Considering the involvement of the opioid system in major depressive disorder (MDD), mainly concerning refractory MDD, and the evidence that ascorbic acid may exert a beneficial effect for the ...treatment of this disorder, this study investigated the involvement of the opioid system in the antidepressant-like effect of ascorbic acid in the tail suspension test (TST). Treatment of Swiss mice with the non-selective opioid receptor antagonist naloxone (1 mg/kg, i.p.) prevented the reduced immobility time caused by ascorbic acid (1 mg/kg, p.o.) in the TST. Additionally, administration of the selective μ1-opioid receptor antagonist, naloxonazine (10 mg/kg, i.p.), also abolished the antidepressant-like action of the same dose of ascorbic acid in the TST. We also investigated the possible relationship between the opioid system and NMDA receptors in the mechanism of action of ascorbic acid or ketamine (0.1 mg/kg, i.p.) in the TST. Treatment of mice with naloxone (1 mg/kg, i.p.) blocked the synergistic antidepressant-like effect of ascorbic acid (0.1 mg/kg. p.o.) and MK-801 (0.001 mg/kg, p.o., a non-competitive NMDA receptor antagonist) in the TST. Combined administration of ketamine and MK-801 induced a synergistic antidepressant-like action, and naloxone partially abolished this effect. Our results indicate that the antidepressant-like effect of ascorbic acid in the TST appears to be dependent on the activation of the opioid system, especially μ1-opioid receptors, which might be an indirect consequence of NMDA receptor inhibition elicited by ascorbic acid administration.
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 6 days 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 12 days. 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 6 days. 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.
In the present study, we aimed to examine the effects of repeated D-amphetamine (AMPH) exposure, a well-accepted animal model of acute mania in bipolar disorder (BD), and histone deacetylase (HDAC) ...inhibitors on locomotor behavior and HDAC activity in the prefrontal cortex (PFC) and peripheral blood mononuclear cells (PBMCs) of rats. Moreover, we aimed to assess brain-derived neurotrophic factor (BDNF) protein and mRNA levels in these samples.
We treated adult male Wistar rats with 2 mg/kg AMPH or saline intraperitoneally for 14 days. Between the 8th and 14th days, rats also received 47.5 mg/kg lithium (Li), 200 mg/kg sodium valproate (VPT), 2 mg/kg sodium butyrate (SB), or saline. We evaluated locomotor activity in the open-field task and assessed HDAC activity in the PFC and PBMCs, and BDNF levels in the PFC and plasma.
AMPH significantly increased locomotor activity, which was reversed by all drugs. This hyperactivity was associated with increased HDAC activity in the PFC, which was partially reversed by Li, VPT, and SB. No differences were found in BDNF levels.
Repeated AMPH administration increases HDAC activity in the PFC without altering BDNF levels. The partial reversal of HDAC increase by Li, VPT, and SB may account for their ability to reverse AMPH-induced hyperactivity.
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.
► Metabolism impairment and abnormal PKC activity are involved in bipolar disorder. ► TMX is a PKC inhibitor and interacts with mitochondrial respiratory chain. ► In an animal model of mania TMX decreases locomotor activity. ► TMX changes energetic metabolism parameters in parallel with behavioral changes. ► Inhibitors of PKC may act as a possible target for new medications to BD.
Bark infusion of Tabebuia avellanedae Lorentz ex Griseb is consumed in tropical America folk medicine for the treatment of several diseases, including depressive disorders. It was recently ...demonstrated that the extract from this plant has antidepressant properties. The present study was aimed at investigating the contribution of N-methyl-D-aspartate (NMDA) receptors and the L-arginine–nitric oxide (NO)–cyclic guanosine 3′5′-monophosphate (cGMP) pathway to the antidepressant-like action of the ethanolic extract from T. avellanedae (EET) in the tail suspension test (TST). The anti-immobility effect of the extract (30 mg/kg, orally p.o.) was prevented by pretreatment of mice with NMDA (0.1 pmol/site, intracerebroventicular i.c.v.), L-arginine (750 mg/kg, intraperitoneally i.p.), and sildenafil (5 mg/kg, i.p.). Additionally, the combination of MK-801 (0.01 mg/kg, p.o.), 7-nitroindazole (25 mg/kg, i.p.), and 1H-1,2,4oxadiazole4,3-aquinoxalin-1-one (ODQ) (30 pmol/site, i.c.v.) with a subeffective dose of EET (1 mg/kg, p.o.) produced a synergistic antidepressant-like effect in the TST, without causing significant alterations in the locomotor activity. Moreover, the administration of an effective dose of EET (30 mg/kg, p.o.) produced a reduction in NOx levels in the cerebral cortex. Conversely, a subeffective dose of EET (1 mg/kg, p.o.) caused no changes in the cortical NOx levels. Results suggest that the antidepressant-like effect of EET in the TST is dependent on a blockade of NMDA receptor activation and inhibition of NO-cGMP synthesis, significantly extending literature data about the antidepressant-like action of this plant and reinforcing the notion that this plant may be useful in the management of depressive disorders.
