Zinc deficiency in rats is associated with up-regulation of hippocampal NMDA receptor

Doboszewska, Urszula; Sowa-Kućma, Magdalena; Młyniec, Katarzyna; Pochwat, Bartłomiej; Hołuj, Małgorzata; Ostachowicz, Beata; Pilc, Andrzej; Nowak, Gabriel; Szewczyk, Bernadeta

doi:10.1016/j.pnpbp.2014.09.013

Cited by 44 publications

(37 citation statements)

References 68 publications

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“…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).…”

Section: Introductionmentioning

confidence: 98%

Antidepressant-like effect of zinc is dependent on signaling pathways implicated in BDNF modulation

Manosso

Moretti

Ribeiro

et al. 2015

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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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 (1μg/site, PKA inhibitor), KN-62 (1μg/site, CAMKII inhibitor), chelerythrine (1μg/site, PKC inhibitor), PD98059 (5μg/site, MEK1/2 inhibitor), U0126 (5μg/site, MEK1/2 inhibitor), LY294002 (10nmol/site, PI3K inhibitor) on the reduction of immobility time in the tail suspension test (TST) elicited by ZnCl2 (10mg/kg, p.o.) was investigated. Moreover, the effect of the combination of sub-effective doses of ZnCl2 (1mg/kg, p.o.) and AR-A014418 (0.001μg/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.

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Section: Introductionmentioning

confidence: 98%

Antidepressant-like effect of zinc is dependent on signaling pathways implicated in BDNF modulation

Manosso

Moretti

Ribeiro

et al. 2015

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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“…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 [4–6] 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].…”

Section: Introductionmentioning

confidence: 99%

Concentration-Dependent Dual Mode of Zn Action at Serotonin 5-HT1A Receptors: In Vitro and In Vivo Studies

et al. 2015

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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 [3H]-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.

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“…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 [21–24] or anhedonia [25–27]. 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].…”

Section: Zincmentioning

confidence: 99%

“…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.…”

Section: Serotonin (5-ht)mentioning

confidence: 99%

Zinc in the Monoaminergic Theory of Depression: Its Relationship to Neural Plasticity

et al. 2017

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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.

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Zinc deficiency in rats is associated with up-regulation of hippocampal NMDA receptor

Cited by 44 publications

References 68 publications

Antidepressant-like effect of zinc is dependent on signaling pathways implicated in BDNF modulation

Antidepressant-like effect of zinc is dependent on signaling pathways implicated in BDNF modulation

Concentration-Dependent Dual Mode of Zn Action at Serotonin 5-HT1A Receptors: In Vitro and In Vivo Studies

Zinc in the Monoaminergic Theory of Depression: Its Relationship to Neural Plasticity

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