Lesion of the isthmo-optic nucleus impairs target selection for visually guided reaching

Flavonoids, which are polyphenolic compounds, have been reported to possess remarkable antioxidant and anti-inflammatory activities. Among the dietary flavonoids, fisetin (3,3′,4′,7-tetrahydroxyflavone) possesses a significant spectrum of biochemical and pharmacological actions. The present study aimed to investigate the antidepressant potential of fisetin and its possible mechanism. Two mouse models of despair tests were used to evaluate the antidepressant-like effect of fisetin. The results suggested that fisetin (10 and 20 mg/kg, p.o.) dose dependently inhibited the immobility time in both behavioral tests, while the doses that affected the immobile response did not affect locomotor activity. Two behavioral models, reserpine-induced hypothermia and ptosis, and p-chlorophenylalanine (PCPA)-induced depletion of serotonin, were used to explore the possible involvement of fisetin in the noradrenergic and serotonergic system. The higher dose of fisetin was found to effectively antagonize the hypothermia, but not ptosis, induced by reserpine. Pre-treatment with PCPA abolished the anti-immobility effect of fisetin in the forced swimming and tail suspension tests. Moreover, neurochemical assays showed that fisetin produced an increase in serotonin and noradrenaline levels in the frontal cortex and hippocampus. Monoamine oxidase (MAO) activity in the mouse brain was inhibited by 14.7% after treatment with fisetin, while MAO-B activity was not affected. These findings indicate that the antidepressant-like effect of fisetin involves the regulation of the central serotonin and noradrenaline levels.     

Antidepressant-like behavioral, neurochemical and neuroendocrine effects of naringenin in the mouse repeated tail suspension test

Our previous study demonstrated that the citrus bioflavonoid naringenin ameliorated behavioral alterations via the central serotonergic and noradrenergic systems in the tail suspension test (TST) induced mice. To better understand its pharmacological activity, mice were submitted to three 6min-TSTs one week apart (Day 1: test, Day 7: retest 1, Day 14: retest 2) followed by hippocampal glucocorticoid receptor (GR), monoamine neurotransmitters and serum corticosterone measurement. The results suggested that repeated TST detected the gradual increase in the efficacy of naringenin over time, additionally 1-day (20mg/kg), 7-day (10, 20mg/kg) and 14-day (5, 10, 20mg/kg) naringenin treatment markedly decreased the immobility time. Moreover, administration of naringenin for 14days (20mg/kg) increased hippocampal serotonin (5-HT), norepinephrine (NE) and GR levels, and reduced serum corticosterone levels in mice exposed to the repeated TST. Overall, the present study indicated that the re-exposure would facilitate the detection of the anti-immobility effects of antidepressant drugs in the mouse TST, and clearly demonstrated that the antidepressant-like effect of naringenin may be mediated by an interaction with neuroendocrine and neurochemical systems.     

Antidepressants differentially modify the extinction of an aversive memory task in female rats

Treatment of major depression, posttraumatic stress disorder and other psychopathologies with antidepressants can be associated with improvement of the cognitive deficits related to these disorders. Although the mechanisms of these effects are not completely elucidated, alterations in the extinction of aversive memories are believed to play a role in these psychopathologies. We have recently verified that female rats present low levels of extinction when submitted to the plus-maze discriminative avoidance task. In the present study, female rats were treated long term with clinically used antidepressants (fluoxetine, nortriptyline or mirtazapine) and subjected to the plus-maze discriminative avoidance task to evaluate learning, memory, extinction and anxiety-related behaviors as well as behavioral despair in the forced swimming test. All groups learned the task and exhibited retrieval. Chronic treatment with fluoxetine (but not with the other antidepressants tested) increased extinction of the discriminative task. In the forced swimming test, the animals treated with fluoxetine and mirtazapine showed decreased immobility duration. In conclusion, fluoxetine potentiated extinction, while both fluoxetine and mirtazapine were effective in ameliorating depressive-like behavior in the forced swimming test, suggesting a possible dissociation between the effects on mood and the extinction of aversive memories in female rats.     