Ascorbic acid, a water-soluble vitamin, is highly concentrated in the brain and participates in neuronal modulation and regulation of central nervous system (CNS) homeostasis. Ascorbic acid has ...emerged as a neuroprotective compound against neurotoxicants and neurodegenerative diseases, including Alzheimer's disease, multiple sclerosis and amyotrophic lateral sclerosis. Moreover, it improves behavioral and biochemical alterations in psychiatric disorders, including schizophrenia, anxiety, major depressive disorder, and bipolar disorder. Some recent studies have advanced the knowledge on the mechanisms associated with the preventive and therapeutic effects of ascorbic acid by showing that they are linked to improved neurogenesis and synaptic plasticity. This review shows that ascorbic acid has the potential to regulate positively stem cell generation and proliferation. Moreover, it improves neuronal differentiation of precursors cells, promotes adult hippocampal neurogenesis, and has synaptogenic effects that are possibly linked to its protective or therapeutic effects in the brain.
Bipolar disorder (BD) is a common and severe mood disorder associated with higher rates of suicide and disability. The development of new animal models, and the investigation employing those ...available have extensively contributed to understand the pathophysiological mechanisms of BD. Intracerebroventricular (i.c.v.) administration of ouabain, a specific Na
+
,K
+
-ATPase inhibitor, has been used as an animal model for BD. It has been demonstrated that Na
+
,K
+
-ATPase is altered in psychiatric disorders, especially BD. Creatine kinase (CK) is important for brain energy homeostasis by exerting several integrated functions. In the present study, we evaluated CK activity in the striatum, prefrontal cortex and hippocampus of rats subjected to i.c.v. administration of ouabain. Adult male Wistar rats received a single i.c.v. administration of ouabain (10
−2
and 10
−3
M) or vehicle (control group). Locomotor activity was measured using the open field test. CK activity was measured in the brain of rats immediately (1 h) and 7 days after ouabain administration. Our results showed that spontaneous locomotion was increased 1 h after ouabain administration and that hyperlocomotion was also observed 7 days after that. Moreover, CK activity was inhibited immediately after the administration of ouabain in the striatum, hippocampus and prefrontal cortex. Moreover, the enzyme was not affected in the striatum and hippocampus 7 days after ouabain administration. On the other hand, an inhibition in CK activity in the prefrontal cortex was observed. If inhibition of CK also occurs in BD patients, it will be tempting to speculate that the reduction of brain metabolism may be related probably to the pathophysiology of this disease.
Ascorbate has critical roles in the central nervous system (CNS); it is a neuromodulator of glutamatergic, cholinergic, dopaminergic, and γ-aminobutyric acid (GABA)-ergic neurotransmission, provides ...support and structure to neurons, and participates in processes such as differentiation, maturation, and survival of neurons. Over the past decade, antioxidant properties of ascorbate have been extensively characterized and now it is known that this compound is highly concentrated in the brain and neuroendocrine tissues. All this information raised the hypothesis that ascorbate may be involved in neurological disorders. Indeed, the biological mechanisms of ascorbate in health and disease and its involvement in homeostasis of the CNS have been the subject of extensive research. In particular, evidence for an association of this vitamin with schizophrenia, major depressive disorder, and bipolar disorder has been provided. Considering that conventional pharmacotherapy for the treatment of these neuropathologies has important limitations, this review aims to explore basic and human studies that implicate ascorbic acid as a potential therapeutic strategy. Possible mechanisms involved in the beneficial effects of ascorbic acid for the management of psychiatric disorders are also discussed.
Depression is a mental disorder triggered by the interaction of social, psychological and biological factors that have an important impact on an individual's life. Despite being a well-studied ...disease with several established forms of treatment, its prevalence is increasing, especially among older adults. New forms of treatment and prevention are encouraged, and some researchers have been discussing the effects of vitamin D (VitD) on depression; however, the exact mechanism by which VitD exerts its effects is not yet conclusive. In this study, we aimed to discuss the possible mechanisms underlying the association between VitD and depression in older adults. Therefore, we conducted a systematic search of databases for indexed articles published until 30 April 2021. The primary focus was on both observational studies documenting the association between VitD and depression/depressive symptoms, and clinical trials documenting the effects of VitD supplementation on depression/depressive symptoms, especially in older adults. Based on pre-clinical, clinical and observational studies, it is suggested that the maintenance of adequate VitD concentrations is an important issue, especially in older adults, which are a risk population for both VitD deficiency and depression. Nevertheless, it is necessary to carry out more studies using longitudinal approaches in low- and middle-income countries to develop a strong source of evidence to formulate guidelines and interventions.
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.
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