Lithium and methylphenidate: opposite effects on perirenal brown fat / Lítio e metilfenidato: efeitos opostos sobre a gordura perirrenal

OBJECTIVE: To evaluate the effects of the administration of lithium to adult rats on brown (perirenal) and white (inguinal) adipose tissues and to assess whether methylphenidate modulates lithium effects. METHODS: Twenty-five adult male Wistar rats were fed with either regular or lithium-containing chow for 30 days. Between days 15 to 30 of treatment, animals received daily intraperitoneal administrations of either methylphenidate or saline. RESULTS: Lithium significantly reduced perirenal fat, and this effect was minimized by the administration of methylphenidate. There were no significant differences between the groups in terms of the effects of lithium on inguinal fat. CONCLUSION: Our findings suggest that different effects on white and brown tissue distribution may be involved in lithium-induced weight gain.

OBJETIVO: Avaliar como a administração de lítio afeta o tecido adiposo marrom (perirrenal) e branco (inguinal) e se o metilfenidato modula os efeitos do lítio. MÉTODOS: Vinte e cinco ratos Wistar adultos machos foram alimentados com ração normal ou contendo lítio por 30 dias. Entre os dias 15 e 30 de tratamento, os animais receberam doses intraperitoneais diárias de metilfenidato ou solução salina. RESULTADOS: A administração de lítio reduziu significativamente a gordura perirrenal. Esse efeito foi reduzido com a administração de metilfenidato. Não houve diferenças significativas entre os grupos em relação à gordura inguinal. CONCLUSÃO: Os achados sugerem que efeitos diferenciados sobre os tecidos adiposos marrom e branco podem estar envolvidos no ganho de peso induzido pelo tratamento com lítio.

Sex-specific differences on caffeine consumption and chronic stress-induced anxiety-like behavior and DNA breaks in the hippocampus.

Caffeine is widely consumed in beverages and food, and its consumption in high doses is associated with anxiety increase. Stress situations are often associated to coffee consumption, and have a strong influence on oxidative DNA damage. As there are sex-specific differences in many metabolic, neurochemical and behavioral aspects, the aim of this study is to verify the interaction between chronic consumption of caffeine and chronic stress on anxiety and DNA breaks in the hippocampus on male and female rats. Wistar rats were submitted to restraint stress for at least 50 days. The diet consisted of standard rat chow and caffeine 0.3 or 1 g/L in drinking water "ad libitum" as the only drinking source. Controls received tap water. Anxiety-like behavior and DNA breaks in the hippocampus were evaluated. Caffeine consumption and chronic stress increased anxiety-like behavior as well as DNA breaks in the hippocampus of male rats. No effect on these parameters was observed in females. These results may be related to the presence of estradiol, which may have anxiolytic and neuroprotective properties.

Interactions between chronic stress and chronic consumption of caffeine on the enzymatic antioxidant system.

We studied the effect of chronic caffeine on parameters related to oxidative stress in different brain regions of stressed and non-stressed rats. Wistar rats were divided into three groups: control (receiving water), caffeine 0.3 g/L and caffeine 1.0 g/L (in the drinking water). These groups were subdivided into non-stressed and stressed (repeated restraint stress during 40 days). Lipid peroxide levels and the total radical-trapping potential were assessed, as well as antioxidant enzyme activities superoxide dismutase, gluthatione peroxidase, and catalase in hippocampus, striatum and cerebral cortex. Results showed interactions between stress and caffeine, especially in the cerebral cortex, since caffeine increased the activity of some antioxidant enzymes, but not in stressed animals. We concluded that chronic administration of caffeine led, in some cases, to increased activity of antioxidant enzymes. However, these effects were not observed in the stressed animals.

Effects of chronic restraint stress and estradiol replacement on glutamate release and uptake in the spinal cord from ovariectomized female rats.

