01 mg/kg, p.o.) and ketamine (0.1 mg/kg, i.p.) was effective in mice submitted to NSF test. Subsequently, the intracellular mechanism underpinning the augmentation effect of ketamine by guanosine was investigated. Our results suggest that augmentation response of ketamine by guanosine in the NSF test probably involves the activation of mTOR signaling, since the treatment with rapamycin (0.2 nmol/site, i.c.v., a selective mTOR inhibitor) completely abolished this effect. This augmentation strategy also increased mTOR phosphorylation (Ser2448) in the hippocampus, reinforcing the role of mTOR in this augmentation response. However, no changes in the p70S6K, PSD-95, GluA1, and synapsin immunocontents were found in the hippocampus of ketamine plus guanosine-treated mice. Overall, results provide evidence that guanosine is able to augment the effect of ketamine in the NSF test via mTOR activation, a finding that might have therapeutic implications for the management of depression/anxiety. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the effects of folic acid on depressive-like behavior induced by chronic administration of corticosterone in mice. Corticosterone (20 mg/kg, p.o.) was administered once a day for 21 days. Folic acid (30 mg/kg, p.o.) or fluoxetine (10 mg/kg, positive control, p.o.) was administered immediately after corticosterone injection during the last 7 days of corticosterone treatment. On the 22nd day, animals were submitted to tail suspension test, open-field test and splash test. Corticosterone treatment caused a depressive-like behavior, evidenced by increased immobility time in the tail suspension test and decreased time in which mice spent grooming in the splash test. Repeated folic acid or fluoxetine administration significantly abolished corticosterone-induced depressive-like behavior. Chronic administration of corticosterone decreased levels of serum corticosterone in mice. Neither folic acid, nor fluoxetine treatment reversed this impairment. These findings indicate a robust effect of folic acid in reversing behavioral alterations induced by corticosterone model of depression in mice, suggesting that this vitamin may be an alternative approach for the management of depressive symptoms. [ABSTRACT FROM AUTHOR]

Agmatine is an endogenous neuromodulator which, based on animal and human studies, is a putative novel antidepressant drug. In this study, we investigated the ability of sub-chronic (21 days) p.o. agmatine administration to produce an antidepressant-like effect in the tail suspension test and examined the hippocampal cell signaling pathways implicated in such an effect. Agmatine at doses of 0.01 and 0.1 mg/kg (p.o.) produced a significant antidepressant-like effect in the tail suspension test and no effect in the open-field test. Additionally, agmatine (0.001-0.1 mg/kg, p.o.) increased the phosphorylation of protein kinase A substrates (237-258% of control), protein kinase B/Akt (Ser473) (116-127% of control), glycogen synthase kinase-3β (Ser9) (110-113% of control), extracellular signal-regulated kinases 1/2 (119-137% and 121-138% of control, respectively) and cAMP response elements (Ser133) (127-152% of control), and brain-derived-neurotrophic factor (137-175% of control) immunocontent in a dose-dependent manner in the hippocampus. Agmatine (0.001-0.1 mg/kg, p.o.) also reduced the c-jun N-terminal kinase 1/2 phosphorylation (77-71% and 65-51% of control, respectively). Neither protein kinase C nor p38MAPK phosphorylation was altered under any experimental conditions. Taken together, the present study extends the available data on the mechanisms that underlie the antidepressant action of agmatine by showing an antidepressant-like effect following sub-chronic administration. In addition, our results are the first to demonstrate the ability of agmatine to elicit the activation of cellular signaling pathways associated with neuroplasticity/cell survival and the inhibition of signaling pathways associated with cell death in the hippocampus. [ABSTRACT FROM AUTHOR]

Abstract: Lectins recognize and reversibly bind to carbohydrates attached to proteins and lipids modulating a variety of signaling pathways. We previously showed that ConBr, a lectin from Canavalia brasiliensis seeds, produced an antidepressant-like effect in mice by modulating the monoaminergic neurotransmitter systems. Moreover, ConBr blocked hippocampal neurotoxicity induced by quinolinic acid in vivo and by glutamate in vitro, suggesting a neuroprotective activity of ConBr via glutamatergic system modulation. Therefore, the present study was undertaken to investigate the involvement of the N-methyl-d-aspartate (NMDA) receptor and the l-arginine–nitric oxide (NO) pathway in the antidepressant-like action displayed by ConBr in the forced swimming test (FST). With the aim of verifying the involvement of NMDA receptors in the antidepressant-like effect of ConBr (10μg/site, i.c.v.), an intracerebroventricular (i.c.v.) pretreatment with either NMDA (0.1pmol/site) or d-serine (30μg/site) was carried out. The results show that both treatments blocked the effect of ConBr. Furthermore, the coadministration of subeffective doses of the NMDA receptor antagonist MK-801 (0.001mg/kg, i.p.) or ketamine (0.1mg/kg, i.p.; NMDA receptor antagonist) and ConBr (0.1μg/site, i.c.v.) caused a synergistic reduction in immobility time. In order to verify the dependence of the l-arginine–NO–cGMP pathway, on the effect of ConBr in the FST, a pretreatment with the NO precursor, l-arginine (750mg/kg, i.p.), or the PDE5 inhibitor, sildenafil (5mg/kg, i.p.), was performed. Both drugs abolished the antidepressant-like action of ConBr. Finally, the administration of subeffective doses of the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 30pmol/site, i.c.v.) and ConBr (0.1μg/site, i.c.v.) produced a synergistic antidepressant-like effect in the FST. Taken together, the results suggest that the antidepressant-like effect of ConBr in the FST involves NMDA receptor inhibition and reduction in NO and cGMP synthesis. [Copyright &y& Elsevier]

