Chronic treatment with zinc and antidepressants induces enhancement of presynaptic/extracellular zinc concentration in the rat prefrontal cortex

Abstract

Zinc exhibits antidepressant-like activity in preclinical tests/models. Moreover, zinc homeostasis is implicated in the pathophysiology of affective disorders. The aim of the present study was to examine the effect of chronic zinc, citalopram and imipramine intraperitoneal administration on the presynaptic and extracellular zinc concentration in the rat prefrontal cortex and hippocampus. We used two methods: zinc-selenium histochemistry (which images the pool of presynaptic-vesicle zinc) and anodic stripping voltammetry (ASV) for zinc determination in microdialysate (which assays the extracellular zinc concentration). We report that chronic (14 ×) zinc (hydroaspartate, 10 and 65 mg/kg) and citalopram (20 mg/kg) administration increased the pool of presynaptic zinc (by 34, 50 and 37%, respectively) in the rat prefrontal cortex. The 21% increase induced by imipramine (20 mg/kg) was marginally significant. Likewise, zinc (hydroaspartate, 65 mg/kg), citalopram and imipramine increased the extracellular zinc (although with a different pattern: time point, area under the curve and/or basal level) in this brain region. Furthermore, zinc induced an increase in presynaptic (by 65%) and extracellular zinc (by 90%) in the hippocampus, while both citalopram and imipramine did not. These results indicate that all of the treatments increase presynaptic/extracellular zinc concentrations in the rat prefrontal cortex, which may then contribute to their antidepressant mechanisms. Alterations induced by zinc (but not antidepressants) administration in the hippocampus may be related to specific zinc mechanisms. All the data (previous and present) on the effect of antidepressant treatments on the presynaptic/extracellular zinc concentrations suggest the involvement of this biometal presynaptic/synaptic homeostasis in the antidepressant mechanism(s).

Fig. 1

a The effect of chronic (14 days) treatment with zinc hydroaspartate, imipramine and citalopram on presynaptic zinc level in the rat prefrontal cortex measured by the selenium method. Values are expressed in relative optical density (ROD) as mean ± SEM of 15–20 sections from each of six rats per group. *P < 0.05, **P < 0.01 versus control (Dunnett’s post hoc test). b Photomicrographs representing synaptic zinc staining in the prefrontal cortical sections from control (I, III) and zinc hydroaspartate (65 mg/kg) treated rats (II, IV). Calibration bars in I and II, 500 μm; III and IV, 200 μm

Fig. 2

The effect of chronic (14 days) treatment with zinc hydroaspartate, imipramine and citalopram on the presynaptic zinc level in the rat hippocampus measured by the selenium method. Values are expressed in relative optical density (ROD) as mean ± SEM of 15–20 sections from all of the six rats per group. a Ammon’s horn (CA) area, b dentate gyrus (DG) area, c whole hippocampus. The results of zinc hydroaspartate at a dose of 65 mg/kg were calculated from the detailed data published previously (Szewczyk et al. 2006). *P < 0.05, **P < 0.01 versus control (Dunnett’s post hoc test or Student’s t test)

Fig. 3

The effect of chronic (14 days) treatment with zinc hydroaspatate, imipramine and citalopram on extracellular concentration of zinc in the rat prefrontal cortex measured in microdialysates by anodic stripping voltammetry. a Time course of the effect. The last administration is indicated by an arrow. b Area under the curve of 160 min collection time. Values are expressed as mean ± SEM, n = 4–5 rats. *P < 0.05, **P < 0.01, ***P < 0.001 versus basal level or control group (Tukey’s post hoc test)

Fig. 4

The effect of chronic (14 days) treatment with zinc hydroaspartate and citalopram on extracellular concentration of zinc in the rat hippocampus measured in microdialysates by anodic stripping voltammetry. a Time course of the effect. The last administration is indicated by an arrow. b Area under the curve of 160 min collection time. Values are expressed as mean ± SEM, n = 4–5 rats. *P < 0.05 versus basal level (Tukey’s post hoc test)