Influence of zinc supplementation on imipramine effect in a chronic unpredictable stress (CUS) model in rats.

Zinc is an endogenous modulator of neuronal activity and may play an important role in the pathogenesis of depression. Recent studies have shown that zinc exhibits antidepressant-like activity in some models of depression in rodents. Our previous studies have shown that the footshock-induced fighting behavior was reduced in the rats subjected to chronic unpredictable stress (CUS). This test is used as the new experimental model of depression. Various antidepressant drugs given repeatedly prevented this kind of behavioral depression. The aim of the present study was to evaluate the effect of prolonged treatment with zinc hydroaspartate and to examine if zinc supplementation could modulate the imipramine effect in CUS model of behavioral depression in rats. The experiments were carried out on male Wistar rats. Chronic stress (persisting for 16 days) was induced by the modified method described by Katz et al. Zinc hydroaspartate at the dose of 30 mg/kg/day or 15 mg/kg/day and imipramine at the dose of 5 mg/kg/day were administered once daily for 14 days. Imipramine was given (ip) 1 h before every stress session and zinc hydroaspartate (ip) l h before the antidepressant. The footshock-induced fighting behavior test was performed 48 h after the last session of the chronic stress. It was demonstrated that in chronically stressed rats the number of fighting attacks was significantly reduced (by about 75%). Zinc hydroaspartate at the dose of 30 mg/kg/day, given alone, prevented the deficit in fighting behavior in chronically stressed rats. Neither imipramine at the dose of 5 mg/kg/day nor zinc hydroaspartate (15 mg/kg/day) administered alone changed the intensity of fighting behavior in chronically stressed rats. However, when imipramine was given at the same dose in the rats pretreated with zinc hydroaspartate (15 mg/kg/day) the deficit of fighting behavior was not observed. The present results indicate that zinc similarly to antidepressants protects the rats against the CUS-induced behavioral depression. Moreover, our findings suggest that zinc supplementation could potentiate the antidepressant effect of imipramine.

Antidepressants in chronic unpredictable mild stress (CUMS)-induced deficit of fighting behavior.

Chronic unpredictable stress (CUS) is one of the behavioral models resembling in some respects (loss of normal aggresiveness) human depression. In the present study, consistent with the ethical principles for scientific experiments on animals, we have decided to modify the CUS procedure. In this new modified model named chronic unpredictable mild stress (CUMS), we have introduced mild stressor (14 h period of 45 degrees cage tilt) instead of one severe stressor (20 s exposure to electric footshock). The purpose of the present study was to determine whether this new procedure CUMS, similarly to CUS, affected the footshock-induced fighting behavior. We have also investigated the effect of antidepressant drugs with different pharmacological profiles (imipramine, mianserin, fluoxetine, moclobemide, tianeptine) and anxiolytic drug (oxazepam) on fighting behavior in rats submitted to CUMS. It was found that in rats subjected to CUMS procedure the number of fighting attacks was significantly reduced (by about 80%). Prolonged treatment (once daily, for 14 days) with imipramine (10 mg/kg/day), tianeptine (12.5 mg/kg/day), mianserin (10 mg/kg/day), moclobemide (50 mg/kg/day), fluoxetine (10 mg/kg/day), but not oxazepam (5 mg/kg/day) prevented the deficit in fighting behavior in rats subjected to CUMS. In conclusion, the results of the present study indicate that CUMS, similarly to CUS procedure, induced behavioral deficit in rats which was normalized by antidepressants with a different pharmacological profile.

Histological examination of the kidney after experimental administration of MK-801 and dexamethasone.

The aim of the research was histological assessment of the influence of MK-801 (NMDA receptor antagonist) and dexamethasone on the kidney. The experiment was carried out on adult Albino-Swiss mouse males. MK-801 was administered in the dose of 0.3 mg/kg/24 h for 8 days, dexamethasone--in the toxic dose of 120 mg/kg/24 h. Kidney slices stained with hematoxylin and eosin and with PAS method were examined with light microscope. The performed experiments revealed that MK-801 causes morphological changes in the shape of slight narrowing of the urinary spaces in renal corpuscles and narrowing of the lumen of the proximal convoluted tubules and dexamethasone administered in toxic doses causes dilatation of these spaces with kidney's hyperemia. MK-801 intensifies morphological changes of the kidney induced by toxic doses of dexamethasone.

Effect of imipramine on brain D-1 and 5-HT-2A receptors in a chronic unpredictable stress model in rats.

Chronic unpredictable stress (CUS) model of depression is one of the well validated animal models of depression. In this paper, we report the results of investigations into dopaminergic D-1 and serotonergic 5-HT-2A receptors in the brain of rats subjected to CUS procedure and treated chronically with imipramine. We have examined the dopaminergic D-1 ([3H-SCH 23390) in the limbic area and serotonergic 5-HT-2A ([3H-ketanserin) receptors in the cerebral cortex by a saturation radioligand binding method in rats subjected to CUS paradigm, imipramine, both CUS and imipramine and control animals. CUS procedure resulted in a significant 36% increase in the D-1 receptor density in the limbic system, which was attenuated by chronic imipramine treatment. Also a 21% increase in the density of 5-HT-2A receptors in the cerebral cortex induced by CUS was reduced by chronic imipramine treatment. The present data indicate that the increases in the density of brain D-1 and 5-HT-2A receptors of rats subjected to CUS, which are "normalized" by imipramine, might be involved in the pathophysiology of "animal depression" (and, thus, in pathophysiology of human depression) and in the mechanism of antidepressant therapy.

Repeated treatment with selective serotonin reuptake inhibitors but not anxiolytics prevents the stress-induced deficit of fighting behavior.

Several animal models of "depression" have been examined. One of them is chronic unpredictable stress (CUS)-induced deficit of fighting behavior in rats. In the present study, we compared the effects of two antidepressants (fluoxetine or fluvoxamine) and three anxiolytics (buspirone, lorazepam or oxazepam) on the electric footshock-induced fighting behavior in the pairs of male Wistar rats exposed to CUS procedure (16-day application of various unpredictable stressors). It was found that, in chronically stressed rats, the number of fighting attacks was significantly reduced (by about 70%). Prolonged (for 14 days) treatment of rats with fluoxetine or fluvoxamine (both at the dose of 10 mg/kg/day) counteracted the deficit of aggression induced by the chronic stress. On the contrary, the anxiolytics: lorazepam (0.5 mg/kg/day), oxazepam (5 mg/kg/day) or buspirone (0.2 mg/kg/day) administered for 14 days, did not modify the deficit of fighting induced by CUS procedure. It must be underlined that prolonged treatment with all used drugs did not change the intensity of fighting in normal (unstressed) rats. In conclusion, prolonged treatment with antidepressant drugs prevents the CUS-induced deficit of fighting behavior, whereas no beneficial effect of anxiolytic agents was found.