Glutamate is an excitatory neurotransmitter involved in neuronal plasticity and neurotoxicity. Chronic stress produces several physiological changes on the spinal cord, many of them presenting sex-specific differences, which probably involve glutamatergic system alterations. The aim of the present study was to verify possible effects of exposure to chronic restraint stress and 17beta-estradiol replacement on [3H]-glutamate release and uptake in spinal cord synaptosomes of ovariectomized (OVX) rats. Female rats were subjected to OVX, and half of the animals received estradiol replacement. Animals were subdivided in controls and chronically stressed. Restraint stress or estradiol had no effect on [3H]-glutamate release. The chronic restraint stress promoted a decrease and 17beta-estradiol induced an increase on [3H]-glutamate uptake, but the uptake observed in the restraint stress +17beta-estradiol group was similar to control. Furthermore, 17beta-estradiol treatment caused a significant increase in the immunocontent of the three glutamate transporters present in spinal cord. Restraint stress had no effect on the expression of these transporters, but prevented the 17beta-estradiol effect. We suggest that changes in the glutamatergic system are likely to take part in the mechanisms involved in spinal cord plasticity following repeated stress exposure, and that 17beta-estradiol levels may affect chronic stress effects in this structure.

Long lasting sex-specific effects upon behavior and S100b levels after maternal separation and exposure to a model of post-traumatic stress disorder in rats.

This study was undertaken to verify if repeated long-term separation from dams would affect the development of parameters related to post-traumatic stress disorder (PTSD) after animals are subjected to inescapable shock when adults. Wistar rats were subjected to repeated maternal separation during post-natal days 1-10. When adults, rats from both sexes were submitted to a PTSD model consisting of exposure to inescapable footshock, followed by situational reminders. We observed long-lasting effects of both interventions. Exposure to shock increased fear conditioning. Anxiety-like behavior was increased and exploratory activity decreased by both treatments, and these effects were more robust in males. Additionally, basal corticosterone in plasma was decreased, paralleling effects observed in PTSD patients. Levels of S100B protein in serum and cerebrospinal fluid (CSF) were measured. Levels in serum correlated with the effects observed in anxiety-like behavior, increasing in males exposed to shock, and presenting no effect in females. S100B in CSF was increased in females submitted to maternal separation during the neonatal period. These results suggest that, in rats, an early stress experience such as maternal separation may aggravate some effects of exposure to a stressor during adult age, and that this effect is sex-specific. Additionally, data suggest that the increased S100B levels, observed in serum, have an extracerebral origin, possibly mediated by an increase in the noradrenergic tonus. Increased S100B in brain could be related to its neurotrophic actions.

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.

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.

Acute and repeated restraint stress influences cellular damage in rat hippocampal slices exposed to oxygen and glucose deprivation.

Several studies have shown that high corticosteroid hormone levels increase neuronal vulnerability. Here we evaluate the consequences of in vivo acute or repeated restraint stress on cellular viability in rat hippocampal slices suffering an in vitro model of ischemia. Cellular injury was quantified by measuring lactate dehydrogenase (LDH) and neuron-specific enolase released into the medium. Acute stress did not affect cellular death when oxygen and glucose deprivation (OGD) was applied both immediately or 24h after restraint. The exposure to OGD, followed by reoxygenation, resulted in increased LDH in the medium. Repeated stress potentiated the effect of OGD both, on LDH and neuron-specific enolase released to the medium. There was no effect of repeated stress on the release of S100B, an astrocytic protein. Additionally, no effect of repeated stress was observed on glutamate uptake by the tissue. These results suggest that repeated stress increases the vulnerability of hippocampal cells to an in vitro model of ischemia, potentiating cellular damage, and that the cells damaged by the exposure to repeated stress+OGD are mostly neurons. The uptake of glutamate was not observed to participate in the mechanisms responsible for rendering the neurons more susceptible to ischemic damage after repeated stress.

Repeated restraint stress reduces opioid receptor binding in different rat CNS structures.

Different effects of exposure to acute or to repeated stress have been observed upon the nociceptive response in rats. In the present study, we repeatedly submitted Wistar rats to restraint for 40 days, a treatment known to induce an increase in the nociceptive response in the tail-flick test. Afterwards, the effect of repeated restraint stress on the density of opioid receptors in rat spinal cord, frontal cortex, and hippocampus was investigated. Results showed that repeatedly stressed rats displayed a significant decrease in opioid receptors density in all structures studied; cortex (141.3 +/- 5.7 for control and 103.3 +/- 15.9 for stressed rats), hippocampus (92.4 +/- 7.2 for control and 64.8 +/- 7.7 for stressed rats), and spinal cord (122.2 +/- 12.8 for control and 79.7 +/- 9.7 for stressed rats). These findings suggest opioid mediation of the altered responses observed in these repeatedly-stressed animals, although the participation of non-opioid mechanisms in this phenomenon cannot be ruled out.

