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Zinc deficiency in rats is associated with up-regulation of hippocampal NMDA receptor
... Functionally, decreased zinc-mediated inhibition of the NMDAr leads to greater calcium (Ca 2+ ) conductance, increasing the probability of Ca 2+ -induced excitotoxicity [66]. In rodents, zinc restriction leads to significantly increased synaptic expression of GluN2A and GluN2B NMDAr subunits in glutamatergic neurons of the hippocampus and PFC [67]. Notably, mice with the greatest vulnerability in activity-based anorexia (ABA) models (e.g. ...
... The proposed mechanisms of zinc therapeutic effects have predominantly been inferred from preclinical studies of induced zinc deficiency, which have observed increases in NMDAr expression [67] and hippocampal extracellular glutamate [174], decreased neurogenesis [175] and altered monoaminergic signalling [33]. Furthermore, as reviewed in Sect. ...
... Preclinical research has also shown zinc's antidepressant effects are associated with changes in AMPAr sub-unit and synaptic protein expression in the PFC [177], serotonergic receptor expression in the hippocampus and increased activation of the mTOR [33], BDNF and cAMP-response element binding intracellular signalling pathways [34]. In part, zinc's up-regulation of BDNF and cAMP-response element binding expression occurs via its interaction with the G-protein-coupled receptor (GPR-39), as decreased GPR-39 signalling, either dietary induced and genetic knockout, reduced cAMP-response element binding and BDNF expression in the frontal cortex [67] and hippocampus [178,179]. Similar to ketamine, mTOR phosphorylation is critical to zinc's antidepressant effects, as rapamycin occluded the effects of a single dose of zinc in rodents [177]. ...
Anorexia nervosa is a disorder associated with serious adverse health outcomes, for which there is currently considerable treatment ineffectiveness. Characterised by restrictive eating behaviours, distorted body image perceptions and excessive physical activity, there is growing recognition anorexia nervosa is associated with underlying dysfunction in excitatory and inhibitory neurometabolite metabolism and signalling. This narrative review critically explores the role of N-methyl-d-aspartate receptor-mediated excitatory and inhibitory neurometabolite dysfunction in anorexia nervosa and its associated biomarkers. The existing magnetic resonance spectroscopy literature in anorexia nervosa is reviewed and we outline the brain region-specific neurometabolite changes that have been reported and their connection to anorexia nervosa psychopathology. Considering the proposed role of dysfunctional neurotransmission in anorexia nervosa, the potential utility of zinc supplementation and sub-anaesthetic doses of ketamine in normalising this is discussed with reference to previous research in anorexia nervosa and other neuropsychiatric conditions. The rationale for future research to investigate the combined use of low-dose ketamine and zinc supplementation to potentially extend the therapeutic benefits in anorexia nervosa is subsequently explored and promising biological markers for assessing and potentially predicting treatment response are outlined.
... It is possible that the absolute values of zinc concentration measured in serum of mice would be different than those reported above after sampling at different time. Nevertheless, the serum zinc concentration declined by 53% after 4 weeks of dietary zinc restriction, which is consistent with previous data [34][35][36]. The mean serum zinc concentration in mice fed the ZnA diet that underwent MES seizures was 1.3 µg/mL ( Figure 2B), while the concentration in ZnD mice that underwent MES seizures was 0.65 µg/mL ( Figure 2C). ...
... , x FOR PEER REVIEW 8 of 22 reported above after sampling at different time. Nevertheless, the serum zinc concentra-tion declined by 53% after 4 weeks of dietary zinc restriction, which is consistent with previous data [34][35][36]. The mean serum zinc concentration in mice fed the ZnA diet that underwent MES seizures was 1.3 µ g/mL ( Figure 2B), while the concentration in ZnD mice that underwent MES seizures was 0.65 µ g/mL ( Figure 2C). ...
... Zinc deficiency has profound consequences for decreasing neurogenesis [52]. Chronic ZnD diet decreased the levels of BDNF in the hippocampus of rodents [34,35] but contrasting findings have also been reported [53]. In turn, treatment with zinc increased BDNF in the hippocampus but the effects of zinc administration on increasing BDNF level depend on the dose, mode of administration (acute/chronic), and time of sampling for the analysis [54,55]. ...
The G-protein coupled receptor 39 (GPR39) is gaining increasing attention as a target for future drugs, yet there are gaps in the understanding of its pharmacology. Zinc is an endogenous agonist or an allosteric modulator, while TC-G 1008 is a synthetic, small molecule agonist. Zinc is also a positive allosteric modulator for the activity of TC-G 1008 at GPR39. Activation of GPR39 by TC-G 1008 facilitated the development of epileptogenesis in the pentylenetetrazole (PTZ)-induced kindling model of epilepsy. Congruently, TC-G 1008 decreased the seizure threshold in the maximal electroshock seizure threshold (MEST) test. Here, we investigated the effects of TC-G 1008 under the condition of zinc deficiency. Mice were fed a zinc-adequate diet (ZnA, 50 mg Zn/kg) or a zinc-deficient diet (ZnD, 3 mg Zn/kg) for 4 weeks. Following 4 weeks of dietary zinc restriction, TC-G 1008 was administered as a single dose and the MEST test was performed. Additional groups of mice began the PTZ-kindling model during which TC-G 1008 was administered repeatedly and the diet was continued. TC-G 1008 administered acutely decreased the seizure threshold in the MEST test in mice fed the ZnD diet but not in mice fed the ZnA diet. TC-G 1008 administered chronically increased the maximal seizure severity and the percentage of fully kindled mice in those fed the ZnA diet, but not in mice fed the ZnD diet. Our data showed that the amount of zinc in a diet is a factor contributing to the effects of TC-G 1008 in vivo.
... Similar behavioral consequences of zinc deficiency have been reported in rats. Rats fed with a low Zn diet exhibited longer immobility time in the FST, reduced sucrose intake, and reduced social interactions [20][21][22]. Increased immobility time in the FST in ZnD rats was normalized by two weeks of treatment with the serotonin selective reuptake inhibitor (SSRI) fluoxetine [21]. However, it should be emphasized that the relationship between ZnD and the efficacy of particular antidepressant strategies is not fully understood. ...
... From a mechanistic standpoint, we have previously shown that dietary Zn restriction in rats reduced the levels of this microelement in the serum, Hp, and PFC of rats. The reduction was accompanied by increased glutamate release in the PFC after KCl stimulation [19][20][21]41]. Since Zn blocks NMDAR and is crucial for the proper functioning of glutamatergic/zincergic neurons in the hippocampus and PFC [34][35][36][37]42], we wanted to find out whether Zn depletion has an impact on the antidepressant response of glutamate-based atypical compounds. ...
... Because Ro, in contrast to ketamine, showed the trend to enhance locomotor activity, its antidepressant efficacy in the FST should be interpreted with caution, as these effects could be nonspecific. Because we previously found that ZnD rats exhibited reduced sucrose intake compared to ZnA animals [20], we further evaluated the antidepressant-like activity of both compounds in this behavioral test. We confirmed our earlier observations that dietary Zn restriction decreases sucrose intake. ...
Clinical and preclinical studies indicate that zinc (Zn) is an essential factor in the development and treatment of major depressive disorder (MDD). Conventional monoamine-based antidepressants mobilize zinc in the blood and brain of depressed patients as well as rodents. N-methyl-D-aspartate acid receptor (NMDAR) antagonists exhibit antidepressant-like activity. However, not much is known about the antidepressant efficacy of NMDAR antagonists in zinc-deficient (ZnD) animals. We evaluated the antidepressant-like activity of two NMDAR antagonists (ketamine; global NMDAR antagonist and Ro 25-6981 (Ro); selective antagonist of the GluN2B NMDAR subunit) in ZnD rats using the forced swim test (FST) and sucrose intake test (SIT). A single dose of either Ro 25-6981 or ketamine normalized depressive-like behaviors in ZnD rats; however, Ro was effective in both tests, while ketamine was only effective in the FST. Additionally, we investigated the mechanism of antidepressant action of Ro at the molecular (analysis of protein expression by Western blotting) and anatomical (density of dendritic spines by Golgi Cox-staining) levels. ZnD rats exhibited decreased phosphorylation of the p70S6K protein, and enhanced density of dendritic spines in the prefrontal cortex (PFC) compared to control rats. The antidepressant-like activity of Ro was associated with the increased phosphorylation of p70S6K and ERK in the PFC. In summary, single doses of the NMDAR antagonists ketamine and Ro exhibited antidepressant-like activity in the ZnD animal model of depression. Animals were only deprived of Zn for 4 weeks and the biochemical effects of Zn deprivation and Ro were investigated in the PFC and hippocampus. The shorter duration of dietary Zn restriction may be a limitation of the study. However, future studies with longer durations of dietary Zn restriction, as well as the investigation of multiple brain structures, are encouraged as a supplement to this study.
... downregulation or decreased sensitivity of NMDA receptors) (Portbury et al., 2019). However, this homeostasis may be compromised by chronic dietary zinc deprivation, and as a result, cause brain dysfunction (Portbury and Adlard, 2017;Takeda, 2001), whereby the zinc deficient state may lead to NMDA receptor upregulation (Doboszewska et al., 2015) and an ensuing positive feedback problem. ...
... Decreased zinc in the synapse leads to an increase (upregulation) in NMDA receptors (Doboszewska et al., 2015) and this may cause significant problems as ensuing NMDA receptor overactivation can initiate excitotoxicity: a surge of calcium ions, resulting in cellular damage (Mlyniec, 2015;Petrilli et al., 2017;Swardfager et al., 2013). More specifically, four weeks of zinc restriction in rats led to significantly increased levels of NR2A and NR2B levels in hippocampus (with concomitant decreased expression of brain-derived neurotrophic factor (BDNF)). ...
... More specifically, four weeks of zinc restriction in rats led to significantly increased levels of NR2A and NR2B levels in hippocampus (with concomitant decreased expression of brain-derived neurotrophic factor (BDNF)). Furthermore, after six weeks of zinc restriction, upregulation of NR2A levels was observed in the prefrontal cortex (PFC) (Doboszewska et al., 2015). ...
Anorexia nervosa (AN) is a severe, biological brain disorder with significant medical risks and a tenacious development over time. Unfortunately, few treatments show efficacy in people with AN although numerous therapies including pharmacological have been explored. Zinc deficiency has been implicated in AN and zinc is important in a large range of processes in the brain. In particular, it is an allosteric modulator of NMDA receptors – the maintenance of zinc levels within a normal, narrow range is essential for glutamatergic functioning. Chronic zinc deficiency increases neuronal stores of calcium and reduces direct modulation of NMDA receptors which collectively lead to overactivation and upregulation of NMDA receptors. This may facilitate pathologically high levels of glutamate, calcium influx and subsequent excitotoxicity, which can disrupt synaptogenesis and synaptic plasticity. While studies of zinc supplementation in AN have shown some promise, the efficacy of this treatment is limited. This may be due to AN illness chronicity and the significant changes already made, as well as a reduced potency of zinc to inhibit NMDA receptors in a pathological state. Thus, we propose that the safe (at low doses) yet more potent NMDA receptor antagonist, ketamine, may act to normalise a perturbed glutamatergic system and increase synaptogenesis in the short term. This ‘kickstart’ via ketamine could then allow zinc supplementation and other forms of treatment to enhance recovery in AN.
... Moreover, the intake of zinc was suggested to be among the dietary factors that may be associated with a risk for depression. Studies performed in rodents indicated a causative role of dietary zinc restriction in the induction of depressive-like symptoms [21][22][23][24] or anhedonia [25][26][27]. Some large, cross-sectional, population-based epidemiological studies have suggested that a low dietary zinc intake is associated with depression in women [28,29], but not in men [28]. ...
... This finding may have resulted from different study design. In the study of Doboszewska et al. [66] the rats received the zinc-deficient diet for 4 weeks (i.e., for a period of time after which behavioral (increased immobility time in the FST, anhedonia) and neurobiological changes associated with depression are established [27]) and for subsequent 2 weeks they received fluoxetine (10 mg/kg/day intraperitoneally (i.p.)) in addition to the diet, whereas in the study of Tassabehji et al. [25] the rats received the zinc-deficient diet and fluoxetine (10 mg/kg/day via drinking water) for 3 weeks. Therefore, a shorter duration of the zinc-deficient diet in the study of Tassabehji et al. [25] (3 weeks) may have been an insufficient amount of time in which to observe a depressive-like behavior. ...
... Zinc deficiency induces depression-like behavior [21,22,24,25,27]. Animals subjected to a zinc-deficient diet and treated with an acute injection of imipramine or reboxetine displayed increased immobility time in the FST compared with animals treated with a zinc-adequate diet and the respective antidepressant [65]. ...
Preclinical and clinical studies have demonstrated that zinc possesses antidepressant properties and that it may augment the therapy with conventional, that is, monoamine-based, antidepressants. In this review we aim to discuss the role of zinc in the pathophysiology and treatment of depression with regard to the monoamine hypothesis of the disease. Particular attention will be paid to the recently described zinc-sensing GPR39 receptor as well as aspects of zinc deficiency. Furthermore, an attempt will be made to give a possible explanation of the mechanisms by which zinc interacts with the monoamine system in the context of depression and neural plasticity.
... In studies conducted by Tassabehji et al. [61], 3 weeks of zinc deficiency (10 mgZn/kg) led to increased immobility time in the FST and decreased sucrose intake in adult rats. Similar results were obtained by Doboszewska et al. [62] who showed that 4 or 6 weeks consumption of feed low in zinc (3 mg Zn/kg) caused the decreased intake of sucrose solution and increased immobility time in the FST. Additionally, 4 or 6 weeks zinc deficiency significantly reduced social interaction in adult rats [62]. ...
... Similar results were obtained by Doboszewska et al. [62] who showed that 4 or 6 weeks consumption of feed low in zinc (3 mg Zn/kg) caused the decreased intake of sucrose solution and increased immobility time in the FST. Additionally, 4 or 6 weeks zinc deficiency significantly reduced social interaction in adult rats [62]. ...
... The overstimulation of NMDAR leading to atrophy cell death is named excitotoxicity [65,66]. The role of glutamate transmission in behavioral abnormalities induced by zinc deficiency was indicated by Doboszewska et al. [62]. They showed that zinc deprivation led to a significantly enhanced expression of GluN1, GluN2A, and GluN2B subunits of NMDAR in the hippocampus and GluN2B subunit in the prefrontal cortex (PFC) [62,67]. ...
Zinc deficiency has multiple effects, including neurological and somatic symptoms. Zinc deficiency can lead to depression, increased anxiety, irritability, emotional instability, and induced deficits in social behavior. Clinical studies have shown that low levels of zinc intake contributes to the symptoms of depression and patients suffering from depression have a lower serum zinc level. Also the animal studies have shown an important role of dietary zinc deficiency in the induction of depressive‐like symp‐ toms. Moreover, both preclinical and clinical studies have indicated the potential benefits of zinc supplementation as an adjunct to conventional antidepressant drugs or as a stand‐alone intervention. This chapter focuses on the role of the zinc deficiency in the pathogenesis of depression, changes in animal behavior induced by dietary zinc restriction, the role of zinc supplementation in the treatment of depression, and the possible mechanisms involved in these relationships. Both clinical and preclinical studies related to these findings will be discussed.
... Other reports have revealed a negative correlation between the serum Zn levels and severity of MDD symptoms (Hansen et al., 1983;Maes et al., 1997); decreased serum Zn levels have also been reported in people suffering from MDD (Marcellini et al., 2006;Lehto et al., 2013;Siwek et al., 2013;Markiewicz-Zukowska et al., 2015). The role of Zn level deficit in inducing MDD symptoms has also been demonstrated in preclinical paradigms; in these studies, rats and mice chronically fed with a ZnD exhibited depression-like symptoms in a set of behavioral tests (Whittle et al., 2009;Mlyniec and Nowak, 2012;Doboszewska et al., 2015a;Doboszewska et al., 2015b). Similarly, rodents fed a low-zinc diet exhibited a depression-like behavioral phenotype similar to rats and mice subjected to chronic stresses. ...
... Similarly, rodents fed a low-zinc diet exhibited a depression-like behavioral phenotype similar to rats and mice subjected to chronic stresses. Chronic stressed and ZnD rodents were characterized by anhedonia (measured by SPT or sucrose intake test (SIT)), increased immobility time (forced swimming test or tail suspension test (TST)), or altered social behaviors (Whittle et al., 2009;Li et al., 2011;Castro et al., 2012;Mlyniec and Nowak, 2012;Pochwat et al., 2014;Doboszewska et al., 2015a;Doboszewska et al., 2015b;Yang et al., 2018). Moreover, the efficacy of classic monoamine-based (chronic administration) or atypical (fast-acting compounds, such as ketamine) antidepressants are similar in the two preclinical paradigms Doboszewska et al., 2015b;Pochwat et al., 2020). ...