Abstract: In this study, we assessed the oxidative stress parameters in rats submitted to an animal model of mania induced by ouabain (OUA), which included the use of lithium (Li) and valproate (VPA). Li and VPA treatment reversed and prevented the OUA-induced damage in these structures, however, this effect varies depending on the brain region and treatment regimen. Moreover, the activity of the antioxidant enzymes, namely, superoxide dismutase (SOD) and catalase (CAT) was found to be increased and decreased, respectively, in the brain of OUA-administered rats. Li and VPA modulated SOD and CAT activities in OUA-subjected rats in both experimental models. Our results support the notion that Li and VPA exert antioxidant-like properties in the brain of rats submitted to animal model of mania induced by ouabain. [ABSTRACT FROM AUTHOR]

Abstract: Bipolar disorder (BD) is a devastating major mental illness associated with high rates of suicide and work loss. There is an emerging body of data suggesting that bipolar disorder is associated with mitochondrial dysfunction. In this context, the present study aims to investigate the effects of mood stabilizers lithium (Li) and valproate (VPT) on mitochondrial respiratory chain activity in brain of rats undergoing treatment with the pro-manic agent d-AMPH d-amphetamine (d-AMPH). In the reversal treatment, Wistar rats were first given d-AMPH or saline for 14 days, and then, between days 8 and 14, rats were treated with Li, VPA or saline (Sal). In the prevention treatment, rats were pretreated with Li, VPA or Sal. Locomotor behavior was assessed using the open-field task and mitochondrial chain activity complexes I, II, III and IV were measured in brain structures (hippocampus, striatum and prefrontal). Li and VPA reversed and prevented d-AMPH-induced hyperactivity. In both experiments, d-AMPH inhibited mitochondrial respiratory chain activity in all analyzed structures. In the reversal treatment, VPA reversed d-AMPH-induced dysfunction in all brain regions analyzed. In the prevention experiment, the effects of Li and VPA on d-AMPH-induced mitochondrial dysfunction were dependent on the brain region analyzed. These findings suggested that dopamine can be an important link for the mitochondrial dysfunction seen in BD and, Li and VPA exert protective effects against this d-AMPH-induced mitochondrial dysfunction, but this effect varies depending on the brain region and the treatment regimen. [ABSTRACT FROM AUTHOR]

Abstract: There is an emerging body of data suggesting that bipolar disorder is associated with DNA damage. Intracerebroventricular (ICV) administration of ouabain in rats results in manic-like alterations. We evaluated DNA damage of peripheral blood, cerebrospinal fluid and hippocampus of rats after ICV ouabain injection. Ouabain-induced hyperlocomotion was examined in an open field. Additionally, we used single cell gel electrophoresis (comet assay) to measure early transient damage in cerebrospinal fluid (CSF), hippocampus and blood; and the micronucleus test to measure persistent damage in total blood samples of rats after ouabain administration. Our findings demonstrated that ouabain induced hyperlocomotion in rats, and this response remained up to 7 days following a single ICV injection. In addition, we observed that the persistent increase in the rat spontaneous locomotion is associated with increased hippocampal and peripheral index of early DNA damage in rats. No significant alterations were observed in the micronucleus frequency in total blood samples of the rats after the ouabain ICV injection. These results suggest that ouabain may induce peripheral and central early DNA damage, but this early damage may be repaired. [Copyright &y& Elsevier]