Anterior cingulate cortical lesion attenuates food foraging in rats

We have developed a novel laboratory rodent model to detect competitive, non-competitive and no-hurdle foraging behaviors as seen in natural environment. However, it is not clear which brain region is important for the food foraging activity. In the present study, we evaluated the effect of lesions in the bilateral anterior cingulate cortex (ACC) on the rat food foraging behavior with the established model. In contrast to the sham lesion group (saline microinjection into the ACC), bilateral complete ACC chemical lesions (kainic acid microinjection into the ACC) significantly decreased the amount of foraged food in the competitive food foraging tests, non-competitive or no-hurdle foraging test. Moreover, the deficit of the food foraging activity was more prominent in the competitive food foraging test than in the non-competitive food and no-hurdle foraging test after ACC lesions. No alterations after ACC lesions were found in other behaviors including elevated plus-maze test (EPM), forced swimming test (FST), open field test (OFT), sucrose preference test and exploratory behavior. These findings suggest that the ACC mediate the food foraging-related behaviors.     

Time course of zinc deprivation-induced alterations of mice behavior in the forced swim test

BackgroundZinc 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.MethodsIn 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).ResultsAfter 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).ConclusionsThe obtained results indicate that zinc deprivation induced “pro-depressive” behavior (after the initial period of “anti-depressive” behavior). This pro-depressive behavior correlates with enhanced serum corticosterone concentration.     

Hyper-phosphorylation of GSK-3β: Possible roles in chlorpyrifos-induced behavioral alterations in animal model of depression

In recent years, the widespread use of chlorpyrifos (CPF) has aroused concerns regarding its potential neurotoxic effects, especially in developing individuals. One of the major consequences of CPF exposure is mood disorders such as depression. Epidemiological studies have demonstrated susceptibility to depression in populations with a history of CPF exposure. Our previous study indicated that repeated CPF exposure in doses from 10 to 160 mg/kg elicits depression- and anxiety-like alterations. However, whether this alteration is due to persistent inhibition of acetylcholinesterase (AChE) was not determined. In this study, we used lower doses of CPF to avoid evident inhibition of AChE to investigate other potential target systems that contribute to CPF's neurotoxic effect. Four-week-old adolescent male rats were repeatedly exposed to CPF at doses of 2.5, 5, or 10 mg/kg (s.c., 10 days) and then were subjected to either neurobehavioral testing or immunoblot analysis. Depression-like behaviors as manifested by increased immobility time was observed in force swimming test, while immunoblot analysis revealed a dramatically increased phosphorylation of glycogen synthase kinase-3β (GSK-3β) in the hippocampus and striatum, with no effect on the levels of Wnt2, GSK-3β, or β-catenin. These results suggest a noncholinergic mechanism, the hyper-phosphorylation of GSK-3β, which may contribute to the cellular neurotoxicity of CPF, thus increasing the susceptibility to mood disorders.     

Antidepressant-like effects of nicotine and reduced nicotinic receptor binding in the Fawn-Hooded rat, an animal model of co-morbid depression and alcoholism