Clinical and preclinical studies show evidence that chronic stress or nutritional deficits in dietary zinc (Zn) intake may be risk factors for developing major depressive disorder (MDD). Furthermore, there may be possible links between low serum Zn levels and development of treatment-resistant depression. In the present work, we combined chronic restraint stress (CRS) and a low-zinc diet (ZnD) in mice and carried out a set of behavioral and biochemical studies. The mice were treated with four different antidepressant compounds, namely, ketamine, Ro 25–6981 (Ro), hyperforin and lanicemine (Hyp + Lan), and imipramine (IMI). We show that CRS or ZnD alone or a combination of CRS and ZnD (CRS + ZnD) induces anhedonia observed in the sucrose preference test (SPT). The behavioral effects of CRS were restored by ketamine or IMI. However, only Hyp + Lan restored the deficits in behavioral phenotype in mice subjected to CRS + ZnD. We also showed that the antidepressant-like effects observed in Hyp + Lan-treated CRS + ZnD mice were associated with changes in the morphology of the dendritic spines (restored physiological level) in the hippocampus (Hp). Finally, we studied the metabolism of ketamine and its brain absorption in CRS and CRS + ZnD mice. Our results suggest that CRS + ZnD does not alter the metabolism of ketamine to (2R,6R;2S,6S)-HNK; however, CRS + ZnD can induce altered bioavailability and distribution of ketamine in the Hp and frontal cortex (FC) in CRS + ZnD animals compared to the control and CRS groups.
... Ademais, o zinco também impede o comportamento tipo-depressivo induzido por alguns protocolos de indução de depressão em roedores 102,105-109 .De modo interessante, vários estudos demonstram que animais alimentados com dieta deficiente em zinco apresentam um comportamento tipo-depressivo 52,110-116 e que essas dietas deficientes em zinco impedem o efeito de medicamentos antidepressivos nesses roedores110,112,113 . Uma dieta deficiente em zinco também pode gerar alterações cerebrais que estão envolvidas no mecanismos fisiopatológico da depressão, entre elas: diminuição dos níveis de glutamato, GABA e glutamina no hipocampo 117 , aumento do glutamato extracelular hipocampal 115 e aumento de algumas subunidades do receptor NMDA no hipocampo114,116 ; aumento dos níveis séricos de corticosterona115,118 ; diminuição dos níveis de BDNF no hipocampo e no córtex préfrontal52,53,114,116 , aumento da ativação do CREB www.vponline.com.br também demonstram que a administração de antidepressivos conseguem aumentar a quantidade do receptor GPR39, bem como do CREB, BDNF e TrkB no córtex pré-frontal52,125 . ...
... Ademais, o zinco também impede o comportamento tipo-depressivo induzido por alguns protocolos de indução de depressão em roedores 102,105-109 .De modo interessante, vários estudos demonstram que animais alimentados com dieta deficiente em zinco apresentam um comportamento tipo-depressivo 52,110-116 e que essas dietas deficientes em zinco impedem o efeito de medicamentos antidepressivos nesses roedores110,112,113 . Uma dieta deficiente em zinco também pode gerar alterações cerebrais que estão envolvidas no mecanismos fisiopatológico da depressão, entre elas: diminuição dos níveis de glutamato, GABA e glutamina no hipocampo 117 , aumento do glutamato extracelular hipocampal 115 e aumento de algumas subunidades do receptor NMDA no hipocampo114,116 ; aumento dos níveis séricos de corticosterona115,118 ; diminuição dos níveis de BDNF no hipocampo e no córtex préfrontal52,53,114,116 , aumento da ativação do CREB www.vponline.com.br também demonstram que a administração de antidepressivos conseguem aumentar a quantidade do receptor GPR39, bem como do CREB, BDNF e TrkB no córtex pré-frontal52,125 . ...
... The antidepressant-like effect of zinc in rodents is well established [19,20,29,36] and although it is known that zinc acts by a mechanism dependent on the serotonergic [37,38] and glutamatergic systems [36,38,39], much still remains to be uncovered on this issue. The present study provides clear evidence that both the activation of HO-1 and the TrkB receptors are involved in the anti-immobility effect of zinc in the TST, further contributing to the understanding of the mechanisms underlying its antidepressant-like effects. ...
... It is well established that both oxidative stress [48] and increased glutamate levels cause excitotoxicity [49], an event well established to contribute to the development of depressive symptoms. Additionally, preclinical studies suggest that one of the reasons by which zinc can exert its antidepressant-like effect is due to the modulation of antioxidant enzymes [23,24] and regulation of receptors or transporters involved in glutamatergic neurotransmission [38,39,50]. Notably, a deficit in zinc availability impairs Nrf2-DNA binding in rat fetal brain [51]. ...
Background:
Considering that heme oxygenase-1 (HO-1) and the brain-derived neurotrophic factor (BDNF)-mediated pathway are involved in the pathophysiology of depression and that zinc has been shown to exert beneficial effects in the management of depression, this study investigated the influence of these targets on the antidepressant-like effect of zinc.
Methods:
Mice were treated with sub-effective or effective doses of zinc chloride (ZnCl2, 10mg/kg, po), and 45min later, they received intracerebroventricular (icv) injections of sub-effective doses of either zinc protoporphyrin IX (ZnPP, 10?g/mouse, HO-1 inhibitor), cobalt protoporphyrin IX (CoPP, 0.01?g/mouse, HO-1 inducer) or K-252a (1?g/mouse, TrkB receptor antagonist). Immobility time and locomotor activity were evaluated through the tail suspension test (TST) and open-field test (OFT), respectively. HO-1 immunocontents were evaluated in the prefrontal cortex and hippocampus 60min after ZnCl2 (10mg/kg, po) treatment.
Results:
The antidepressant-like effect of ZnCl2 was prevented by the treatment with ZnPP and K-252a. Furthermore, sub-effective doses of CoPP and ZnCl2 produced a synergistic antidepressant-like effect in the TST. None of the treatments altered locomotor activity. ZnCl2 administration increased HO-1 immunocontents only in the prefrontal cortex.
Conclusions:
The results indicate that the antidepressant-like effect of ZnCl2 in the TST may depend on the induction of HO-1, and activation of TrkB receptor.
... Clinical studies have long shown that depressed patients exhibit a lower serum Zn level than psychiatrically normal controls and that Zn supplementation may enhance antidepressant therapy in depressed patients (Nowak et al., 2003a;Siwek et al., 2009;Siwek et al., 2010;Ranjbar et al., 2013;Swardfager et al., 2013;Ranjbar et al., 2014;Nowak, 2015). Additionally, preclinical studies show that Zn exerts antidepressant-like activity in different tests and models of depression and that Zn deficiency induces depression-like symptoms in animals (Kroczka et al., 2000;Kroczka et al., 2001;Rosa et al., 2003;Nowak et al., 2003b;Cunha et al., 2008;Tassabehji et al., 2008;Szewczyk et al., 2009;Tamano et al., 2009;Whittle et al., 2009;Szewczyk et al., 2010;Mlyniec et al., 2012;Doboszewska et al., 2015a;Doboszewska et al., 2015b) and humans (Amani et al., 2010;Jacka et al., 2012;Maserejian et al., 2012). ...
... However, information on Zn levels in the brain of depressed patients is very sparse or non-existent. Animal studies, in turn show that Zn deficiency induces depressivelike symptoms, which are associated with decreased serum and brain Zn level (Mlyniec et al., 2012;Doboszewska et al., 2015a;Doboszewska et al., 2016). These results suggest that depression may be associated with Zn dyshomeostasis, but it is not clear whether alterations in Zn levels occur in the brain and which Zn pool is affected. ...
Background:
Zinc transporters (ZnTs) and metallothioneins (MT) are important in maintaining Zn homeostasis in the brain. The present study was designed to find out whether alterations in ZnTs and MTs are associated with the pathophysiology of depression and the mechanism of antidepressant action.
Methods:
Messenger RNA and proteins of ZnT1, ZnT3, ZnT4, ZnT5, ZnT6 and MT1/2 were measured in the prefrontal cortex (PFC) and hippocampus (Hp) of rats subjected to olfactory bulbectomy (OB) (a model of depression) and chronic amitriptyline (AMI) treatment by Real Time PCR and Western Blot/Immunohistochemistry (IHP).
Results:
Results in the OB rats showed: increases in the protein levels of ZnT1 in the PFC and Hp and MT1/2 in the PFC; a decrease in ZnT3 protein level in the PFC; no changes in ZnT4, ZnT5 and ZnT6 in the PFC and Hp. IHP labeling revealed increases in the optical densities of ZnT1-IR in the PFC and Hp and decreases in ZnT3 and ZnT4-IR in the PFC of OB rats. Although OB had no effects on gene expression of ZnTs, mRNAs for MT1/2 were increased. Chronic AMI treatment did not influence protein levels of ZnTs and MT1/2 in Sham and OB rats; however decreased mRNA levels of ZnT4 and ZnT5 in PFC and ZnT1, ZnT3, ZnT4 and ZnT6 in Hp of Sham rats and normalized OB induced increase in MT1/2 gene expression.
Conclusions:
Changes in ZnTs and MT1/2 suggest altered cortical distribution of Zn in the OB model which further supports the hypothesis that Zn dyshomeostasis may be involved in the pathophysiology of depression.
... GluN2A, GluN2B-subunits of the glutamate N-methyl-D-aspartate receptor; p-CREBphosphorylated cyclic AMP response element-binding protein; BDNF-brain-derived neurotrophic factor; :-increased protein level; ;decreased protein level; $ no effects. Based on Doboszewska et al. 2015 As mentioned above, we have previously found significantly increased level of NMDAR GluN2A protein in the PFC of rats after the 6-week ZnD diet; however, no differences in the levels of NMDAR GluN2A or GluN2B proteins were observed in the PFC between the ZnD and control animals after the 4-week ZnD diet (Table 2). These data, together with the present data concerning increased glutamate release after 6 weeks of the ZnD diet administration, indicate that prolonged (6 weeks) zinc restriction may lead to activation of NMDAR in the PFC. ...
... Dietary zinc restriction induces peripheral and central alterations of bio-elements (namely zinc and iron) and enhances oxidative damage and pro-inflammatory status. These alterations share some similarities to those observed after exposure to stress and in depression, which further highlights that zinc deficiency [recently proposed as a model of depression (Whittle et al. 2009;Mlyniec et al. 2013;Doboszewska et al. 2015)] and depression may share a common pathophysiology. The changes observed in the present study may have a link to depression-like behavior in the zinc deficiency paradigm and may lead to/result from enhanced glutamate transmission through NMDAR. ...
Our previous study showed that dietary zinc restriction induces depression-like behavior with concomitant up-regulation of the N-methyl-D-aspartate receptor (NMDAR). Because metal ions, oxidative stress, and inflammation are involved in depression/NMDAR function, in the present study, bio-elements (zinc, copper, iron, magnesium, and calcium), oxidative (thiobarbituric acid-reactive substances; protein carbonyl content), and inflammatory (IL-1α, IL-1β) factors were measured in serum, hippocampus (Hp), and prefrontal cortex (PFC) of male Sprague-Dawley rats subjected to a zinc-adequate (ZnA) (50 mg Zn/kg) or a zinc-deficient (ZnD) (3 mg Zn/kg) diet for 4 or 6 weeks. Both periods of dietary zinc restriction reduced serum zinc and increased serum iron levels. At 4 weeks, lowered zinc level in the PFC and Hp as well as lowered iron level in the PFC of the ZnD rats was observed. At 6 weeks, however, iron level was increased in the PFC of these rats. Although at 6 weeks zinc level in the PFC did not differ between the ZnA and ZnD rats, extracellular zinc concentration after 100 mM KCl stimulation was reduced in the PFC of the ZnD rats and was accompanied by increased extracellular iron and glutamate levels (as measured by the in vivo microdialysis). The examined oxidative and inflammatory parameters were generally enhanced in the tissue of the ZnD animals. The obtained data suggest dynamic redistribution of bio-elements and enhancement of oxidative/inflammatory parameters after dietary zinc restriction, which may have a link with depression-like behavior/NMDAR function/neurodegeneration.
... We have previously shown that depression-like behavior induced by dietary zinc restriction is associated with changes in NMDAR signaling pathway. Up-regulation of GluN2A and GluN2B subunits of NMDAR with concomitant decreased expression of phosphorylated CREB (p-CREB) and BDNF proteins in the hippocampus (Hp) were observed following zinc regimen [48]. Here we tested whether chronic treatment with an SSRI, FLX, would rescue behavioral and biochemical deficits induced by zinc restriction. ...
... Here we examined the effects of chronic treatment with a selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX) on zinc-deficiency induced alterations. We have recently shown that 4 or 6 weeks of dietary zinc restriction in rats induces depression-like behavior with concomitant neurobiological alterations [48], thus, in the present study the rats were fed the zinc deficient diet for 4 weeks prior to treatment with FLX. ...
... The affinity of glycine to glycine/NMDA receptors was demonstrated to be decreased by chronic Zn 2+ administration [140]. Increased levels of GluN2A and GluN2B in the rat hippocampus were found following Zn 2+ restriction [150]. Also, the role of the AMPA receptor in antidepressant-like effects of Zn 2+ has been shown. ...
Zinc (Zn2+) is the second most abundant necessary trace element in the human body, exerting a critical role in many physiological processes such as cellular proliferation, transcription, apoptosis, growth, immunity, and wound healing. It is an essential catalyst ion for many enzymes and transcription factors. The maintenance of Zn2+ homeostasis is essential for the central nervous system, in which Zn2+ is abundantly distributed and accumulates in presynaptic vesicles. Synaptic Zn2+ is necessary for neural transmission, playing a pivotal role in neurogenesis, cognition, memory, and learning. Emerging data suggest that disruption of Zn2+ homeostasis is associated with several central nervous system disorders including Alzheimer’s disease, depression, Parkinson’s disease, multiple sclerosis, schizophrenia, epilepsy, and traumatic brain injury. Here, we reviewed the correlation between Zn2+ and these central nervous system disorders. The potential mechanisms were also included. We hope that this review can provide new clues for the prevention and treatment of nervous system disorders.
... A study has shown that in rats, zinc deficiency-induced depression-like behaviors are associated with increased NMDAR (GluN1, GluN2A, GluN2B), decreased AMPAR(GluA1), p-CREB, and BDNF in the hippocampus to change the NMDAR neuronal signal [100]. Another study also showed that in rats, zinc deficiency-induced depressionlike behaviors are associated with increased NMDAR (GluN2A and GluN2B), decreased PSD-95, p-CREB, and BDNF in the hippocampus [101]. ...
Depression is a common mental disorder that seriously affects the quality of life and leads to an increasing global suicide rate. Macro, micro, and trace elements are the main components that maintain normal physiological functions of the brain. Depression is manifested in abnormal brain functions, which are considered to be tightly related to the imbalance of elements. Elements associated with depression include glucose, fatty acids, amino acids, and mineral elements such as lithium, zinc, magnesium, copper, iron, and selenium. To explore the relationship between these elements and depression, the main literature in the last decade was mainly searched and summarized on PubMed, Google Scholar, Scopus, Web of Science, and other electronic databases with the keywords “depression, sugar, fat, protein, lithium, zinc, magnesium, copper, iron, and selenium”. These elements aggravate or alleviate depression by regulating a series of physiological processes, including the transmission of neural signals, inflammation, oxidative stress, neurogenesis, and synaptic plasticity, which thus affect the expression or activity of physiological components such as neurotransmitters, neurotrophic factors, receptors, cytokines, and ion-binding proteins in the body. For example, excessive fat intake can lead to depression, with possible mechanisms including inflammation, increased oxidative stress, reduced synaptic plasticity, and decreased expression of 5-Hydroxytryptamine (5-HT), Brain Derived Neurotrophic Factor (BDNF), Postsynaptic density protein 95(PSD-95), etc. Supplementing mineral elements, such as selenium, zinc, magnesium, or lithium as a psychotropic medication is mostly used as an auxiliary method to improve depression with other antidepressants. In general, appropriate nutritional elements are essential to treat depression and prevent the risk of depression.
... Those processes require interaction between PSD95, NMDAR and AMPAR on postsynaptic membrane [58]. As it was reported before, this protein is highly sensitive to zinc concentration [59,60] which is in line with our results. ...
Background:
Despite our poor understanding of the pathophysiology of depression, a growing body of evidence indicates the role of both glutamate and gamma-aminobutyric acid (GABA) signaling behind the effects of rapid-acting antidepressants (RAADs). GPR39 is a zinc-sensing receptor whose activation leads to a prolonged antidepressant-like response in mice. Both GPR39 and zinc can modulate glutamatergic and GABAergic neurotransmission, however, exact molecular mechanisms are still elusive. In this study, we aimed to research the role of glutamatergic and GABAergic system activation in TC-G 1008 antidepressant-like effects and the disruptions in this effect caused by a low-zinc diet.
Methods:
In the first part of our study, we investigated the role of joint administration of the GPR39 agonist (TC-G 1008) and ligands of the glutamatergic or GABAergic systems, in antidepressant-like response. To evaluate animal behaviour we used the forced swim test in mice. In the second part of the study, we assessed the effectiveness of TC-G 1008-induced antidepressant-like response in conditions of decreased dietary zinc intake and its molecular underpinning by conducting a Western Blot analysis of selected proteins involved in glutamatergic and GABAergic neurotransmission.
