Searching for mechanism of antidepressant zinc action


Cichy, Agnieszka


glutamatergic receptors ; serotonergic receptors ; depressive disorder ; zinc


Zinc, a divalent metal, is involved in a myriad of cellular processes, ranging from interactions with zinc-finger proteins and protein kinases to modulation of synaptic neurotransmission. It is possible that zinc function is linked to the mental function. It seems to be especially important in zinc deficiency in the context of psychiatrie diseases, such as anxiety and depression. Recent data indicated that zinc is implicated in pathophysiology of depression and the mechanism of action by antidepressant drugs. Preclinical studies showed the antidepressant-like activity of zinc in tests and models of depression. The greatest concentration of zinc sequestring glutamatergic neurons is localized in structures, such as hippocampus and cortex, in which progressive morfological changes are beeing observed during depression ilness. Zinc modulates responses from NMDA receptors; protect on this way neurons from excessive activity. It also affects the BDNF expression and indirectly neurogenesis and synaptic plasticity. However, the exact zinc antidepressant mechanism of action remains unknown. The aim of this study was to investigate the mechanism of antidepressant zinc activity. Experiments were carried out by using both: biochemical (radioligand binding assay) and behavioral (forced swim test) methods. Experiments were directed on glutamateric, serotonergic and adrenergic systems. ; First part examined several adaptive changes after repeated zinc treatment in rodent brains using radioreceptor methods. In glutamatergic system adaptive changes (reduction in glycine affinity to glycine site of the NMDA receptor complex) in rat cortex were shown. Multiple zinc administration had no effect on the density/affinity of mGluR5 receptors. In serotoninergic system 5-HT1A "up"- regulation (in hippocampus) and 5-HT2 "up"- regulation (in cerebral cortex) were observed. The results of our studies also shown a "B-down" and "a1- up"- regulation in the mouse cerebral cortex. No changes were shown in a2- adrenoceptors. Adaptive changes in NMDA, 5-HT1A, B- and a1-adrenergic receptors caused by chronic zinc administration are similar to these alterations induced by conventional antidepressant drugs. On the other hand, adaptation in 5-HT2A receptors, is similar to changes induced by electroconvulsive shocks, one of the most effective treatment of depression. In the second part forced swim test was used to estimate the involvement of glutamatergic and serotonergic systems in antidepressant zinc action. Results demonstrated that antidepressant zinc activity is dependent on NMDA, AMPA, 5-HT1A and 5-HT2A/C receptor's activity. Results presented in this dissertation indicate some similarities in the mechanisms of action of zinc and classic antidepressant drugs that ; confirms possibility of using zinc in the clinical therapy. It seems to be especially important in the therapy of treatment- resistant depression, in which zinc may augment antidepressants' effect, inefficient in monotherapy. Moreover, there are many subpopulations with a variety of psychopathological and biochemical features among people suff ering from depression. One of them seems to be depression with lowered serum zinc level. In those patients zinc supplementation may be crucial for therapy efficacy enhancement. In the context of the available data which indicates that almost half of the world human population are not receiving an adequate amount of zinc and increasing prevalence of depression, the determination of mechanisms of antidepressant zinc action becomes really important to reduce this illness expansion.

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2 - studia doktoranckie

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Wydział Farmaceutyczny


Nowak, Gabriel



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Praca doktorska

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