A strong positive association between depression and alcoholism is evident in epidemiological studies. Curiously, the incidence of smoking (nicotine intake) is also very high among depressed individuals. Because neuronal nicotinic receptors have been implicated in mood regulation as well as in reinforcing effects of alcohol, it was of interest to determine whether inherent changes in these receptors may be manifested in an animal model that expresses both depressive-like characteristics and high alcohol intake. Thus, Fawn-Hooded (FH) rats along with their control ACI rats were used to measure the density of the high affinity nicotinic receptor in discrete brain regions. Furthermore, the effects of acute and chronic nicotine on depressive-like characteristics of FH rats were also evaluated. Measurements of [(3)H]cytisine binding (selective for alpha4beta2 nicotinic receptor subtype) revealed a reduction in these receptors only in the striatum of FH rats, a result very similar to that observed in selectively-bred alcohol-preferring (P) rats. Administration of nicotine acutely (0.4 mg/kg, sc) resulted in a significant reduction of immobility in the forced swim test (FST) in FH rats only, implying an antidepressant-like effect of nicotine. Another group of FH rats were administered 0.4 mg/kg nicotine (daily, sc) for 14 days and their behavior in the FST was evaluated 22-24 h after the last injection. In this case, nicotine also had a significant antidepressant-like effect in FH rats suggesting no tolerance to nicotine had occurred. The effects of nicotine on FST behavior are very similar to those observed in Flinders Sensitive Line rats, a putative animal model of depression. Together, these findings provide additional evidence for antidepressant-like effects of nicotine and strengthen the postulated association between striatal nicotinic receptors and high alcohol intake. Thus, nicotinic receptors could be suitable targets for the development of novel pharmacotherapy for treatment of depression and possibly alcoholism.     

Antidepressant-like effects of the active acidic polysaccharide portion of ginseng in mice

Aim of the study

The biological of activity of Panax ginseng C.A. Meyer (ginseng) is complex but some of its known effects are related to affective and anxiety disorders, including the enhancement of neuroprotection, cellular resilience and plasticity. Whereas such effects suggest that ginseng might have antidepressant activity, previous studies show incongruent results. The sources of contrasting results might be many but one possibility is the utilization of different ginseng preparations in different studies. The current study was therefore designed to examine the effects of a very specific component of ginseng extract, the acidic polysaccharide portion of the plant (WGPA), containing arabinogalactan, type-I rhamnogalacturonan (RG-I)- and homogalacturonan (HG)-rich pectins.

Materials and methods

WGPA was extracted from ginseng roots and administered orally to mice at 100 mg/kg and 200 mg/kg doses. WGPA was administered chronically, once daily for 1 week before the start of experiments and throughout the behavioral tests battery. Mice were tested for spontaneous activity, social interactions, anxiety-like behavior in the elevated plus-maze (EPM) and despair-like behavior in the forced swim test (FST).

Results

WGPA had no effects on spontaneous activity or behavior in the EPM. In contrast, 100 mg/kg (but not the 200 mg/kg) WGPA significantly reduced immobility time in the FST and both doses significantly increased social interactions and decreased aggressive behaviors in mice.

Conclusion

These results suggest that chronic WGPA treatment might have antidepressant-like effects that are unrelated to generalized behavioral changes. The results are discussed in the context of the known ability of the active ingredients of ginseng to increase neuroprotection, similar to many of the current antidepressant and mood stabilizing drugs.     

Astrocytic TNFα regulates the behavioral response to antidepressants

Recent studies have suggested that cytokines, and in particular tumor necrosis factor alpha (TNFα), have a role in modulating antidepressant efficacy. To directly test this idea, we compared the response of TNFα^−/− mice and astrocyte-specific TNFα^−/− mice to the antidepressants fluoxetine and desipramine. Using standard behavior models for measuring antidepressant efficacy, the forced swim test (FST) and tail suspension test (TST), we determined that TNFα^−/− mice were essentially normal in basal behavior in the FST and TST. However, TNFα^−/− mice showed no behavioral response to a standard dose of chronic antidepressant treatment, in sharp contrast to wildtype mice. Similar results were seen with acute antidepressant treatment, but TNFα^−/− mice did respond to a very high-dose acute antidepressant treatment. We also assessed in vitro and in vivo effects of fluoxetine on TNFα expression. Glia responded to serotonin in vitro and fluoxetine in vivo by upregulating TNFα mRNA. Consistent with this source of TNFα, mice with an astrocyte-specific deletion of TNFα also did not respond to standard chronic antidepressant treatment. These data suggest that astrocytic TNFα is important to the sensitivity of the behavioral response to administration of antidepressants.