Results:
The TC-G 1008-induced effect was blocked by the administration of NMDA or picrotoxin. The joint administration of TC-G 1008 along with muscimol or SCH50911 showed a trend toward decreased immobility time. Zinc-deficient diet resulted in dysregulation of GluN1, PSD95, and KCC2 protein expression.
Conclusions:
Our findings indicate the important role of glutamate/GABA signaling in the antidepressant-like effect of TC-G 1008 and imply that GPR39 regulates the balance between excitatory and inhibitory activity in the brain. Thus, we suggest the zinc-sensing receptor be considered an interesting new target for the development of novel antidepressants.
... Reduced grey matter volume in the amygdala (Burkert et al., 2019) and heightened activity (i.e., overcontrol, stress, anxiety) are reported in AN (Pauligk et al., 2021;Takano et al., 2001;Miyake et al., 2010;Joos et al., 2011b;Seidel et al., 2018;Seeger et al., 2002) and theorised to be a factor in fear-learning and neurobiology in AN (Reyes- Rodríguez et al., 2011;Guarda et al., 2015). Zinc plays a key role in regulating glutamatergic neurotransmission via allosteric inhibition of NMDA receptor, requiring a restricted margin for normal NMDAR upregulation (Blaylock, 2011;Doboszewska et al., 2015;Hermens, 2020;Murray and Holton, 2021). Reduced appetite can be induced by zinc deficiency (Bhowmik et al., 2010;Kwun et al., 2007), leading to cyclical food restriction and chronic zinc deficiency. ...
Anorexia nervosa (AN) is a severe illness with diverse aetiological and maintaining contributors including neurobiological, metabolic, psychological, and social determining factors. In addition to nutritional recovery, multiple psychological and pharmacological therapies and brain-based stimulations have been explored; however, existing treatments have limited efficacy. This paper outlines a neurobiological model of glutamatergic and γ-aminobutyric acid (GABA)-ergic dysfunction, exacerbated by chronic gut microbiome dysbiosis and zinc depletion at a brain and gut level. The gut microbiome is established early in development, and early exposure to stress and adversity contribute to gut microbial disturbance in AN, early dysregulation to glutamatergic and GABAergic networks, interoceptive impairment, and inhibited caloric harvest from food (e.g., zinc malabsorption, competition for zinc ions between gut bacteria and host). Zinc is a key part of glutamatergic and GABAergic networks, and also affects leptin and gut microbial function; systems dysregulated in AN. Low doses of ketamine in conjunction with zinc, could provide an efficacious combination to act on NMDA receptors and normalise glutamatergic, GABAergic and gut function in AN.
... The sucrose intake test was performed as published by Doboszewska [25]. A training session preceded a test session. ...
Currently used antidepressants do not always provide the desired results, and many patients suffer from treatment-resistant depression. Clinical studies suggest that zinc deficiency (ZnD) may be an important risk factor for depression and might blunt the effect of antidepressants. This study aimed to examine whether ZnD might blunt the effectiveness of antidepressants in the olfactory bulbectomy model (OB) of depression in rats. For this purpose, rats were subjected to the OB model, fed a zinc-deficient diet (3 mg Zn/kg) for 3 weeks, and finally treated with escitalopram (Esc), venlafaxine (Ven) 10 mg/kg, i.p., or combined Esc/Ven (1 mg/kg, i.p.) with zinc (5 mg/kg) for another 3 weeks. Open field (OFT), forced swim (FST), and sucrose intake (SIT) tests were used to evaluate depressive-like behavioral changes. In addition, serum, intracellular, and synaptic Zn concentrations and the level of zinc transporter (ZnT) proteins were analyzed. The OB + ZnD model induced hyperactivity in rats in the OFT, increased immobility time in the FST, and anhedonia in the SIT. Chronic treatment with Esc reduced immobility time in the FST in the OB + ZnD model. Esc/Ven +Zn increased sucrose intake in rats from the OB + ZnD group. The OB + ZnD decreased serum zinc levels and intracellular and synaptic Zn concentration in the prefrontal cortex (PFC) and cerebellum. These changes were normalized by chronic administration of Esc/Ven +Zn. Moreover, OB + ZnD decreased levels of the ZnT1 protein in the PFC and Hp and ZnT3 in Hp. Chronic administration of antidepressants did not alter the levels of ZnT proteins. The OB + ZnD model induces more depressive-like effects than either model alone. Our results show that ZnD may induce drug resistance in rats. Normalizing serum or brain zinc concentration is insufficient to reverse behavioral abnormalities caused by the OB + ZnD model. However, zinc supplementation might improve the effectiveness of antidepressants in reversing particular depression symptoms.
... In mice, a diet of 2 mg Zn/kg resulted in renal and myocardial fibrosis [9,10] and promoted testicular cell apoptosis [5]. Meanwhile, a diet of 3 mg Zn/kg changed behavior, with the procedure being similar to the pathophysiology of depression in rats [11]. Some studies have shown that Zn deficiency is related to preneoplastic lesions in chemically induced hepatocarcinogenesis by establishing a 3.5 mg Zn/ kg diet Zn-deficient model [12]. ...
Zinc (Zn) is an important trace element in the human body, and Zn deficiency affects the Zn content of major tissues. Marginal Zn deficiency is more common than severe Zn deficiency in humans. The objective of the present study was to compare the content and distribution of Zn and the change in the copper (Cu)–Zn superoxide dismutase (SOD) and metallothionein (MT) levels of soft tissues. Mice were fed with 30 mg/kg (control) or 10 mg/kg (marginally Zn-deficient, MZD) Zn diet for 35 days. We observed that only the Zn contents of serum, bones, and muscles in the control group were higher than those in the MZD group. Autometallography (AMG) was used as a method for staining Zn ions, and the semi-quantitative result indicated that the AMG products of the liver, duodenum, heart, lung, testes, and epididymis in the control group were higher than those in the MZD group. Furthermore, the contents of MT and the activities of Cu–Zn SOD in the testes, brain, duodenum, and liver were higher in the control group than those in the MZD group. However, the AMG products and the activities of Cu–Zn SOD of the kidney in the MZD group were more/higher than those in the control group. These results indicated that a change in the total Zn content of soft tissues may be not obvious and insensitive, and thus, more attention should be given to the distribution and localization of Zn ions. The functional indicators, MT and Cu–Zn SOD, are suitable biomarkers for evaluating zinc nutritional status. The brain, testes, duodenum, and liver are susceptive organs to Zn deficiency.
... In the case of olfaction, an early study reported that the histological structure and cell turnover of the olfactory epithelium were unchanged after 42 consecutive days of dietary zinc deficiency (Mackay-Sim and Dreosti 1989). In contrast, studies indicated that hippocampal function was evidently affected following zinc deficiency (Doboszewska et al. 2015;Han et al. 2015). These data suggest that the hippocampus and other brain regions, rather than the olfactory epithelium, were critically involved in zinc deficiency-induced olfactory deficit. ...
Dietary zinc deficiency may lead to olfactory deficits, whose mechanism remains largely elusive. Olfactory ensheathing cells (OECs), a type of glial cells that support the function and neurogenesis in the olfactory bulb (OB), may play a pivotal role in the maintenance of the olfactory system. In the present study, we established a rat model of dietary zinc deficiency and found that severe zinc deficiency, but not marginal zinc deficiency, caused significantly reduced food intake, growth retardation, and apparent olfactory deficit in growing rats. We showed that severe zinc deficiency resulted in the loss of OECs in the olfactory nerve layer (ONL) of the olfactory bulb. In addition, we revealed that the number of TUNEL-positive cells increased markedly in the region, suggesting an involvement of apoptotic cell death in zinc deficiency-induced loss of OECs. Moreover, we found that treatment with zinc chelator N,N,N'N',-tetrakis (2-pyridylmethyl)ethylenediamine (TPEN) triggered the apoptosis of in vitro-cultured primary OECs. The apoptosis of OECs was correlated with significantly elevated expression of p53. Importantly, TUNEL and CCK-8 assays both demonstrated that treatment with p53 antagonist pifithrin-α (PFT-α) markedly attenuated TPEN-induced OEC apoptosis. These findings implicated that p53-triggered apoptosis of OECs might play an integral role in zinc deficiency-induced olfactory malfunction.
... Experiments assessing the effects of zinc deficient (ZnD) and zinc adequate (ZnA) diets on seizures/epilepsy may be another step in delineating the role of zinc in epilepsy. We reported altered expression of NMDAR and AMPAR subunits at the protein level in the hippocampi of rats fed the ZnD diet, which was associated with depressive-like behavior (Doboszewska et al., 2015a;Doboszewska et al., 2015b). These results are suggestive of altered function of NDMAR and AMPAR, and thus of imbalance between excitation and inhibition, in ZnD rats. ...
Evidence from both preclinical and clinical studies suggest the importance of zinc homeostasis in seizures/epilepsy. Undoubtedly, zinc, via modulation of a variety of targets, is necessary for maintaining the balance between neuronal excitation and inhibition, while an imbalance between excitation and inhibition underlies seizures. However, the relationship between zinc signaling and seizures/epilepsy is complex as both extracellular and intracellular zinc may produce either protective or detrimental effects. This review provides an overview of preclinical/behavioral, functional and molecular studies, as well as clinical data on the involvement of zinc in the pathophysiology and treatment of seizures/epilepsy. Furthermore, the potential of targeting elements associated with zinc signaling or homeostasis and zinc levels as a therapeutic strategy for epilepsy is discussed.
... Structural changes in areas of the brain that may be important in the development of behavior problems, including the basal ganglia, hippocampus, amygdala, and prefrontal cortex, occur throughout childhood (14). Rodent experiments indicate that exposure to gestational, perinatal, and post-weaning iron deficiency (15)(16)(17), post-weaning zinc (18) or vitamin A (19) deficiencies, low gestational vitamin B-12 (20), or gestational folate deficiency (21) can disrupt the normal development of these regions, but data in humans are scant. ...
Background:
Iron deficiency (ID) in infancy is related to subsequent behavior problems. The effects of micronutrient status in middle childhood are uncertain.
Objective:
The aim of the study was to examine the associations of micronutrient status biomarkers in middle childhood with externalizing and internalizing behavior problems in adolescence.
Methods:
We assessed whether ID (ferritin <15 µg/L), anemia (hemoglobin <12.7 g/dL), or blood concentrations of zinc, vitamins A and B-12, and folate at ages 5-12 y were associated with externalizing or internalizing behavior problems in adolescence in 1042 schoolchildren from Bogotá, Colombia. Behavior problems were assessed with the Youth Self-Report questionnaire after a median 6.2 y of follow-up. Mean problem score differences with 95% CIs were estimated between categories of micronutrient status biomarkers with the use of multivariable linear regression.
Results:
Mean ± SD externalizing and internalizing problems scores were 52.6 ± 9.6 and 53.8 ± 9.9, respectively. Among boys, middle-childhood ID, anemia, and low plasma vitamin B-12 were associated with 5.9 (95% CI: 1.0, 10.7), 6.6 (95% CI: 1.9, 11.3), and 2.7 (95% CI: 0.4, 4.9) units higher mean externalizing problems scores in adolescence, respectively-after adjustment for baseline age, time spent watching television or playing video games, mother's height, and socioeconomic status. Also in boys, ID was related to an adjusted 6.4 (95% CI: 1.2, 11.6) units higher mean internalizing problems score. There were no associations among girls. Other micronutrient status biomarkers were not associated with behavior problems.
Conclusions:
ID, anemia, and low vitamin B-12 in middle childhood are related to behavior problems in adolescent boys. This study was registered at clinicaltrials.gov as NCT03297970.
... Mechanistic studies in cell culture model revealed that the observed Zn deficiency was likely due to decreased expression of Zn uptake transporters 27 . Besides attention and cognitive deficits, several studies using animal depression model showed that zinc-deficient diets could induce quantitative and qualitative changes in phospholipid-protein balance, and up-regulation of N-methyl-D-aspartate receptor (NMDAR) in hippocampus and prefrontal cortex [28][29][30] . ...
Zinc status is an important modifiable factor in Attention Deficit and Hyperactive Disorders (ADHD) and Autistic Spectrum Disorders (ASD), the two most common neurodevelopmental disorders. Many studies reported low serum or plasma zinc level in children with these conditions. While hair zinc level can be obtained non-invasively in young children, the reports of the hair zinc levels in ASD and ADHD children were varied. ASD children were reported to have lower than or indifferent level of hair zinc from that of healthy children. In ADHD children, hair zinc levels were reported as either lower or higher than their healthy control groups. Many factors interplayed and affected measurement of hair zinc level. Until more standardized method has been established, currently the zinc level in hair samples may be used as screening or supporting evidence. Other functional zinc markers such as serum zinc concentrations, dietary zinc intakes, and percentage of stunting rate, are still needed to assess the zinc status in susceptible children.
... Preclinical and clinical studies have shown the antidepressantlike properties of zinc (Nowak, 2015) which, like ketamine, is an antagonist of the glutamatergic system. Zinc deficiency has been found to be the cause of depressive-and anxiety-like behaviour and has been proposed as the state marker of major depression ( Doboszewska et al., 2015;Maes et al., 1999;Młyniec et al., 2014a, 2012Siwek et al., 2013). Zinc co-released with glutamate at the glutamatergic terminals binds via a zinc-specific binding site at the NMDA channel and inhibits action of the NMDA receptor (Młyniec, 2015). ...
... By modulating N-Methyld-aspartate receptors for glutamate, the zinc signaling is involved in synaptic plasticity and cognitive activity (32). In animal models, zincdeficient rats showed an up-regulation of hippocampal N-Methyl-daspartate receptors (33) and zinc deficient diet caused depressive like behavior in the forced swim test and increased anxiety-like behavior in a light-dark box test (34,35). Recent research also indicates a link between zinc levels and serotonin. ...
Background
Zinc plays an important role for behavioral and mental function, maintaining the correct functions of intracellular signal transduction, cellular and trans-membrane transport, protein synthesis, and antioxidant system. We investigated both dietary zinc intake and plasma zinc levels and the correlation with depressive symptoms in a large sample of community-dwelling old.
Design
One thousand five hundred fourteen older people (aged 60–84 years, 772 women) from the Berlin Aging Study II were included. Zinc intake was assessed by the EPIC Food Frequency Questionnaire. Plasma zinc levels were assessed with atomic-absorption spectrophotometry. Depressive symptoms were assessed with the “Center for Epidemiological Studies Depression Scale” and the “Geriatric Depression Scale.”
Results
Zinc deficiency in blood plasma was found in 18.7% of participants, and depressive symptoms in 15.7%. Participants with depressive symptoms had lower energy-adjusted zinc intake (median 11.1 vs 11.6 µmol/L; p = .048) and lower plasma zinc levels (median 12.2 vs12.3 mg/dL; p = .037). Even after adjustment for known predictors of depression, plasma zinc deficiency remained significantly associated with depressive symptoms (odds ratio: 1.490, 95% confidence interval: 1.027–2.164; p = .036). In the multiple logistic regression model stratified by sex, we found that plasma zinc deficiency was strongly associated with a higher risk for depressive symptoms in women (odds ratio: 1.739, 95% confidence interval: 1.068–2.833; p = .026).
Conclusions
Plasma zinc deficiency was common in our old study population. An increase in dietary zinc and higher plasma zinc levels may reduce the risk of depressive symptoms. A screening for reduced dietary zinc intake or plasma zinc deficiency might be beneficial in older people at risk of depressive symptoms.
... Zinc and glutamate have been shown to co-release from gluzinergic neurons in a calcium-and impulse-dependent manner followed by the decrease of NMDA receptor's stimulation [6]. Therefore, the overload of calcium signaling may explain a positive correlation between two, four or six weeks zinc deficiency associated with anxiety signs such as hypothalamic-pituitary-adrenal (HPA) dysregulation or increased oxidative stress in the plus maze and open field test [7][8][9]. ...
... In contrast to social interaction that currently serves as the major model for social behavior 26,27 , in our maze no direct body contact was available, thus excluding behaviors such as biting, sniffing or grooming any part of the partner's body. Furthermore, these physical contact behaviors are also suggested as aggression gestures and one can doubt the content validity when aiming to measure merely social behaviors 28 . ...
Social cooperation is defined as a joint action for mutual benefit that depends on the individual and the counterparts' behaviors. To gain valid evidence for social cooperation behavior we conducted a series of experiments in our suggested fully automated non-conditioned maze and depicted three major findings: (i) During 18 days of training the rats showed a progressive social learning curve as well as latent social learning; (ii) Examining the perceptual communication between the cooperating partners, we found a correlation between the available perceptual modalities and the social cooperation performance; and (iii) Investigating contextual learning as a competing process to the social cooperation, we found that additional contextual cues impaired the social cooperation performance. In conclusion, our suggested automated cooperation maze is designed to further our understanding of social cooperation under normal conditions, such as decision-making, and to examine the neural basis of social cooperation. A variety of neuropsychiatric disorders are characterized by disruptions in social behavior and social cognition, including depression, autism spectrum disorders, obsessive-compulsive disorder, and schizophrenia. Thus, on the pathological end, our maze for social cooperation evaluation can contribute significantly to the investigation of a wide range of social cooperation impairments in a rodent model.