Hyperthyroidism changes nociceptive response and ecto-nucleotidase activities in synaptosomes from spinal cord of rats in different phases of development.

Changes in transport, receptors and production of extracellular adenosine have been observed after induction of hyperthyroidism. Adenosine is associated with inhibitory actions such as reduction in release of excitatory neurotransmitters and antinociception at spinal site. In contrast, ATP acts as an excitatory neurotransmitter and produces pronociceptive actions. ATP may be completely hydrolyzed to adenosine by an enzyme chain constituted by an ATP diphosphohydrolase and an ecto-5'-nucleotidase, as previously described in the spinal cord. Thus, we now investigated the effects of the hyperthyroidism on adenine nucleotide hydrolysis in the spinal cord and verified the nociceptive response in this pathology during different phases of development. Hyperthyroidism was induced in male Wistar rats, aged 5, 60 and 330 days by daily intraperitoneal injections of L-thyroxine (T4) for 14 days. Nociception was assessed with a tail-flick apparatus. Rats starting the treatment aged 5 days demonstrated a significant increase in ADP and AMP hydrolysis and increased tail-flick latency (TFL). In contrast, in the spinal cord from hyperthyroid rats aged 60 and 330 days old, the hydrolysis of ATP, ADP and AMP were significantly decreased. Accordingly, the tail-flick latency was decreased, indicating a hyperalgesic response. These results suggest the involvement of ecto-nucleotidases in the control of the hyperthyroidism-induced nociceptive response in rats at distinct developmental stages.

Estradiol protects against oxidative stress induced by chronic variate stress.

Neurochemical gender-specific effects have been observed following chronic stress. The aim of this study was to verify the effects of chronic variable stress on free radical production (evaluated by DCF test), lipoperoxidation (evaluated by TBARS levels), and total antioxidant reactivity (TAR) in three distinct structures of brain: hippocampus, cerebral cortex and hypothalamus of female rats, and to evaluate whether the replacement with estradiol in female rats exerts neuroprotection against oxidative stress. Results demonstrate that chronic stress had a structure-specific effect upon lipid peroxidation, since TBARS increased in hypothalamus homogenates of stressed animals, without alterations in the other structures analyzed. Estradiol replacement was able to counteract this effect. In hippocampus, estradiol induced a significant increase in TAR. No differences in DCF levels were observed. In conclusion, the hypothalamus is more susceptible to oxidative stress in female rats submitted to chronic variable stress, and this effect is prevented by estradiol treatment.

Acute and chronic stress alter ecto-nucleotidase activities in synaptosomes from the rat hippocampus.

Hyperactivity of the stress response has long been recognized as maladaptive. The hippocampus, a brain structure important in mediating this response, is known to be affected by chronic stress, a situation reported to induce changes in adenine nucleotide hydrolysis in the rat. The enzymes catalyzing the hydrolysis of ATP to adenosine in the synaptic cleft are thought to have a role in modulating and controlling synaptic transmission. This study aimed to investigate the effect of acute and repeated restraint stress on the ATP, ADP and AMP hydrolyses in rat hippocampal synaptosomes. Adult male Wistar rats were submitted to acute or repeated (15 and 40 days) stress, and ATPase-ADPase, and 5'nucleotidase activities were assayed in the hippocampal synaptosomal fraction. Acute stress induced increased hydrolyses of ATP (21%), ADP (21%) and AMP (40%). In contrast, ATP hydrolysis was increased by 20% in repeatedly stressed rats, without changes in the ADP or AMP hydrolysis. The same results were observed after 15 or 40 days of stress. Therefore, acute stress increases ATP diphosphohydrolase activity which, in association with 5'-nucleotidase, contributes to the elimination of ATP and provides extracellular adenosine. Interestingly, increased ecto-ATPase activity in response to chronic stress reveals an adaptation to this treatment.