The development of fast-acting antidepressants is crucial considering that conventional antidepressants require a long period to elicit therapeutic effects. Creatine, an ergogenic guanidine-like compound, stands out as a candidate to exert fast antidepressant-like responses. The present study investigated whether a single dose of creatine elicits a fast response in mice submitted to the novelty-suppressed feeding (NSF) test, a paradigm that may assess depression-like and anxiety-like behaviors. Ketamine, an NMDA receptor antagonist that has rapid antidepressant effects, and conventional antidepressants were also tested. The involvement of the mTORC1 signaling pathway in the behavioral responses was also investigated. Biochemical analyses included hippocampal BDNF level (ELISA) and total and phospho-mTORC1 (Ser2448), PSD95 and synapsin immunocontent (Western Blotting). Creatine (10 mg/kg, p.o.) or ketamine (1 mg/kg, i.p.) reduced the latency to feed in the NSF test. Conversely, fluoxetine (10 mg/kg, p.o.), imipramine (1 mg/kg, p.o.) or bupropion (10 mg/kg, p.o.) did not alter this parameter. The administration of rapamycin (mTOR inhibitor, 0.2 nmol/site, i.c.v.) abolished the effects of creatine or ketamine in the NSF test. Creatine or ketamine-treated mice presented increased hippocampal BDNF level, an effect abolished by rapamycin. The hippocampal phospho-mTORC1 (Ser2448) immunocontent was increased by creatine, but not by ketamine. However, ketamine, but not creatine, increased PSD95 and synapsin immunocontent. Creatine and ketamine elicit a rapid response in the NSF test by a mechanism dependent on the mTORC1 signaling pathway. • Conventional antidepressants did not show fast behavioral effect in the NSF test. • Creatine and ketamine presented rapid behavioral effect in the NSF test via mTORC1. • The increase on BDNF levels evoked by creatine and ketamine is dependent on mTORC1. • Ketamine promoted mTORC1-dependent hippocampal synaptic protein translation. [ABSTRACT FROM AUTHOR]

Growing evidence has suggested that ascorbic acid may exhibit rapid anxiolytic and antidepressant-like effects. In this study the effects of a single administration of ascorbic acid (1 mg/kg, p.o.), ketamine (1 mg/kg, i.p., a fast-acting antidepressant) and fluoxetine (10 mg/kg, p.o., conventional antidepressant) were investigated on: a) behavioral performance in the novelty suppressed feeding (NSF) test; b) hippocampal synaptic protein immunocontent; c) dendritic spine density and morphology in the dorsal and ventral dentate gyrus (DG) of the hippocampus and d) hippocampal dendritic arborization. Ascorbic acid or ketamine, but not fluoxetine, decreased the latency to feed in the NSF test in mice. This effect was accompanied by increased p70S6K (Thr389) phosphorylation 1 h after ascorbic acid or ketamine treatment, although only ascorbic acid increased synapsin I immunocontent. Ketamine administration increased the dendritic spine density in the dorsal DG, but none of the treatments affected the maturation of dendritic spines in this region. In addition, both ascorbic acid and ketamine increased the dendritic spine density in the ventral DG, particularly the mature spines. Sholl analysis demonstrated no effect of any treatment on hippocampal dendritic arborization. Altogether, the results provide evidence that the behavioral and synaptic responses observed following ascorbic acid administration might occur via the upregulation of synaptic proteins, dendritic spine density, and maturation in the ventral DG, similar to ketamine. These findings contribute to understand the cellular targets implicated in its antidepressant/anxiolytic behavioral responses and support the notion that ascorbic acid may share with ketamine the ability to increase synaptic function. • Ascorbic acid or ketamine decreased the latency to feed in the NSF test. • Ascorbic acid increased hippocampal phospho-p70S6K and synapsin I immunocontent. • Ascorbic acid and ketamine increased the dendritic spine density in the ventral DG. • Ascorbic acid may share with ketamine the ability to increase synaptic function. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is characterized by progressive cognitive impairments as well as non-cognitive symptoms such as depressed mood. Physical exercise has been proposed as a preventive strategy against AD and depression, an effect that may be related, at least partially, to its ability to prevent impairments on cell proliferation and neuronal survival in the hippocampus, a structure implicated in both cognition and affective behavior. Here, we investigated the ability of treadmill exercise (4 weeks) to counteract amyloid β 1–40 peptide-induced depressive-like and anxiety-like behavior in mice. Moreover, we addressed the role of the BDNF/mTOR intracellular signaling pathway as well as hippocampal cell proliferation and survival in the effects of physical exercise and/or Aβ 1–40. Aβ 1–40 administration (400 pmol/mouse, i.c.v.) increased immobility time and reduced the latency to immobility in the forced swim test, a finding indicative of depressive-like behavior. In addition, Aβ 1–40 administration also decreased time spent in the center of the open field and increased grooming and defecation, alterations indicative of anxiety-like behavior. These behavioral alterations were accompanied by a reduction in the levels of mature BDNF and mTOR (Ser2448) phosphorylation in the hippocampus. In addition, Aß 1–40 administration reduced cell proliferation and survival in the ventral, dorsal and entire dentate gyrus of the hippocampus. Importantly, most of these behavioral, neurochemical and structural impairments induced by Aβ 1–40 were not observed in mice subjected to 4 weeks of treadmill exercise. These findings indicate that physical exercise has the potential to prevent the occurrence of early emotional disturbances associated with AD and this appears to be mediated, at least in part, by modulation of hippocampal BDNF and mTOR signaling as well as through promotion of cell proliferation and survival in the hippocampal DG. • Exercise prevented Aß 1–40 -induced depressive-like behavior in mice. • Exercise prevented decreased hippocampal mTOR phosphorylation induced by Aß 1–40. • Exercise abolished decreased hippocampal BDNF levels in Aß 1–40 -exposed mice. • Exercise abolished Aß 1–40 induced reduction in cell proliferation and survival in DG. [ABSTRACT FROM AUTHOR]