... In contrast, chronic zinc exposure decreased the surface expression of GluN2A-containing NMDARs in cultured hippocampal neurons (Zhu et al. 2012). After four or six weeks of zinc restriction, expression of GluN2A was increased in the hippocampus and prefrontal cortex of rats (Doboszewska et al. 2015). Furthermore, high-dose zinc supplementation induced significant loss of dendritic spines and decreased GluN2A expression in hippocampus . ...
The NMDA receptor is the most widely studied ionotropic glutamate receptor, and it is central to many physiological and pathophysiological processes in the central nervous system. GluN2A is one of the two main types of GluN2 NMDA receptor subunits in the forebrain. The proper activity of GluN2A is important to brain function, as the abnormal regulation of GluN2A may induce some neuropsychiatric disorders. This review will examine the regulation of GluN2A by endogenous and exogenous regulators in the central nervous system.
... Preclinical and clinical studies have shown the antidepressant-like properties of zinc (Nowak, 2015) which, like ketamine, is an antagonist of the glutamatergic system. Zinc deficiency has been found to be the cause of depressive-and anxiety-like behaviour and has been proposed as the state marker of major depression (Doboszewska et al., 2015;Maes et al., 1999;Młyniec et al., 2014aMłyniec et al., , 2012Siwek et al., 2013). Zinc co-released with glutamate at the glutamatergic terminals binds via a zinc-specific binding site at the NMDA channel and inhibits action of the NMDA receptor (Młyniec, 2015). ...
Some forms of depression appear to be more related to the glutamatergic system. G-coupled protein receptor 39 (GPR39) is the metabotropic zinc receptor, which may be involved in the pathophysiology of depression and in the antidepressant response. Its deficiency abolishes the antidepressant response, which means that GPR39 is required to obtain a therapeutic effect in depression. This raises the possibility that agonists of the zinc receptor may have a role in antidepressant treatment. To explore this possibility we investigated animal behaviour in the forced swim test, the tail suspension test (to assess antidepressant-like properties), the light/dark test and the elevated plus maze test (to assess anxiolytic-like properties), following acute administration of a GPR39 agonist (TC G-1008). We found an antidepressant response (as measured by the forced swim test but not by the tail suspension test) in mice following the GPR39 agonist treatment. Additionally, we observed the opposite results in the light/dark box (decreased overall distance; increased time spent in the lit compartment; decreased time spent in the dark compartment; increased freezing time) and elevated plus maze (no significant changes), which may be a consequence of the sedative effect of TC G-1008. We also found hippocampal GPR39 and brain-derived neurotrophic factor (BDNF) up-regulation following administration of the GPR39 agonist, which may be undiscovered so far as a possible novel agent in the treatment of mood disorders.
... N-methyl-d-aspartate (NMDA) (glutamate) has an important anti-depression and anti-anxiety effect. Zinc and magnesium, the potent antagonists of the NMDA receptor complex, are involved in the pathophysiology of depression and anxiety, and exhibit antidepressant and anti-anxiety activities; therefore, reduction of zinc and magnesium levels may lead to functional NMDA receptor hyperactivity (Doboszewska et al., 2015; Sowa-Kucma et al., 2013). In addition, magnesium controls HPA (Hypothalamic–pituitary–adrenal) activity, thereby decreases anxiety symptoms by the reduction of corticotrophin releasing hormone (CRH) level (Sartori, Whittle, Hetzenauer, & Singewald, 2012). ...
p> OBJECTIVE: According to the World Health Organization, depression will be the second prevalent problem after ischemic heart diseases by the year 2020. Postpartum depression (PPD) as a major depressive episode has devastating impacts on the health of mother, newborn, infant, and even the whole family. This study was conducted to investigate the relationship of zinc and magnesium serum levels with PPD, as one of the commonly assumed causes of depression.
METHODS: This cross-sectional study was done on 122 postpartum women aged 18 years and more in two educational hospitals and one non-educational hospital in Tabriz-Iran, 2015. The eligible women were selected using convenience sampling method. Then, the demographic characteristics questionnaire and Edinburgh Depression Scale were completed by participants, and 5cc of blood sample was drawn from each participant. For data analysis, logistic regression test was used.
RESULTS: The mean score of depression scale was 8.0 (SD: 4.7), meaning that 18.9% of mothers were depressed. Results indicated a significant inverse correlation between Edinburgh depression score and magnesium serum level (p= 0.001). However, there was no statistically significant relationship between the zinc serum level and Edinburgh depression score (p=0.831), in so far as based on logistic regression analysis, increased magnesium serum level decreased the odds of depression [Odds ratio: 0.05; CI 95%: 0.01 to 0.29].
CONCLUSIONS: In this study, there was a significant inverse relationship between magnesium serum level and Edinburgh depression score.</p
... Indeed, it has been shown that inhibition of NMDA receptors (Rosa et al. 2003) as well as other alterations in glutamatergic system ) are possible mechanisms involved in antidepressant-like effect of zinc. Interestingly, in rats fed with a zinc-deficient diet alterations in hippocampal NMDA receptors were reported (increased expression of GluN2A in the hippocampus and prefrontal cortex and GluN2B in the hippocampus) in a manner similar to that observed in depression (Doboszewska et al. 2015). Therefore, although studies suggest that zinc antidepressant-like behavior involves, at least in part, NMDA receptor inhibition, and that stress can also influence the glutamatergic neurotransmission, we did not observe any protective effect of zinc in our experimental protocol. ...
Stress and excessive glutamatergic neurotransmission have been implicated in the pathophysiology of depression. Therefore, this study was aimed at investigating the influence of zinc on depressive-like behavior induced by chronic unpredictable stress (CUS), on alterations in glutamate-induced toxicity and immunocontent of proteins involved in the control of glutamatergic neurotransmission in the hippocampus of mice. Mice were subjected to CUS procedure for 14 days. From the 8th to the 14th day, mice received zinc chloride (ZnCl2) (10 mg/kg) or fluoxetine (10 mg/kg, positive control) once a day by oral route. CUS caused a depressive-like behavior evidenced by the increased immobility time in the tail suspension test (TST), which was prevented by treatment with ZnCl2 or fluoxetine. Ex vivo exposure of hippocampal slices to glutamate (10 mM) resulted in a significant decrease on cell viability; however, neither CUS procedure nor drug treatments altered this reduction. No alterations in the immunocontents of GLT-1 and GFAP or p-Akt were observed in any experimental group. The ratio of p-Akt/AKT was also not altered in any group. However, Akt immunocontent was increased in stressed mice and in animals treated with ZnCl2 (stressed or non-stressed mice) and EAAC1 immunocontent was increased in stressed mice treated with ZnCl2, fluoxetine or vehicle and in non-stressed mice treated with ZnCl2 and fluoxetine. These findings indicate a robust effect of zinc in reversing behavioral alteration induced by CUS in mice, through a possible modulation of the glutamatergic neurotransmission, extending literature data regarding the mechanisms underlying its antidepressant-like action.
... Recent data have indicated that disturbances in Zn homeostasis are involved in the aetiology of some neurological disorders. Several studies, including both preclinical and clinical studies, showed that Zn deficiency leads to the development of depression [4][5][6] and that Zn supplementation improves the effectiveness of standard antidepressant treatment [7,8]. One of the possible mechanisms involved in Zn antidepressant activity is the modulation of the serotonergic system through 5-HT 1A and 5-HT 2A receptors [9,10]. ...
Recent data has indicated that Zn can modulate serotonergic function through the 5-HT1A receptor (5-HT1AR); however, the exact mechanisms are unknown. In the present studies, radioligand binding assays and behavioural approaches were used to characterize the pharmacological profile of Zn at 5-HT1ARs in more detail. The influence of Zn on agonist binding to 5-HT1ARs stably expressed in HEK293 cells was investigated by in vitro radioligand binding methods using the agonist [(3)H]-8-OH-DPAT. The in vivo effects of Zn were compared with those of 8-OH-DPAT in hypothermia, lower lip retraction (LLR), 5-HT behavioural syndrome and the forced swim (FST) tests. In the in vitro studies, biphasic effects, which involved allosteric potentiation of agonist binding at sub-micromolar Zn concentrations and inhibition at sub-millimolar Zn concentrations, were found. The in vivo studies showed that Zn did not induce LLR or elements of 5-HT behavioural syndrome but blocked such effects induced by 8-OH-DPAT. Zn decreased body temperature in rats and mice; however, Zn failed to induce hypothermia in the 5-HT1A autoreceptor knockout mice. In the FST, Zn potentiated the effect of 8-OH-DPAT. However, in the FST performed with the 5-HT1A autoreceptor knockout mice, the anti-immobility effect of Zn was partially blocked. Both the binding and behavioural studies suggest a concentration-dependent dual mechanism of Zn action at 5-HT1ARs, with potentiation at low dose and inhibition at high dose. Moreover, the in vivo studies indicate that Zn can modulate both presynaptic and postsynaptic 5-HT1ARs; however, Zn's effects at presynaptic receptors seem to be more potent.
... A depressive-and anxiety-like phenotype related to zinc deficiency has been confirmed in other studies with mice or rats (Doboszewska et al., 2015;Młyniec and Nowak, 2012;Młyniec et al., 2014bMłyniec et al., , 2013Tassabehji et al., 2008;Whittle et al., 2009). From studies conducted in recent decades it is well known that depression is linked to zinc concentrations. ...
Depression is a serious psychiatric disorder affecting not only the monaminergic, glutamatergic, and GABAergic neurosystems, but also the immune system. Patients suffering from depression show disturbance in the immune parameters as well as increased susceptibility to infections. Zinc is well known as an anti-inflammatory agent, and its link with depression has been proved, zinc deficiency causing depression- and anxiety-like behavior with immune malfunction. It has been discovered that trace-element zinc acts as a neurotransmitter in the central nervous system via zinc receptor GPR39. In this study we investigated whether GPR39 knockout would cause depressive-like behavior as measured by the forced swim test, and whether these changes would coexist with immune malfunction. In GPR39 knockout mice versus a wild-type control we found: i) depressive-like behavior; ii) significantly reduced thymus weight; (iii) reduced cell viability of splenocytes; iv) reduced proliferative response of splenocytes; and v) increased IL-6 production of splenocytes after ConA stimulation and decreased IL-1b and IL-6 release after LPS stimulation. The results indicate depressive-like behavior in GPR39 KO animals with an immune response similar to that observed in depressive disorder. Here for the first time we show immunological changes under GPR39-deficient conditions.
... In preclinical studies to investigate whether low zinc levels lead to the development of depressive symptoms, a special diet that was low in zinc was prepared. Administration of the zinc-deficient diet for several weeks caused depressive-like behavior as measured by the forced swim test and the tail suspension test in mice and rats [65][66][67][68][69][70][71]. Moreover, zinc deficiency altered the antidepressant response [67]. ...
Depression is one of the most common mental disorders and social issue worldwide. Although there are many antidepressants available, the effectiveness of the therapy is still a serious issue. Moreover, there are many limitations of currently used antidepressants, including slow onset of action, numerous side effects, or the fact that many patients do not respond adequately to the treatment. Therefore, scientists are searching for new compounds with different mechanisms of action. Numerous data indicate the important role of glutamatergic, GABA-ergic, and cholinergic receptors in the pathomechanism of major depressive disorder. This review presents the role of glutamatergic, GABA-ergic, and cholinergic receptors in depression and antidepressant-like effect.
... Other clinical studies suggested that Zn deficiency induced the depressive and anxiety-like behavioral symptoms (Amani et al., 2010;Roy et al., 2010) and zinc supplementation has been used with benefits to enhance standard antidepressant therapy, especially in treatment-resistant patients (Nowak et al., 2003a;Siwek et al., 2009). Preclinical studies in turn, showed pro-depressive-like behavior (increased immobility in the FST or anhedonia) in mice and rats subjected to zinc-deprivation (Tamano et al., 2009;Whittle et al., 2009;Mlyniec and Nowak, 2012;Doboszewska et al., 2015). Moreover, Zn was found to induce antidepressant-like effects in rodent tests and models of depression as well as intensify the action of standard antidepressants (Kroczka et al., 2000(Kroczka et al., , 2001Rosa et al., 2003;Nowak et al., 2003b;Cunha et al., 2008;Franco et al., 2008). ...
The rapid antidepressant response to the N-methyl-D-aspartate (NMDA) receptor antagonists is mediated by activation of the mammalian target of the rapamycin (mTOR) signaling pathway, an increase in the synthesis of synaptic proteins and formation of new synapses in the prefrontal cortex (PFC) of rats. Zinc (Zn), which is a potent NMDA receptor antagonist, exerts antidepressant-like effects in screening tests and models of depression. We focused these studies in investigating whether activation of the mTOR signaling pathway is also a necessary mechanism of the antidepressant-like activity of Zn. We observed that a single injection of Zn (5mg/kg) induced an increase in the phosphorylation of mTOR and p70S6K 30min and 3h after Zn treatment at time points when Zn produced also an antidepressant-like effect in the forced swim test (FST). Furthermore, Zn administered 3h before the decapitation increased the level of brain derived neurotrophic factor (BDNF), GluA1 and synapsin I. An elevated level of GluA1 and synapsin I was still observed 24h after the Zn treatment, although Zn did not produce any effects in the FST at that time point. We also observed that pretreatment with rapamycin (mTORC1 inhibitor), LY294002 (PI3K inhibitor), H-89 (PKA inhibitor) and GF109203X (PKC inhibitor) blocked the antidepressant-like effect of Zn in FST in rats and blocks Zn-induced activation of mTOR signaling proteins (analyzed 30 min after Zn administration). These studies indicated that the antidepressant-like activity of Zn depends on the activation of mTOR signaling and other signaling pathways related to neuroplasticity, which can indirectly modulate mTOR function.
Copyright © 2015. Published by Elsevier Ltd.
... Because hippocampal function plays a central role in cognitive processing and spatial learning, many researchers have focused the physiological alterations of hippocampus after zinc deprivation. These researches established that hippocampal neuron functions, including synaptic responses, the release of neurotransmitters as well as the expression of neuronal receptors, were heavily affected after zinc deficiency (Hesse 1979, Takeda et al. 2003, Doboszewska et al. 2015. Notably, studies implicated that NSCs might be also involved in zinc deficiency-induced hippocampal disorders. ...
Zinc plays an important role in the development and maintenance of central neural system. Zinc deficiency has been known to alter normal brain function, whose molecular mechanism remains largely elusive. In the present study, we established a Zinc deficiency-exposed rat model, and, using Western blot and immunohistochemical analyses, found that the expression of FoxO3a and p27(kip1) was remarkably upregulated in the rat brain hippocampus. Immunofluorescence assay showed that FOXO3a and p27(kip1) were significantly co-localized with Nestin, the marker of neural stem cells (NSCs). Furthermore, we identified that the proportion of proliferating NSCs was markedly decreased in Zinc-deficient rat hippocampaus. Using C17.2 neural stem cells, it was revealed that exposure to Zinc chelator N,N,N',N'-tetrakis-(2-pyridylmethy) ethylenediamine (TPEN) induced the expression of FoxO3a and p27(kip1) , which coincided with reduced NSC proliferation. Furthermore, depletion of FoxO3a inhibited p27(kip1) expression and restored the growth of NSCs. On the Basis of these data, we concluded that FoxO3a/p27(kip1) signaling might play a significant role in Zinc deficiency-induced growth impairment of NSCs and consequent neurological disorders. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
... In our previous study we found that GPR39 is down-regulated in suicide victims, as well as in zinc-deficient rodents, and this demonstrated the existence of a 'depressive-like' phenotype (Młyniec et al., 2014b(Młyniec et al., , 2013b. Animal studies have demonstrated the causative role of dietary zinc deficiency in the onset of depressive, aggressiveand anxiety-like behaviors (Doboszewska et al., 2015;Młyniec et al., 2013aTakeda et al., 2012;Whittle et al., 2009). Decreased serum zinc concentrations in the course of depression have been also noted in a number of clinical studies (Gower-Winter et al., 2013;Lai et al., 2012;Swardfager et al., 2013a), and therefore zinc was considered as a state-marker of that illness (Siwek et al., 2013). ...
Zinc can regulate neural function in the brain via the GPR39 receptor. In the present study we investigated whether inhibition of serotonin, noradrenaline and dopamine synthesis and potentialization of glutamate, via administration of p-chlorophenylalanine (pCPA), α-methyl-p-tyrosine (αMT) and N-methyl-D-aspartatic acid (NMDA), respectively, would cause changes in GPR39 levels. Western blot analysis showed GPR39 up-regulation following 3-day administration of αMT and NMDA in the frontal cortex, and GPR39 down-regulation following 10-day administration of pCPA, αMT, and NMDA in the hippocampus of CD-1 mice. There were no changes in serum zinc levels. Additionally, we investigated tryptophan, tyrosine and glutamate concentrations in the hippocampus and frontal cortex of GPR39 knockout (GPR39 KO) mice. Liquid chromatography-mass spectrometry (LC-MS) showed a significant decrease in tryptophan and tyrosine, but not in glutamate concentrations in the hippocampus of GPR39 KO mice. There were no changes in the frontal cortex between GPR39 KO and wild type. These results indicate a possible role of the GPR39 receptor in monoaminergic and glutamatergic neurotransmission, which plays an important role in the pathophysiology of depression.
