Chronic stress and lithium treatments alter hippocampal glutamate uptake and release in the rat and potentiate necrotic cellular death after oxygen and glucose deprivation.

This study was undertaken to evaluate the effects of chronic variate stress and lithium treatment on glutamatergic activity and neuronal vulnerability of rat hippocampus. Male Wistar rats were simultaneously treated with lithium and submitted to a chronic variate stress protocol during 40 days, and afterwards the hippocampal glutamatergic uptake and release, measured in slices and synaptosomes, were evaluated. We observed an increased synaptosomal [(3)H]glutamate uptake and an increase in [(3)H]glutamate stimulated release in hippocampus of lithium-treated rats. Chronic stress increased basal [(3)H]glutamate release by synaptosomes, and decreased [(3)H]glutamate uptake in hippocampal slices. When evaluating cellular vulnerability, both stress and lithium increased cellular death after oxygen and glucose deprivation (OGD). We suggest that the manipulation of glutamatergic activity induced by stress may be in part responsible for the neuroendangerment observed after stress exposure, and that, in spite of the described neuroprotective effects of lithium, it increased the neuronal vulnerability after OGD.

Chronic lithium treatment has antioxidant properties but does not prevent oxidative damage induced by chronic variate stress.

This study evaluated the effects of chronic stress and lithium treatments on oxidative stress parameters in hippocampus, hypothalamus, and frontal cortex. Adult male Wistar rats were divided into two groups: control and submitted to chronic variate stress, and subdivided into treated or not with LiCl. After 40 days, rats were killed, and lipoperoxidation, production free radicals, total antioxidant reactivity (TAR) levels, and superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were evaluated. The results showed that stress increased lipoperoxidation and that lithium decreased free radicals production in hippocampus; both treatments increased TAR. In hypothalamus, lithium increased TAR and no effect was observed in the frontal cortex. Stress increased SOD activity in hippocampus; while lithium increased GPx in hippocampus and SOD in hypothalamus. We concluded that lithium presented antioxidant properties, but is not able to prevent oxidative damage induced by chronic variate stress.

The nociceptive response of stressed and lithium-treated rats is differently modulated by different flavors.

Pleasant and unpleasant flavors and odors can modulate pain perception, and the efficacy of sweet flavors in reducing pain seems to be related to its hedonic value. Chronic variate stress paradigm is a model of depression, and is suggested to induce anhedonia. We observed previously that lithium may prevent behavioral and neurochemical alterations induced by chronic stress; so we hypothesized that chronically stressed animals may present different nociceptive response to pleasant and unpleasant tastes that could be prevented by lithium treatment. Adult male Wistar rats were divided into four groups, control and stressed, treated or not with lithium. A Chronic Variate Stress paradigm was used, and lithium was added to the chow. After 40 days of treatment, the tail flick latency of the animals was evaluated, and rats were immediately placed in a box with access to a 5% acetic acid solution (acid flavor). After 5 min, tail flick latency was measured again. On the following day, animals were submitted to the same procedure, with the substitution of acetic acid by condensed sweet milk (sweet flavor). The stressed group was the only group who did not present analgesia after sweet taste exposition. All groups, except the control group, presented increased tail flick latency after exposition to the acid flavor. These results indicate that pleasant and unpleasant flavors present different relevance for the induction of antinociception in stressed animals, and the absence of sweet flavor-induced analgesia may represent an anhedonic effect of the chronic variate stress paradigm. On the other hand, perception of different flavors may be more prominent in animals treated with lithium.

Na+,K(+)-ATPase activity is reduced in hippocampus of rats submitted to an experimental model of depression: effect of chronic lithium treatment and possible involvement in learning deficits.

This study was undertaken to verify the effects of chronic stress and lithium treatments on the hippocampal Na+,K(+)-ATPase activity of rats, as well as to investigate the effects of stress interruption and post-stress lithium treatment on this enzyme activity and on spatial memory. Two experiments were carried out; in the first experiment, adult male Wistar rats were divided into two groups: control and submitted to a chronic variate stress paradigm, and subdivided into treated or not with LiCl. After 40 days of treatment, rats were killed, and Na+,K(+)-ATPase activity was determined. In the second experiment, rats were stressed during 40 days, and their performance was evaluated in the Water Maze task. The stressed group was then subdivided into four groups, with continued or interrupted stress treatment and treated or not with lithium for 30 additional days. After a second evaluation of performance in the Water Maze, rats were killed and Na+,K(+)-ATPase activity was also measured. Results showed an impairment in Na+,K(+)-ATPase activity and in Water Maze performance of chronically stressed rats, which were prevented by lithium treatment and reversed by lithium treatment and by stress interruption. These results suggest that the modulation of Na+,K(+)-ATPase activity may be one of the mechanisms of action of lithium in the treatment of mood disorders.