Copyright © 2015. Published by Elsevier Inc.
... The present study demonstrates changes in the GPR39 Zn(2+)-sensing receptor, as well as in CREB, BDNF and TrkB, after acute or chronic administration of antidepressants in the frontal cortex of mice receiving a zinc-deficient diet for 6 weeks. Previous studies have shown depressive-like behavior in mice with inadequate concentrations of zinc, in the form of increased immobility time in the forced swim test [7,[23][24][25] and tail suspension test [18,26], and a reduction in sucrose consumption [27,28] in zinc-deficient rodents. Chronic administration of antidepressants with diverse mechanisms of action caused normalization of serum zinc levels that had previously been decreased by a zinc-deficient diet for 6 weeks, indicating serum zinc as a sensitive marker of depression [29]. ...
Background
The GPR39-Zn2+-sensing receptor seems to be involved in the pathophysiology of depression. GPR39 knockout animals show depressive- and anxiety-like behavior. Chronic treatment with selective antidepressants (ADs) up-regulates GPR39.
Objective and methods
In the present study we investigated whether acute or chronic treatment with imipramine, escitalopram, reboxetine and bupropion would cause changes in CREB, BDNF, TrkB and GPR39-Zn2+ receptor proteins (measured by Western Blot) in the frontal cortex of mice fed with a low-zinc diet.
Results
The administration of acute antidepressants induced diverse effects in the proteins that were examined (namely, GPR39 down-regulation and a reduction in CREB protein after administration of all ADs; a decrease in BDNF after administration of imipramine and escitalopram; an increase in BDNF after administration of reboxetine; no change in BDNF following administration of bupropion; and a decrease in TrkB following the administration of all ADs except bupropion). On the other hand, chronic treatment (which is required for depression relief) with all antidepressants increased the levels of all these proteins.
Conclusions
The present study for the first time demonstrates the up-regulation of GPR39 (and CREB, BDNF, and TrkB) protein when induced by chronic treatment with antidepressants (with different pharmacological profiles) in a zinc-deficiency model in mice. These data further indicate that the GPR39 receptor may be an important target in the antidepressant response.
... GPR39 expression was decreased in the hippocampus and frontal cortex of zinc deficient mice and rats as well as in the hippocampus and cerebral cortex of suicide victims (Mlyniec et al., 2014). Zinc deficient diet for four or six weeks also decreased p-CREB and BDNF levels in the hippocampus (Doboszewska et al., 2015). On the other hand, chronic treatment with zinc induced an increase in cortical BDNF mRNA level (Nowak et al., 2004). ...
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 ZnCl2 (10 mg/kg, p.o.) was investigated. Moreover, the effect of the combination of sub-effective doses of ZnCl2 (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 ZnCl2 treatment was also investigated. The anti-immobility effect of ZnCl2 in the TST was prevented by treatment with PKA, PKC, CAMKII, MEK1/2 or PI3K inhibitors. Furthermore, ZnCl2 in combination with AR-A014418 caused a synergistic anti-immobility effect in the TST. None of the treatments altered locomotor activity of mice. ZnCl2 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
One of the major causes of global disability is depression. Many patients suffering from
depression are not able show a positive response to treatments used to cure depression. Initial
studies show that parallel nutrition therapy has the ability to ameliorate treatment results in
patients suffering from depression. In this article we review the studies for the effectiveness
and mechanism of the following nutrients: magnesium, vitamin D, Folate, zinc, omega 3
and vitamin B6. The existing knowledge and data proves that these nutrients may aid in
mood management by managing the neurotransmitters, by carrying out oxidation-reduction
or by regulating the structure of neurons. In spite of the fact that the preliminary research
is favorable, larger placebo controlled studies are required to substantiate, corroborate and
verify the effectiveness of the research.
The etiology and pathophysiology of depressive disorders remain unclear. Increasing evidences have demonstrated that trace elements such as zinc, magnesium, iron, calcium, selenium, manganese and chromium play vital roles in depressive symptoms. We used a Chronic Unpredictable Mild Stress (CUMS) model to simulate social pressure in rat model and compared the levels of trace elements in the plasma and brain. The concentrations trace elements were evaluated using inductively coupled plasma mass spectrometry or inductively coupled plasma-atomic emission spectrometry. In the CUMS model, 57% (12/21) of rats showed no significant decrease in sucrose preference and were grouped as CUMS-resilient; otherwise, CUMS-sensitive. The resilient group had higher levels of iron, sodium, sulfur, manganese and cobalt than the sensitive group in the brain samples (P < 0.05). The sensitive group had lower levels of calcium, potassium, sulfur, selenium and cobalt than the resilient groups, in the plasma samples. The higher levels of iron, calcium, selenium, manganese and cobalt in the resilient group indicated these trace elements might be protective against the development of depressive symptoms in response to stress.
The anti-nociceptive mechanisms of MgO and ZnO nanoparticles have not been thoroughly investigated; in this study, we evaluated the effects of anti-nociceptive dose of MgO and ZnO NPs on glutamate level and NMDA receptor subunits expression (NR1, NR2 and NR2B) in the rat whole hippocampus with and without acute restraint stress. Adult rats were divided into control, MgO and ZnO NPs 5 mg/kg, the stress of 90 min alone and with MgO or ZnO NPs 5 mg/kg groups. All components injected intraperitoneally and the nociceptive response was measured with hot plate apparatus 90 min after injections or stress induction. Magnesium, zinc, glutamate levels and NMDA receptor subunits expression were measured in the animal hippocampus. MgO NPs, ZnO NPs and acute stress induced anti-nociceptive effect. MgO NPs observably decreased glutamate and increased magnesium levels and NR2B subunit expression. ZnO NPs decreased glutamate level. Stress elevated endogenous magnesium and zinc levels and also the NR2B expression, but did not change glutamate level. MgO and ZnO NPs in the presence of stress increased the glutamate level and ZnO NPs increased the zinc and the NR2A expression. Stress decreased endogenous magnesium in the hippocampus. MgO and ZnO NPs could affect pain perception by changing glutamate level in the whole hippocampus tissue, while ion level changes followed by injection could probably affect the gene expression in the presence and the absence of stress. It seems that stress indirectly could adverse nanoparticles effects on glutamate level and increase zinc ion releasing from ZnO NPs by activating the gene expression without affecting pain perception.
The present study examined the involvement of zinc (Zn)‐transporters (ZnT3) in cadmium (Cd)‐induced alterations of Zn homeostasis in rat hippocampal neurons. We treated primary rat hippocampal neurons for 24 or 48 hr with various concentrations of CdCl2 (0, 0.5, 5, 10, 25, or 50 μM) and/or ZnCl 2 (0, 10, 30, 50, 70, or 90 μM), using normal neuronal medium as control. By The CellTiter 96 ® Aqueous One Solution Cell Proliferation Assay (MTS; Promega, Madison, WI) assay and immunohistochemistry for cell death markers, 10 and 25 μM of Cd were found to be noncytotoxic doses, and both 30 and 90 μM of Zn as the best concentrations for cell proliferation. We tested these selected doses. Cd, at concentrations of 10 or 25 μM (and depending on the absence or presence of Zn), decreased the percentage of surviving cells. Cd‐induced neuronal death was either apoptotic or necrotic depending on dose, as indicated by 7‐AAD and/or annexin V labeling. At the molecular level, Cd exposure induced a decrease in hippocampal brain‐derived neurotrophic factor‐tropomyosin receptor kinase B (BDNF‐TrkB) and Erk1/2 signaling, a significant downregulation of the expression of learning‐ and memory‐related receptors and synaptic proteins such as the NMDAR NR2A subunit and PSD‐95, as well as the expression of the synapse‐specific vesicular Zn transporter ZnT3 in cultured hippocampal neurons. Zn supplementation, especially at the 30 μM concentration, led to partial or total protection against Cd neurotoxicity both with respect to the number of apoptotic cells and the expression of several genes. Interestingly, after knockdown of ZnT3 by small interfering RNA transfection, we did not find the restoration of the expression of this gene following Zn supplementation at 30 μM concentration. These data indicate the involvement of ZnT3 in the mechanism of Cd‐induced hippocampal neurotoxicity.
Background:
Major depressive disorder (MDD) is a serious psychiatric illness, associated with an increasing rate of suicide. The pathogenesis of depression may be associated with the disruption of zinc (Zn) homeostasis. In the brain, several proteins that regulate Zn homeostasis are present, including Zn transporters (ZnTs) which remove Zn from the cytosol. The present study was designed to investigate whether depression and suicide are associated with alterations in the expression of the ZnTs protein.
Methods:
Protein levels of ZnT1, ZnT3, ZnT4, ZnT5 and ZnT6 were measured in postmortem brain tissue from two different cohorts. Cohort A contained 10 subjects diagnosed with MDD (7 were suicide victims) and 10 psychiatrically-normal control subjects and cohort B contained 11 non-diagnosed suicide victims and 8 sudden-death control subjects. Moreover, in cohort A we measured protein level of NMDA (GluN2A subunit), AMPA (GluA1 subunit) and 5-HT1A receptors and PSD-95. Proteins were measured in the prefrontal cortex (PFC) using Western blotting. In addition, Zn concentration was measured using a voltammetric method.
Results:
There was a significant increase in protein levels of ZnT1, ZnT4, ZnT5 in the PFC in MDD, relative to control subjects, while ZnT3 protein level was decreased in MDD. There was no significant difference in the Zn concentration in the PFC between control and MDD subjects. Similarly, in the PFC of suicide victims (non-diagnosed), an increase in protein levels of ZnT1, ZnT4, ZnT5 and ZnT6 was observed. Conversely, protein levels of ZnT3 were decreased in both suicide victims and subjects with MDD, in comparison with control subjects. There was also a significant decrease in the protein level of GluA1, GluN2A, PSD-95 and 5-HT1A in MDD.
Conclusions:
Our studies suggest that alterations in Zn transport proteins are associated with the pathophysiology of MDD and suicide.
Objective:
This study was carried out to understand the effects of zinc deficiency in rats aged 0∼2 months on learning and memory, and the brain-derived neurotrophic factor (BDNF) gene methylation status in the hippocampus.
Methods:
The lactating mother rats were randomly divided into three groups (n = 12): zinc-adequate group (ZA: zinc 30 mg/kg diet), zinc-deprived group (ZD: zinc 1 mg/kg diet), and a pair-fed group (PF: zinc 30 mg/kg diet), in which the rats were pair-fed to those in the ZD group. After weaning (on day 23), offspring were fed the same diets as their mothers. After 37 days, the zinc concentrations in the plasma and hippocampus were measured, and the behavioral function of the offspring rats was measured using the passive avoidance performance test. We then assessed the DNA methylation patterns of the exon IX of BDNF by methylation-specific quantitative real-time PCR and the mRNA expression of BDNF in the hippocampus by RT-PCR.
Results:
Compared with the ZA and PF groups, rats in the ZD group had shorter latency period, lower zinc concentrations in the plasma and hippocampus (P < 0.05). Interestingly, the DNA methylation of the BDNF exon IX was significantly increased in the ZD group, compared with the ZA and PF groups, whereas the expression of the BDNF mRNA was decreased. In addition, the DNMT1 mRNA expression was significantly upregulated and DNMT3A was downregulated in the ZD group, but not in the ZA and PF groups.
Conclusion:
The learning and memory damage in offspring may be a result of the epigenetic changes of the BDNF genes in response to the zinc-deficient diet during 0∼2 month period. Furthermore, this work supports the speculative notion that altered DNA methylation of BDNF in the hippocampus is one of the main causes of cognitive impairment by zinc deficiency.
Introduction: This study was performed to determine the relationship and share of each nutritional factor with postpartum depression. methods: According to the World Health Organization, depression will be the second most prevalent problem after ischemic heart diseases by the year 2020. Postpartum depression as a major depressive episode has devastating impacts on the health of the mother. This cross-sectional study was performed on 95 women aged 18 years or higher in health centers in Tabriz, Iran, 8 weeks after delivery. Eligible subjects were entered into the study using the convenience sampling method. Inclusion criteria were: women aged 18 years or higher; living in Tabriz; basic literacy level (reading and writing); recent low-risk pregnancy; willingness to participate in the study; and having records in the health care center nearest to the place of residence. Demographic, Edinburg and 24 hr nutritional recode questionnaires were completed by participants. The data was analyzed using neural networks. Results: Mean of depression score was 7.1 (SD 4.4). 83 women (87.4%) had Edinburg scores lower than 12. Based on findings from neural networks, Omega 3 (25%), Cholesterol (32%), Polyunsaturated Fatty Acid (PUFA) (36%), and Omega 6 (42%) had smaller shares in increasing of Edinburg scores, in comparison with Zinc (61%), Magnesium (78%), and Saturated fatty acid (90%). Conclusion: Since Omega 3, Cholesterol, Polyunsaturated Fatty Acids, and Omega 6 intake factors have the smallest shares in increasing postpartum depression, hence protect against increasing the Edinburg score, they can be recommended in nutritional regimes. © 2016, Mashhad University of Medical Sciences. All rights reserved.
Affective disorders (depression) are considered as chronic illnesses leading to substantial disability, morbidity and mortality. While the etiology and pathophysiology of these diseases are still poorly recognized, the most important problems concerning them are low treatment response, treatment resistance and/or tolerance and risk of relapse. Recently published review articles have already demonstrated the important role of zinc in the pathophysiology and treatment of affective disorders, plus discussed the potential value of zinc as a marker of these diseases. This present concise review will update the experimental and clinical data on the antidepressant activity of zinc and focus on the mechanisms of its action. The mechanisms involving NMDA and AMPA glutamate, 5-HT1A serotonin and the GPR39 zinc-sensing receptor and intracellular pathways will be discussed.
Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.
Zinc is a trace element released from glutamatergic terminals, and modulates the pre- and postsynaptic areas, giving a diverse biological response. Zinc is a natural ligand that inhibits the N-methyl-d-aspartate (NMDA) receptor and regulates the excessive release of glutamate. Moreover, zinc exhibits an antidepressant-like profile, as demonstrated in both preclinical and clinical studies. Recent reports indicate that the GPR39 Zn2+-sensing receptor is an important target for zinc "transmission" (its activation modulates/induces diverse biochemical pathways involved in neuroprotection). Preclinical studies provide evidence that zinc deficiency leads to depressive-like behavior related to down-regulation of the GPR39 Zn2+-sensing receptor. Zinc binds to the GPR39 and triggers signals, leading to CRE-dependent gene transcription, resulting in increases in proteins such as brain-derived neurotrophic factor (BDNF), that plays a pivotal role in antidepressant action. Chronic administration of many antidepressants induces GPR39 up-regulation, which suggests that the Zn2+-sensing receptor may be considered as a new target for drug development in the field of depression.
Objective:
Previous studies have shown a positive effect of zinc as an adjunctive therapy on reducing depressive symptoms. However, to our knowledge, no study has examined the effect of zinc monotherapy on mood. The aim of the present study was to determine the effects of zinc monotherapy on depressive symptoms and serum brain-derived neurotrophic factor (BDNF) levels in overweight or obese subjects.
Methods:
Fifty overweight or obese subjects were randomly assigned into two groups and received either 30 mg zinc or placebo daily for 12 weeks. At baseline and post-intervention, depression severity was assessed using Beck depression inventory II (BDI II), and serum BDNF and zinc levels were determined by enzyme-linked immunosorbent assay and atomic absorption spectrophotometry, respectively.
Results:
The trial was completed with 46 subjects. After a 12-week supplementation, serum zinc and BDNF levels increased significantly in the zinc-supplemented group compared with the placebo group. BDI scores declined in both the groups at the end of the study, but reduction in the zinc-supplemented group was significantly higher than the placebo group. More analysis revealed that following supplementation, BDI scores decreased in subgroup of subjects with depressive symptoms (BDI ≥ 10) (n = 30), but did not change in the subgroup of non-depressed subjects (BDI < 10) (n = 16). Moreover, a significant inverse correlation was observed between serum BDNF levels and depression severity in all participants. Interestingly, a significant positive correlation was found between serum BDNF and zinc levels at baseline.
Conclusion:
Zinc monotherapy improves mood in overweight or obese subjects most likely through increasing BDNF levels.
Human and animals studies support the idea that there is a gender-related co-morbidity of pain-related and inflammatory gastrointestinal (GI) diseases with psychological disorders. This co-morbidity is the evidence for the existence of GI-brain axis which consists of immune (cytokines), neural (vagus nerve) and neuroendocrine (HPA axis) pathways. Psychological stress causes disturbances in GI physiology, such as altered GI barrier function, changes in motility and secretion, development of visceral hypersensitivity, and dysfunction of inflammatory responses. Whether GI inflammation would exert impact on psychological behavior is not well established. We examined the effect of experimental gastritis on anxiety- and depression-like behaviors in male and female Sprague-Dawley rats, and evaluated potential mechanisms of action. Gastritis was induced by adding 0.1% (w/v) iodoacetamide (IAA) to the sterile drinking water for 7 days. Sucrose preference test assessed the depression-like behavior, open field test and elevated plus maze evaluated the anxiety-like behavior. IAA treatment induced gastric inflammation in rats of either gender. No behavioral abnormality or dysfunction of GI-brain axis was observed in male rats with IAA-induced gastritis. Anxiety- and depression-like behaviors were apparent and the HPA axis was hyperactive in female rats with IAA-induced gastritis. Our results show that gastric inflammation leads to anxiety- and depression-like behaviors in female but not male rats via the neuroendocrine (HPA axis) pathway, suggesting that the GI inflammation can impair normal brain function and induce changes in psychological behavior in a gender-related manner through the GI-to-brain signaling.
Major depression is a mood disorder that causes changes in physical activity, appetite, sleep and weight. Regarding the role of zinc in the pathology of depression, the present study was aimed to investigate the effects of zinc supplementation in the treatment of this disease.
This study was a double-blind randomized clinical trial. Forty four patients with major depression were randomly assigned to groups receiving zinc supplementation and placebo. Patients in Zinc group received daily supplementation with 25 mg zinc adjunct to antidepressant; Selective Serotonin Reuptake Inhibitors (SSRIs), while the patients in placebo group received placebo with antidepressants (SSRIs) for twelve weeks. Severity of depression was measured using the Beck Depression Inventory at baseline and was repeated at the sixth and twelfth weeks. ANOVA with repeated measure was used to compare and track the changes during the study.
The mean score of Beck test decreased significantly in the zinc supplement group at the end of week 6 (P < 0.01) and 12 (P < 0.001) compared to the baseline. The mean score of Beck Depression Inventory reduced significantly compared to the placebo group at the end of 12th week (P < 0.05).
The results of the present study indicate that zinc supplementation together with SSRIs antidepressant drug improves major depressive disorders more effectively in patients with placebo plus antidepressants (SSRIs).
Zinc is an essential micronutrient with diverse biological roles in cell growth, apoptosis and metabolism, and in the regulation of endocrine, immune, and neuronal functions implicated in the pathophysiology of depression. This study sought to quantitatively summarize the clinical data comparing peripheral blood zinc concentrations between depressed and nondepressed subjects.
PubMed, Cumulated Index to Nursing and Allied Health Literature, and PsycINFO were searched for original peer-reviewed studies (to June 2012) measuring zinc concentrations in serum or plasma from depressed subjects (identified by either screening or clinical criteria) and nondepressed control subjects. Mean (±SD) zinc concentrations were extracted, combined quantitatively in random-effects meta-analysis, and summarized as a weighted mean difference (WMD).
Seventeen studies, measuring peripheral blood zinc concentrations in 1643 depressed and 804 control subjects, were included. Zinc concentrations were approximately -1.85 µmol/L lower in depressed subjects than control subjects (95% confidence interval: [CI]: -2.51 to -1.19 µmol/L, Z17 = 5.45, p < .00001). Heterogeneity was detected (χ(2)17 = 142.81, p < .00001, I(2) = 88%) and explored; in studies that quantified depressive symptoms, greater depression severity was associated with greater relative zinc deficiency (B = -1.503, t9 = -2.82, p = .026). Effect sizes were numerically larger in studies of inpatients (WMD -2.543, 95% CI: -3.522 to -1.564, Z9 = 5.09, p < .0001) versus community samples (WMD -.943, 95% CI: -1.563 to -.323, Z7 = 2.98, p = .003) and in studies of higher methodological quality (WMD -2.354, 95% CI: -2.901 to -1.807, Z7 = 8.43, p < .0001).
Depression is associated with a lower concentration of zinc in peripheral blood. The pathophysiological relationships between zinc status and depression, and the potential benefits of zinc supplementation in depressed patients, warrant further investigation.
There is a need for the development of effective universal preventive approaches to the common mental disorders, depression and anxiety, at a population level. Poor diet, physical inactivity and smoking have long been recognized as key contributors to the high prevalence noncommunicable diseases. However, there are now an increasing number of studies suggesting that the same modifiable lifestyle behaviors are also risk factors for common mental disorders. In this paper we point to the emerging data regarding lifestyle risk factors for common mental disorders, with a particular focus on and critique of the newest evidence regarding diet quality. On the basis of this most recent evidence, we consequently argue for the inclusion of depression and anxiety in the ranks of the high prevalence noncommunicable diseases influenced by habitual lifestyle practices. We believe that it is both feasible and timely to begin to develop effective, sustainable, population-level prevention initiatives for the common mental illnesses that build on the established and developing approaches to the noncommunicable somatic diseases.
Previous imaging and postmortem studies have reported a lower brain volume and a smaller size and density of neurons in the dorsolateral prefrontal cortex (dlPFC) of subjects with major depressive disorder (MDD). These findings suggest that synapse number and function are decreased in the dlPFC of patients with MDD. However, there has been no direct evidence reported for synapse loss in MDD, and the gene expression alterations underlying these effects have not been identified. Here we use microarray gene profiling and electron microscopic stereology to reveal lower expression of synaptic-function-related genes (CALM2, SYN1, RAB3A, RAB4B and TUBB4) in the dlPFC of subjects with MDD and a corresponding lower number of synapses. We also identify a transcriptional repressor, GATA1, expression of which is higher in MDD and that, when expressed in PFC neurons, is sufficient to decrease the expression of synapse-related genes, cause loss of dendritic spines and dendrites, and produce depressive behavior in rat models of depression.
It is now well established that the glutamatergic system contributes to the pathophysiology of depression. Exposure to stress, a major precipitating factor for depression, enhances glutamate release that can contribute to structural abnormalities observed in the brain of depressed subjects. On the other hand, it has been demonstrated that NMDA antagonists, like ketamine, exert an antidepressant effect at preclinical and clinical levels. On these bases, the purpose of our study was to investigate whether chronic mild stress is associated with specific alterations of the NMDA receptor complex, in adult rats, and to establish whether concomitant antidepressant treatment could normalize such deficits. We found that chronic stress increases the expression of the obligatory GluN1 subunit, as well as of the accessory subunits GluN2A and GluN2B at transcriptional and translational levels, particularly in the ventral hippocampus. Concomitant treatment with the antidepressant duloxetine was able to normalize the increase of glutamatergic receptor subunit expression, and correct the changes in receptor phosphorylation produced by stress exposure. Our data suggest that prolonged stress, a condition that has etiologic relevance for depression, may enhance glutamate activity through post-synaptic mechanisms, by regulating NMDA receptors, and that antidepressants may in part normalize such changes. Our results provide support to the notion that antidepressants may exert their activity in the long-term also via modulation of the glutamatergic synapse.
The effects of zinc, the N-methyl-D-aspartate glutamate receptor inhibitor, were studied in mice and rats using the forced swim test. Zinc (ZnSO4) in a dose of 30 mg/kg and imipramine (30 mg/kg), reduced the immobility time in the forced swim test in both species. Moreover, combined treatment in this test with zinc and imipramine at their ineffective doses (1 and 5 mg/kg, respectively) induced a statistically significant effect in rats. The doses active in the forced swim test reduced (in mice) or did not affect (in rats) locomotor activity. The results obtained indicate that zinc induces an antidepressant-like effect and enhances the effect of imipramine in the forced swim test, suggesting a potential antidepressant activity of zinc in humans.
Depressive disorder is a long term, relapsing condition associated with high levels of disability and mortality. It has a neurobiological basis and is associated with functional and structural brain abnormalities.
The data discussed have been obtained mainly from meta-analyses, randomized controlled clinical trials and key review papers as well as animal studies.
Genetic vulnerability and stress are key factors in its aetiopathogenesis. Dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis reduces hippocampal volumes and prefrontal cortex (PFC) activity in depressed patients and disrupts homeostasis within the neurocircuit of depression. Antidepressant drugs increase brain-derived neurotrophin, restoring neuronal growth and activity and modulate interactions between the neurocircuit anatomical structures.
It remains to be confirmed whether structural changes in the brain are purely abnormalities in neuroplasticity and are fully reversible, whether they predate depression and whether they increase in the long term.
Investigation of the molecular mechanisms mediating gene and environment interaction is a growing and potentially fruitful area of research in the neurobiology of depression. Further elucidation of the neuroanatomical and physiological connections between the limbic structures and PFC may help identify key areas to target in treatment. The role of the dysregulation of the HPA axis and identifiable stressors in the recent or remote past which are not always present in depression need further study.
Prospective studies examining the interaction between changes in brain function and structure in relation to stress and identified relevant genes and how these may be influenced by antidepressant drug treatment and the long-term course of depression would help clarify their role in the pathophysiology of this disorder.
PSD-95, a membrane-associated guanylate kinase, is the major scaffolding protein in the excitatory postsynaptic density (PSD) and a potent regulator of synaptic strength. Here we show that PSD-95 is in an extended configuration and positioned into regular arrays of vertical filaments that contact both glutamate receptors and orthogonal horizontal elements layered deep inside the PSD in rat hippocampal spine synapses. RNA interference knockdown of PSD-95 leads to loss of entire patches of PSD material, and electron microscopy tomography shows that the patchy loss correlates with loss of PSD-95-containing vertical filaments, horizontal elements associated with the vertical filaments, and putative AMPA receptor-type, but not NMDA receptor-type, structures. These observations show that the orthogonal molecular scaffold constructed from PSD-95-containing vertical filaments and their associated horizontal elements is essential for sustaining the three-dimensional molecular organization of the PSD. Our findings provide a structural basis for understanding the functional role of PSD-95 at the PSD.
The neurotrophin brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) have emerged as key mediators in the pathophysiology of several mood disorders, including anxiety and depression. However, therapeutic compounds that interact with TrkB receptors have been difficult to develop. Using a combination of structure-based in silico screening and high-capacity functional assays in recombinant and neuronal cells, we identified a low-molecular weight TrkB ligand (ANA-12) that prevented activation of the receptor by BDNF with a high potency. ANA-12 showed direct and selective binding to TrkB and inhibited processes downstream of TrkB without altering TrkA and TrkC functions. KIRA-ELISA analysis demonstrated that systemic administration of ANA-12 to adult mice decreased TrkB activity in the brain without affecting neuronal survival. Mice administered ANA-12 demonstrated reduced anxiety- and depression-related behaviors on a variety of tests predictive of anxiolytic and antidepressant properties in humans. This study demonstrates that structure-based virtual screening strategy can be an efficient method for discovering potent TrkB-selective ligands that are active in vivo. We further propose that ANA-12 may be a valuable tool for studying BDNF/TrkB signaling and may constitute a lead compound for developing the next generation of therapeutic agents for the treatment of mood disorders.
Glutamatergic processes are strongly implicated in the pathophysiology and treatment of depression, including the antidepressant effects of N-methyl-D-aspartate (NMDA) receptor antagonists. This study was designed to see whether memantine, a noncompetitive NMDA antagonist, has antidepressant effects in behaviors and synaptic plasticity. Rats were randomly divided into control, stressed, and stressed+memantine groups. The animal model was established by chronic unpredictable stress. Memantine (20 mg/kg) was administrated i.p. for 21 days. Weight, sucrose consumption, water maze behavior and prefrontal cortical long-term potentiation (LTP) were measured, followed by immunohisotchemistry test of NR2B expression. Results showed that rats' weight and sucrose consumption were significantly lower in stressed group than those in control group, while the last time of sucrose consumption was improved by memantine. Rats in stressed group performed worse in reversal learning related stages, while rats in stressed+memantine group performed worse in spatial memory related stages. LTP test showed lower amplitude of field excitatory postsynaptic potential in prefrontal cortex in stressed group. Immunohistochemistry showed lower expression of NR2B receptor in prefrontal cortex in stressed group, and higher expression in hippocampus in stressed+memantine group. In conclusion, memantine in dose of 20 mg/kg improves the sucrose consumption, reversal learning and prefrontal cortical synaptic plasticity, but impairs spatial memory, which is probably due to different extent of up-regulating NR2B receptor expression in prefrontal cortex and hippocampus in stressed rats.
There is a long-standing paradox that NMDA (N-methyl-D-aspartate) receptors (NMDARs) can both promote neuronal health and kill neurons. Recent studies show that NMDAR-induced responses depend on the receptor location: stimulation of synaptic NMDARs, acting primarily through nuclear Ca(2+) signalling, leads to the build-up of a neuroprotective 'shield', whereas stimulation of extrasynaptic NMDARs promotes cell death. These differences result from the activation of distinct genomic programmes and from opposing actions on intracellular signalling pathways. Perturbations in the balance between synaptic and extrasynaptic NMDAR activity contribute to neuronal dysfunction in acute ischaemia and Huntington's disease, and could be a common theme in the aetiology of neurodegenerative diseases. Neuroprotective therapies should aim to both enhance the effect of synaptic activity and disrupt extrasynaptic NMDAR-dependent death signalling.
The rapid antidepressant response after ketamine administration in treatment-resistant depressed patients suggests a possible
new approach for treating mood disorders compared to the weeks or months required for standard medications. However, the mechanisms
underlying this action of ketamine [a glutamate N-methyl-d-aspartic acid (NMDA) receptor antagonist] have not been identified. We observed that ketamine rapidly activated the mammalian
target of rapamycin (mTOR) pathway, leading to increased synaptic signaling proteins and increased number and function of
new spine synapses in the prefrontal cortex of rats. Moreover, blockade of mTOR signaling completely blocked ketamine induction
of synaptogenesis and behavioral responses in models of depression. Our results demonstrate that these effects of ketamine
are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant
actions of ketamine.
Antidepressant-like activity of zinc in the forced swim test (FST) was demonstrated previously. Enhancement of such activity by joint administration of zinc and antidepressants was also shown. However, mechanisms involved in this activity have not yet been established. The present study examined the involvement of the NMDA and AMPA receptors in zinc activity in the FST in mice and rats. Additionally, the influence of zinc on both glutamate and aspartate release in the rat brain was also determined. Zinc-induced antidepressant-like activity in the FST in both mice and rats was antagonized by N-methyl-D-aspartic acid (NMDA, 75 mg/kg, i.p.) administration. Moreover, low and ineffective doses of NMDA antagonists (CGP 37849, L-701,324, D-cycloserine, and MK-801) administered together with ineffective doses of zinc exhibit a significant reduction of immobility time in the FST. Additionally, we have demonstrated the reduction of immobility time by AMPA receptor potentiator, CX 614. The antidepressant-like activity of both CX 614 and zinc in the FST was abolished by NBQX (an antagonist of AMPA receptor, 10 mg/kg, i.p.), while the combined treatment of sub-effective doses of zinc and CX 614 significantly reduces the immobility time in the FST. The present study also demonstrated that zinc administration potentiated a veratridine-evoked glutamate and aspartate release in the rat's prefrontal cortex and hippocampus. The present study further suggests the antidepressant properties of zinc and indicates the involvement of the NMDA and AMPA glutamatergic receptors in this activity.
One of the main problems in the therapy of depression is the limited efficacy of antidepressants and the limited utility of augmentation strategies. Zinc, a non competitive NMDA receptor antagonist exhibits preclinical antidepressant efficacy. Moreover, a preliminary clinical report suggests augmentation of antidepressant therapy by zinc in depression.
A placebo-controlled, double blind study of zinc supplementation in imipramine therapy was conducted in sixty, 18-55-year old, unipolar depressed patients fulfilling the DSM-IV criteria for major depression without psychotic symptoms. After a one week washout period, patients were randomized into two groups treated with imipramine (approximately 140 mg/day) and receiving once daily either placebo (n=30) or zinc supplementation (n=30, 25 mgZn/day) for 12 weeks.
No significant differences in CGI, BDI, HADRS and MADRS scores were demonstrated between zinc-supplemented and placebo-supplemented antidepressant treatment non-resistant patients. However, zinc supplementation significantly reduced depression scores and facilitated the treatment outcome in antidepressant treatment resistant patients.
Zinc supplementation augments the efficacy and speed of onset of therapeutic response to imipramine treatment, particularly in patients previously nonresponsive to antidepressant pharmacotherapies. These data suggest the participation of disturbed zinc/glutamatergic transmission in the pathophysiology of drug resistance.
Recent preclinical data indicated the antidepressant-like activity of zinc in different tests and models of depression. The present study investigates the involvement of the serotonergic system in zinc activity in the forced swim test (FST) in mice and rats. The combined treatment of sub-effective doses of zinc (hydroaspartate, 2.5 mg Zn/kg) and citalopram (15 mg/kg), fluoxetine (5 mg/kg) but not with reboxetine (2.5 mg/kg) significantly reduces the immobility time in the FST in mice. These treatments had no influence on the spontaneous locomotor activity. Moreover, while the antidepressant-like effect of zinc (5 mg/kg) in the FST was significantly blocked by pretreatment with inhibitor of serotonin synthesis, p-chlorophenylalanine (pCPA, 3x200 mg/kg), 5HT-2(A/C) receptor antagonist, ritanserin (4 mg/kg) or 5HT-1A receptor antagonist, WAY 1006335 (0.1 mg/kg), the zinc-induced reduction in the locomotor activity was not affected by these serotonin modulator agents. These results indicate the specific involvement of the serotonergic system in antidepressant but not the motion behavior of zinc in mice. Also, an increase in the swimming but not climbing parameter of the rat FST observed following zinc administration (2.5 and 5 mg Zn/kg) indicates the serotonin pathway participation. This present data indicates that the antidepressant-like activity of zinc observed in the FST involves interaction with the serotonergic system.
The N-methyl-D-aspartate (NMDA) receptor subserves synaptic glutamate-induced transmission and plasticity in central neurons. The yeast two-hybrid system was used to show that the cytoplasmic tails of NMDA receptor subunits interact with a prominent postsynaptic density protein PSD-95. The second PDZ domain in PSD-95 binds to the seven-amino acid, COOH-terminal domain containing the terminal tSXV motif (where S is serine, X is any amino acid, and V is valine) common to NR2 subunits and certain NR1 splice forms. Transcripts encoding PSD-95 are expressed in a pattern similar to that of NMDA receptors, and the NR2B subunit co-localizes with PSD-95 in cultured rat hippocampal neurons. The interaction of these proteins may affect the plasticity of excitatory synapses.
Background
Several animal and human studies have shown that zinc plays a role in reducing depression, but there have been no longitudinal studies in both men and women on this topic. The aim of this study was to investigate dietary zinc, and the zinc to iron ratio, as predictors of incident depression in two large longitudinal studies of mid-age and older Australians.
Methods
Data were self-reported, as part of the Australian Longitudinal Study on Women׳s Health (women aged 50–61 years) and Hunter Community Study (men and women aged 55–85 years). Validated food frequency questionnaires were used to assess dietary intake. Energy-adjusted zinc was ranked using quintiles and predictors of incident depression were examined using multivariate logistic regression.
Results
Both studies showed an inverse association between dietary zinc intake and risk of depression, even after adjusting for potential confounders. Compared to those with the lowest zinc intake those with the highest zinc intake had significantly lower odds of developing depression with a reduction of about 30–50%. There was no association between the zinc to iron ratio and developing depression in either study.
Limitations
Dietary assessment was carried out only at baseline and although adjustments were made for all known potential confounders, residual confounding cannot be entirely excluded.
Conclusions
Low dietary zinc intake is associated with a greater incidence of depression in both men and women, as shown in two prospective cohorts. Further studies into the precise role of zinc compared to other important nutrients from the diet are needed.
Zinc is one of the most important trace elements in our body. Patients suffering from depression show lower serum zinc levels compared to healthy controls. Zincs antagonism to the glutamatergic system seems to be responsible for mood recovery. Recent years have shown that zinc may regulate neurotransmission via the metabotropic GPR39 receptor. Activation of the GPR39-Zn(2+)-sensing receptor (GPR39) triggers diverse neuronal pathways leading to a cAMP-responsive element binding the protein (CREB) expression, which then induces synthesis of the brain-derived neurotrophic factor and, in turn, activation of the Tropomyosin receptor kinase B (TrkB) receptor. In the present study, we investigated the alteration of the GPR39 in different models of depression, such as zinc deficiency and olfactory bulbectomy and in suicide victims. Additionaly, we focused on CREB-BDNF/TrkB under zinc deficient conditions in mice. To demonstrate depressive-like behaviour, a standard and modified forced swim test (FST) was performed. To evaluate expression of GPR39, CREB, BDNF and TrkB, Western Blot analysis was used. Zinc deficient mice and rats showed decreased GPR39 expression in the hippocampus and frontal cortex. A decreased level of hippocampal and cortical GPR39 was also observed in suicide victims. In contrast, increased GPR39 in the hippocampus of olfactory bulbectomized rats was observed. Additionally, we found a decreased expression of CREB, BDNF and TrkB only in the hippocampus of zinc-deficient mice. Our present study demonstrates the associacion of the GPR39 Zn(2+)-sensing receptor in the pathomechanism of depression. Down-regulation of CREB, BDNF, TrkB and GPR39 receptor found under zinc-deficient conditions in the hippocampus, may play an important role in the pathophysiology of mood disorders, since most of patients suffering from depression show lower serum zinc.
Zinc is one of the most important trace elements in our body. Patients suffering from depression show lower serum zinc levels compared to healthy controls. Zincs antagonism to the glutamatergic system seems to be responsible for mood recovery. Recent years have shown that zinc may regulate neurotransmission via the metabotropic GPR39 receptor. Activation of the GPR39-Zn(2+)-sensing receptor (GPR39) triggers diverse neuronal pathways leading to a cAMP-responsive element binding the protein (CREB) expression, which then induces synthesis of the brain-derived neurotrophic factor and, in turn, activation of the Tropomyosin receptor kinase B (TrkB) receptor. In the present study, we investigated the alteration of the GPR39 in different models of depression, such as zinc deficiency and olfactory bulbectomy and in suicide victims. Additionaly, we focused on CREB-BDNF/TrkB under zinc deficient conditions in mice. To demonstrate depressive-like behaviour, a standard and modified forced swim test (FST) was performed. To evaluate expression of GPR39, CREB, BDNF and TrkB, Western Blot analysis was used. Zinc deficient mice and rats showed decreased GPR39 expression in the hippocampus and frontal cortex. A decreased level of hippocampal and cortical GPR39 was also observed in suicide victims. In contrast, increased GPR39 in the hippocampus of olfactory bulbectomized rats was observed. Additionally, we found a decreased expression of CREB, BDNF and TrkB only in the hippocampus of zinc-deficient mice. Our present study demonstrates the associacion of the GPR39 Zn(2+)-sensing receptor in the pathomechanism of depression. Down-regulation of CREB, BDNF, TrkB and GPR39 receptor found under zinc-deficient conditions in the hippocampus, may play an important role in the pathophysiology of mood disorders, since most of patients suffering from depression show lower serum zinc.
Recent data suggests that the glutamatergic system is involved in the pathophysiology and treatment of major depressive disorder (MDD) and that the N-methyl-d-aspartate (NMDA) receptor is a potential target for antidepressant drugs. The magnesium ion blocks the ion channel of the NMDA receptor and prevents its excessive activation. Some preclinical and clinical evidence suggests also that magnesium may be useful in the treatment of depression. The present study investigated the effect of magnesium treatment (10, 15 and 20 mg/kg, given as magnesium hydroaspartate) in the chronic mild stress (CMS) model of depression in rats. Moreover, the effect of CMS and magnesium (with an effective dose) on the level of the proteins related to the glutamatergic system (GluN1, GluN2A, GluN2B and PSD-95) in the hippocampus, prefrontal cortex (PFC) and amygdala were examined. A significant reduction in the sucrose intake induced by CMS was increased by magnesium treatment at a dose of 15 mg/kg, beginning from the third week of administration. Magnesium did not affect this behavioural parameter in the control animals. CMS significantly increased the level of the GluN1 subunit in the amygdala (by 174%) and GluN2A in the hippocampus (by 191%), both of which were significantly attenuated by magnesium treatment. Moreover, magnesium treatment in CMS animals increased the level of GluN2B (by 116%) and PSD-95 (by 150%) in the PFC. The present results for the first time demonstrate the antidepressant-like activity of magnesium in the animal model of anhedonia (CMS), thus indicating the possible involvement of the NMDA/glutamatergic receptors in this activity.
This study investigated the involvement of NMDA receptors and the L-arginine-nitric oxide (NO) pathway in the antidepressant-like effects of zinc in the forced swimming test (FST). The immobility times in the FST and in the tail suspension test (TST) were reduced by zinc chloride (ZnCl(2), 30 and 10-30 mg/kg intraperitoneal (i.p.), respectively). The doses active in the FST and TST reduced locomotor activity in an open-field. The antidepressant-like effect of ZnCl(2) in the FST was prevented by pre-treatment of animals with guanosine 5'-monophosphate (GMP), ascorbic acid, L-arginine, or S-nitroso-N-acetyl-penicillamine (SNAP), but not with D-arginine, administered at doses that per se produced no anti-immobility effect. The immobility time of mice treated with ZnCl(2)+MK-801 was not different from the result obtained with ZnCl(2) or MK-801 alone, but ZnCl(2)+imipramine had a greater effect in the FST than administration of either drug alone. Pre-treatment of animals with a sub-threshold dose of ZnCl(2) prevented the anti-immobility effect of MK-801, ketamine, GMP, L-arginine or N(G)-nitro-L-arginine (L-NNA), but did not alter the effect of imipramine or fluoxetine. Taken together, the results demonstrate that zinc produced an antidepressant-like effect that seems to be mediated through its interaction with NMDA receptors and the L-arginine-NO pathway.
Over the past 20 years, converging lines of evidence have both linked glutamatergic dysfunction to the pathophysiology of depression and demonstrated that the glutamatergic synapse presents multiple targets for developing novel antidepressants. The robust antidepressant effects of the N-methyl-D-aspartate receptor antagonists ketamine and traxoprodil provide target validation for this family of ionotropic glutamate receptors. This article reviews the preclinical evidence that it may be possible to develop glutamate-based antidepressants by not only modulating ionotropic (N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) and metabotropic glutamate (mGlu) receptors, including mGlu2/3, mGLu5 and mGlu7 receptors, but also by altering synaptic concentrations of glutamate via specialized transporters such as glial glutamate transporter 1 (excitatory amino-acid transporter 2).
Specific patterns of neuronal firing induce changes in synaptic strength that may contribute to learning and memory. If the postsynaptic NMDA (N-methyl-D-aspartate) receptors are blocked, long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission and the learning of spatial information are prevented. The NMDA receptor can bind a protein known as postsynaptic density-95 (PSD-95), which may regulate the localization of and/or signalling by the receptor. In mutant mice lacking PSD-95, the frequency function of NMDA-dependent LTP and LTD is shifted to produce strikingly enhanced LTP at different frequencies of synaptic stimulation. In keeping with neural-network models that incorporate bidirectional learning rules, this frequency shift is accompanied by severely impaired spatial learning. Synaptic NMDA-receptor currents, subunit expression, localization and synaptic morphology are all unaffected in the mutant mice. PSD-95 thus appears to be important in coupling the NMDA receptor to pathways that control bidirectional synaptic plasticity and learning.
During the last decade it has been shown that zinc may activate neural transmissions via the GPR39 Zn(2+-)sensing receptor, which can be involved in the regulation of neuronal plasticity. According to the neurotrophic hypothesis of depression, decreased brain derived neurotrophic factor (BDNF) levels in depressed patients plays a key role in the pathogenesis of this disorder. BDNF, similarly as zinc, is known to be involved in the process of neuron survival and the regulation of neuronal plasticity. The aim of the present study was to determine whether the administration of a 6-week diet deficient in zinc would cause depressive-like behaviour and if such behavioural alterations would correlate with changes in the expression of the BDNF protein and GPR39 receptor. In the first part of the present study the animal behaviour after a 6-week zinc-deficient diet, in the forced swim test (FST) was investigated. In the second part expression of the GPR39 and BDNF protein level in the frontal cortex was measured using the Western Blot method. Administration of a zinc-deficient diet for 6 weeks increased immobility time in the FST by 24%, so exerted depression-like behaviour. A biochemical study showed a significant reduction in GPR39 (by 53%) and BDNF (by 49%) protein expression in the frontal cortex in mice receiving the zinc deficient diet for 6 weeks. Our study provides evidence that the GPR39 Zn(2+-)sensing receptor may be responsible for lowering the BDNF protein level and in consequence may be involved in the pathogenesis of depression.
Zinc is an important trace element essential for numerous bodily functions. It is believed that a deficiency of zinc can lead to various conditions, including depression, on which this study is focused. It is still not known if hypozincemia leads to the development of depression or whether zinc deficiency is a result of depression. It is hypothesized that zinc may be a therapeutic agent or supplement that would help to reverse the symptoms of this disease.
In the present study, the behavior of mice was assessed 2, 4, and 10 weeks following administration of a zinc deficient diet. To evaluate animal activity we used the forced swim test (FST).
After 2-week zinc deprivation we demonstrated a significant reduction in the immobility time. However, after 4 and 10 weeks of zinc deprivation the mice exhibited an increased immobility time. There were no changes in locomotor activity at each time period. After 2-, 4- and 10-week zinc deprivation and the subsequent FST, serum zinc concentration was decreased and determined to be 59, 61 and 20%, respectively, compared with appropriate controls. The serum corticosterone concentration in mice after 2-, 4- and 10-week zinc deprivation and subjected to the FST was also assessed, whereby the differences between the control and experimental animals were demonstrated (increased by: 11, 97 and 225%, respectively).
The obtained results indicate that zinc deprivation induced "pro-depressive" behavior (after the initial period of "antidepressive" behavior). This pro-depressive behavior correlates with enhanced serum corticosterone concentration.
Background: Zinc is an important trace element essential for numerous bodily functions. It is believed that a deficiency of zinc can lead to various conditions, including depression, on which this study is focused. It is still not known if hypozincemia leads to the development of depression or whether zinc deficiency is a result of depression. It is hypothesized that zinc may be a therapeutic agent or supplement that would help to reverse the symptoms of this disease.
Methods: In the present study, the behavior of mice was assessed 2, 4, and 10 weeks following administration of a zinc deficient diet. To evaluate animal activity we used the forced swim test (FST).
Results: After 2-week zinc deprivation we demonstrated a significant reduction in the immobility time. However, after 4 and 10 weeks of zinc deprivation the mice exhibited an increased immobility time. There were no changes in locomotor activity at each time period. After 2-, 4- and 10-week zinc deprivation and the subsequent FST, serum zinc concentration was decreased and determined to be 59, 61 and 20%, respectively, compared with appropriate controls. The serum corticosterone concentration in mice after 2-, 4- and 10-week zinc deprivation and subjected to the FST was also assessed, whereby the differences between the control and experimental animals were demonstrated (increased by: 11, 97 and 225%, respectively).
Conclusions: The obtained results indicate that zinc deprivation induced “pro-depressive” behavior (after the initial period of “antidepressive” behavior). This pro-depressive behavior correlates with enhanced serum corticosterone concentration.
Since publication of the first randomized controlled trial describing rapid antidepressant effects of ketamine, several reports have confirmed the potential utility of this dissociative anesthetic medication for treatment of major depressive episodes, including those associated with bipolar disorder and resistant to other medications and electroconvulsive therapy. These reports have generated several questions with respect to who might respond to ketamine, how, and for how long. To start answering these questions. We used PubMed.gov and ClinicalTrials.gov to perform a systematic review of all available published data on the antidepressant effects of ketamine and of all recently completed, ongoing, and planned studies. To date, 163 patients, primarily with treatment-resistant depression, have participated in case studies, open-label investigations, or controlled trials. All controlled trials have used a within-subject, crossover design with an inactive placebo as the control. Ketamine administration has usually involved an anaesthesiologist infusing a single, subanesthetic, intravenous dose, and required hospitalization for at least 24 hours postinfusion. Response rates in the open-label investigations and controlled trials have ranged from 25% to 85% at 24 hours postinfusion and from 14% to 70% at 72 hours postinfusion. Although adverse effects have generally been mild, some patients have experienced brief changes in blood pressure, heart rate, or respiratory rate. Risk-benefit analyses support further research of ketamine for individuals with severe mood disorders. However, given the paucity of randomized controlled trials, lack of an active placebo, limited data on long-term outcomes, and potential risks, ketamine administration is not recommended outside of the hospital setting.
Recently, experimental zinc deficiency has been correlated with depression-like alterations in rodents.
In the first part of present study, the time course of zinc deficient diet induced alterations in the tail suspension test (TST) in mice was investigated. In the second part, the effect of imipramine and escitalopram in control and zinc-deprived for 3 weeks mice was examined in the TST.
A4- and 10-week administration of a Zn-deficient diet enhanced the immobility time in the TST (by 20% and 57%, respectively). By contrast, a 2-week period of a zinc deficient diet effected the reduction (by 24%) of the immobility time. Moreover, a 2- and 4-week (but not 10-week) of a Zn-deficient diet resulted in the reduction of the body weight (by 37% and 18%, respectively). These results indicate the developing response to zinc deficiency induced by a zinc-deficient diet. The antidepressant-like effect (reduction in the immobility time) of both drugs was significantly reduced in zinc-deprived mice, which suggests treatment-resistance induced by zinc deprivation.
Zinc deprivation induces "pro-depressive" behavior and alters antidepressant efficacy.
Background: Recently, experimental zinc deficiency has been correlated with depression-like alterations in rodents.
Methods: In the first part of present study, the time course of zinc deficient diet induced alterations in the tail suspension test (TST)
in mice was investigated. In the second part, the effect of imipramine and escitalopram in control and zinc-deprived for 3 weeks mice
was examined in the TST.
Results: A4- and 10-week administration of a Zn-deficient diet enhanced the immobility time in the TST (by 20% and 57%, respectively).
By contrast, a 2-week period of a zinc deficient diet effected the reduction (by 24%) of the immobility time. Moreover,
a 2- and 4-week (but not 10-week) of a Zn-deficient diet resulted in the reduction of the body weight (by 37% and 18%, respectively).
These results indicate the developing response to zinc deficiency induced by a zinc-deficient diet. The antidepressant-like effect (reduction
in the immobility time) of both drugs was significantly reduced in zinc-deprived mice, which suggests treatment-resistance
induced by zinc deprivation.
Conclusion: Zinc deprivation induces “pro-depressive” behavior and alters antidepressant efficacy.
The present study aimed to investigate glutamate concentrations in patients with unipolar depression in the midcingulate cortex (MCC) as compared to the left dorsolateral prefrontal cortex (DLPFC). We hypothesized a dissociation of glutamate levels with unchanged levels in DLPFC and abnormally changed levels in MCC as well as differential effects of antidepressant pharmacotherapy. Glutamate was determined using magnetic resonance spectroscopy at 3 T in DLPFC and MCC in fourteen depressed patients and matched healthy volunteers. A follow-up measurement was performed after 4 weeks of antidepressant treatment. The main finding is a region-specific pattern of glutamate concentrations with increased MCC glutamate concentrations and no significant differences in DLPFC glutamate concentrations in unipolar depressive patients compared to healthy controls. Response and non-response to antidepressant pharmacotherapy were predicted by high glutamate at baseline in DLPFC and MCC, respectively. In addition, treatment responders showed a further increase in DLPFC glutamate levels after successful antidepressant treatment. Findings indicate altered region-specific glutamate concentrations in DLPFC and MCC that are predictive of response and non-response, respectively, to antidepressant pharmacotherapy. These findings might serve as a starting point for future studies in which the value of this metabolite pattern for treatment response prediction should be investigated.
Northern blot analysis was utilized to distinguish between catalytic and truncated TrkB mRNA on the basis of transcript size. Repeated (10 days), but not acute, immobilization stress significantly increased levels of catalytic TrkB mRNA, but did not influence expression of truncated TrkB transcripts in rat hippocampus. Exposure to another paradigm, a combination of different, unpredictable stressors, also increased levels of catalytic, but not truncated, TrkB mRNA. In situ hybridization analysis demonstrated that chronic stress up-regulated TrkB mRNA in CA1 and CA3 pyramidal and dentate gyrus granule cells layers of hippocampus. As previously reported, both acute and chronic immobilization stress decreased expression of BDNF mRNA, suggesting that up-regulation of catalytic TrkB mRNA may be a compensatory adaptation to repeated stress.
Abnormal behavior in zinc deficiency and its cause are poorly understood. In the present paper, behavior in the forced swim test and neurochemical changes in the brain associated with its behavior were studied focused on abnormal corticosterone secretion in zinc deficiency. The effect of chronic corticosterone treatment was also studied. Immobility time in the forced swim test was increased in young rats fed a zinc-deficient diet for 2 weeks, as well as corticosterone (40 mg/kg/day × 14 days)-treated control rats. The basal Ca2+ levels in the hippocampus, which were determined by fluo-4FF, AM, were increased in both brain slices from zinc-deficient and corticosterone-treated rats. Serum glucose level was decreased in zinc deficiency and hippocampal glucose metabolism, which is determined by [14C]2-deoxyglucose uptake, was elevated. Hippocampal ATP level was not decreased, whereas, the concentrations of glutamate, GABA and glutamine in the hippocampus, unlike the whole brain, were decreased in zinc deficiency. However, the decrease in these amino acids was restored by adrenalectomy prior to zinc deficiency. These results suggest that glucose is insufficient for the synthesis of amino acids in the hippocampus of zinc-deficient rats. It is likely that the neurochemical and metabolic changes in the hippocampus, which may be associated with abnormal corticosterone secretion, is the base of abnormal behavior associated with neuropsychological symptoms in zinc deficiency.
There is an increasing recognition of the role of nutrition in depression and anxiety. Magnesium, folate and zinc have all been implicated in depressive illness, however there are few data on these nutrients in anxiety disorders and the data from population-studies are limited.
In a large, randomly-selected, population-based sample of women, this study aimed to examine the relationship between the dietary intakes of these three micronutrients and clinically determined depressive and anxiety disorders and symptoms.
Nutrient intakes were determined using a validated food frequency questionnaire. The General Health Questionnaire-12 measured psychological symptoms, and a clinical interview (Structured Clinical Interview for DSM-IV-TR, non-patient edition) assessed current depressive and anxiety disorders.
After adjustments for energy intake, each standard deviation increase in the intake of zinc, magnesium and folate was associated with reduced odds ratio (OR) for major depression/dysthymia (zinc: OR=0.52, 95% confidence interval (CI) 0.31 to 0.88; magnesium: OR=0.60, 95% CI 0.37 to 0.96; folate: OR=0.66, 95% CI 0.45 to 0.97). There was also an inverse association between the intake of magnesium and zinc and GHQ-12 scores (zinc: zβ=-0.16, 95% CI -0.29 to -0.04; magnesium: -0.14, 95% CI -0.26 to -0.03). These relationships were not confounded by age, socioeconomic status, education or other health behaviours. There was no relationship observed between any nutrient and anxiety disorders.
These results demonstrate an association between the dietary intakes of magnesium, folate and zinc and depressive illnesses, although reverse causality and/or confounding cannot be ruled out as explanations.
Age-related cognitive decline is one of the major aspects that impede successful aging in humans. Environmental factors, such as chronic stress, can accelerate or aggravate cognitive deficits during aging. While there is abundant evidence that chronic stress directly affects cognitive performance, the lasting consequences of stress exposures during vulnerable developmental time windows are largely unknown. This is especially true for the adolescent period, which is critical in terms of physical, sexual, and behavioral maturation. Here we used chronic social stress during adolescence in male mice and investigated the consequences of this treatment on cognitive performance during aging. We observed a substantial impairment of spatial memory, but not other memory domains, 12 months after the end of the stress period. This hippocampus-dependent cognitive dysfunction was supported by concomitant impairment in LTP induction in CA1 neurons in 15-month-old animals. Further, we observed a decrease of hippocampal BDNF mRNA and synaptophysin immunoreactivity, suggesting plasticity and structural alterations in formerly stressed mice. Finally, we identified expression changes of specific neurotransmitter subunits critically involved in learning and memory, specifically the NMDA receptor subunit NR2B. Taken together, our results identify possible molecular mechanisms underlying cognitive impairment during aging, demonstrating the detrimental impact of stress during adolescence on hippocampus-dependent cognitive function in aged mice.
Basic and clinical studies demonstrate that stress and depression are associated with atrophy and loss of neurons and glia, which contribute to the decreased size and function of limbic brain regions that control mood and depression, including the prefrontal cortex and hippocampus. Here, we review findings that suggest that opposing effects of stress and/or depression and antidepressants on neurotrophic factor expression and signaling partly explain these effects. We also discuss recent reports that suggest a possible role for glycogen synthase kinase 3 and upstream wingless (Wnt)-frizzled (Fz) signaling pathways in mood disorders. New studies also demonstrate that the rapid antidepressant actions of NMDA receptor antagonists are associated with activation of glutamate transmission and induction of synaptogenesis, providing novel targets for a new generation of fast-acting, more efficacious therapeutic agents.
In this Seminar we discuss developments from the past 5 years in the diagnosis, neurobiology, and treatment of major depressive disorder. For diagnosis, psychiatric and medical comorbidity have been emphasised as important factors in improving the appropriate assessment and management of depression. Advances in neurobiology have also increased, and we aim to indicate genetic, molecular, and neuroimaging studies that are relevant for assessment and treatment selection of this disorder. Further studies of depression-specific psychotherapies, the continued application of antidepressants, the development of new treatment compounds, and the status of new somatic treatments are also discussed. We address two treatment-related issues: suicide risk with selective serotonin reuptake inhibitors, and the safety of antidepressants in pregnancy. Although clear advances have been made, no fully satisfactory treatments for major depression are available.
The postsynaptic side of the synapse is specialized to receive the neurotransmitter signal released from the presynaptic terminal and transduce it into electrical and biochemical changes in the postsynaptic cell. The cardinal functional components of the postsynaptic specialization of excitatory and inhibitory synapses are the ionotropic receptors (ligand-gated channels) for glutamate and γ-aminobutyric acid (GABA), respectively. These receptor channels are concentrated at the postsynaptic membrane and embedded in a dense and rich protein network comprised of anchoring and scaffolding molecules, signaling enzymes, cytoskeletal components, as well as other membrane proteins. Excitatory and inhibitory postsynaptic specializations are quite different in molecular organization. The postsynaptic density of excitatory synapses is especially complex and dynamic in composition and regulation; it contains hundreds of different proteins, many of which are required for cognitive function and implicated in psychiatric illness.
Prior studies indicate that the biochemical alterations of depressive episodes result in decreased serum zinc concentrations. Given these findings, it is plausible that consistently low dietary zinc intakes contribute to depressive symptoms, yet epidemiological data are lacking. The authors tested the hypothesis that low zinc intake is associated with depressive symptoms using cross-sectional data from the population-based Boston Area Community Health survey (2002-2005).
Dietary and supplement use data were collected by validated food frequency questionnaire. Current depressive symptoms were assessed by the abridged validated Center for Epidemiologic Studies Depression scale and analyzed using multivariate logistic regression, adjusting for sociodemographic, health and lifestyle characteristics.
Results showed an interaction (P=0.03) with gender, whereby zinc was associated with depressive symptoms in women (N=2163), but not men (N=1545). Women with low dietary or supplemental zinc intake were more likely to have depressive symptoms (e.g., dietary zinc quartile 1 vs. 4, OR=1.76, 95% CI: 1.26, 2.45; P-trend=0.004; supplemental zinc P-trend=0.03). Associations were stronger among women using antidepressant medications (e.g., total zinc OR=4.75, 95% CI: 1.98, 11.4; P-trend=0.0005).
The cross-sectional, observational nature of the study leaves uncertain whether the observed associations represent actual causal relationships between zinc intake and depressive symptoms.
These findings suggest: (1) gender-specific pathophysiological mechanisms of depression, (2) inadequate dietary zinc intake contributes to depressive symptoms in women, and (3) supplemental zinc is a beneficial adjunct to antidepressant therapy in women. Additional research on both men and women is needed to verify these novel findings. If confirmed by other studies, the potential importance of adequate zinc intake is underscored by the recognized limitations of pharmacotherapy for depression.
Depression is a significant public health problem. Pre-clinical studies suggest a potential role of zinc in reducing or preventing depressive symptoms. Many epidemiological studies have examined the association of low zinc status with depression; however, clinical trials on the effect of zinc supplementation in depression are limited. This review aimed to synthesise results from all published randomised controlled trials on the efficacy of zinc supplementation for reducing or preventing depressive symptoms.
Six databases were searched over all years of records until March 2011. All randomised controlled trials with a comparison group, that examined zinc supplementation as the intervention and depressive symptoms as the primary outcome were included. Pairs of reviewers extracted key information of study characteristics and outcomes, and assessed the quality of each study.
Four randomised controlled trials met inclusion criteria. In studies that examined the effects of zinc supplementation as an adjunct to antidepressants drug treatment, zinc significantly lowered depressive symptom scores of depressed patients. There is less clear evidence on the effectiveness of zinc supplementation alone on depressive symptoms of non-depressed healthy subjects. The overall study quality was rated 'moderate'.
There are limited trials examining the effects of zinc supplementation on depressive symptoms. An overall pooled estimate of effect for all included studies could not be calculated and evidence was difficult to summarise because of substantial heterogeneity.
Evidence suggests potential benefits of zinc supplementation as a stand-alone intervention or as an adjunct to conventional antidepressant drug therapy for depression. However, there are methodological limitations in existing studies and so further well-designed, adequately powered research is required.
There is mounting evidence suggesting a link between serum zinc levels and clinical depression. Not only is serum zinc negatively correlated with the severity of symptoms, but zinc levels appear to be lowest in patients who do not respond to antidepressant drug therapy. It is not known if reduced zinc levels are contributing to depression, or the result of dietary or other factors associated with major depression. Thus, we designed this study to test the hypothesis that dietary zinc deficiency would induce depression-like behaviors in rats. Two-month-old male rats were fed zinc adequate (ZA, 30 ppm), deficient (ZD, 1 ppm), or supplemented (ZS, 180 ppm) diets for 3 weeks. Consistent with the development of depression, ZD rats displayed anorexia (p<0.001), anhedonia (reduced saccharin:water intake, p< 0.001), and increased anxiety-like behaviors in a light-dark box test (p<0.05). Furthermore, the antidepressant drug fluoxetine (10 mg/kg body wt) reduced behavioral despair, as measured by the forced swim test, in rats fed the ZA and ZS rats (p<0.05), but was ineffective in ZD rats. Together these studies suggest that zinc deficiency leads to the development of depression-like behaviors that may be refractory to antidepressant treatment.
Depression, anxiety, and impairments in learning and memory are all associated with traumatic brain injury (TBI). Because of the strong link between zinc deficiency, depression, and anxiety, in both humans and rodent models, we hypothesized that dietary zinc supplementation prior to injury could provide behavioral resiliency to lessen the severity of these outcomes after TBI. Rats were fed a marginal zinc deficient (5 ppm), zinc adequate (30 ppm), or zinc supplemented (180 ppm) diet for 4 weeks followed by a moderately-severe TBI using the well-established model of controlled cortical impact (CCI). Following CCI, rats displayed depression-like behaviors as measured by the 2-bottle saccharin preference test for anhedonia. Injury also resulted in evidence of stress and impairments in Morris water maze (MWM) performance compared to sham-injured controls. While moderate zinc deficiency did not worsen outcomes following TBI, rats that were fed the zinc supplemented diet for 4 weeks showed significantly attenuated increases in adrenal weight (p<0.05) as well as reduced depression-like behaviors (p<0.001). Supplementation prior to injury improved resilience such that there was not only significant improvements in cognitive behavior compared to injured rats fed an adequate diet (p<0.01), there were no significant differences between supplemented and sham-operated rats in MWM performance at any point in the 10-day trial. These data suggest a role for supplemental zinc in preventing cognitive and behavioral deficits associated with TBI.
Preclinical and clinical data indicate the involvement of zinc in the pathophysiology and therapy of depression. A relationship between zinc-deficiency and depression symptoms was recently proposed. The present study investigated alterations in spontaneous locomotor activity and zinc concentrations in the serum, hippocampus and frontal cortex; these alterations were induced by subjecting rats to a zinc-deficient diet, prior subjected after birth to zinc-supplemented diet. Body weight was significantly reduced in animals subjected to the four-week zinc-deficient diet compared to those subjected to the zinc-adequate diet. The two-week zinc-deficient diet induced a significant increase in locomotor activity in all measured time periods (5, 30 and 60 min by 44-62%). The four-week zinc-deficient diet did not affect locomotor activity, while the six-week zinc-deficient diet resulted in a 45% increase in the 5 min time period. Serum zinc concentrations were significantly reduced (by 29%) in animals subjected to the four-week zinc-deficient diet but not in those subjected to the two- or six-week zinc-deficient diets. The zinc-deficient diet did not influence the zinc concentration in the examined brain regions regardless of the length. These results indicate that post-birth supplementation with zinc may protect zinc-deficient diet-induced rapid alterations in zinc homeostasis.
According to new hypothesis, depression is characterized by decreased neurogenesis and enhanced neurodegeneration which, in part, may be caused by inflammatory processes. There is much evidence indicating that depression, age-related changes often associated with impaired brain function and cognitive performances or neurodegenerative processes could be related to dysfunctions affecting the zinc ion availability. Clinical studies revealed that depression is accompanied by serum hypozincemia, which can be normalized by successful antidepressant treatment. In patients with major depression, a low zinc serum level was correlated with an increase in the activation of markers of the immune system, suggesting that this effect may result in part from a depression-related alteration in the immune-inflammatory system. Moreover, a preliminary clinical study demonstrated the benefit of zinc supplementation in antidepressant therapy in both treatment non-resistant and resistant patients. In the preclinical study, the antidepressant activity of zinc was observed in the majority of rodent tests and models of depression and revealed a causative role for zinc deficiency in the induction of depressive-like symptoms, the reduction of neurogenesis and neuronal survival or impaired learning and memory ability. This paper provides an overview of the clinical and experimental evidence that implicates the role of zinc in the pathophysiology and therapy of depression within the context of the inflammatory and neurodegenerative hypothesis of this disease.
Depression is a chronic recurring illness that affects more than 120 million people worldwide. Drugs increasing the synaptic availability of serotonin and norepinephrine (biogenic amine-based agents) have been used to treat depression for more than 50 years. However, significant symptom improvement requires > or =2-4 weeks of treatment and a first course of therapy provides symptom relief to only 60-65% of patients. Roche and Evotec recently announced plans to develop N-methyl-D-aspartate (NMDA) receptor antagonists targeting the NR2B subtype for treatment-resistant depression. This announcement closely follows a report that another NR2B antagonist, traxoprodil (CP 101 606), has antidepressant effects in patients unresponsive to a serotonin selective reuptake inhibitor, as well as reports of rapid and sustained antidepressant effects following a single injection of the NMDA antagonist ketamine. Here we describe evidence that glutamate-based therapies might represent an effective alternative to biogenic-amine-based agents for depression and provide perspectives on the development of these agents.