[Show abstract][Hide abstract] ABSTRACT: Postnatal overfeeding is a well-known model of early-life induced obesity and glucose intolerance in rats. However, little is known about its impact on insulin signaling in specific brain regions such as the mesocorticolimbic system, and its putative effects on dopamine-related hedonic food intake in adulthood. For this study, rat litters were standardized to 4 (small litter -SL) or 8 pups (control - NL) at postnatal day 1. Weaning was at day 21, and all tests were conducted after day 60 of life in male rats. In Experiment 1, we demonstrated that the SL animals were heavier than the NL at all time points and had decreased AKT/pAKT ratio in the Ventral Tegmental Area (VTA), without differences in the skeletal muscle insulin signaling in response to insulin injection. In Experiment 2, the standard rat chow intake was addressed using an automated system (BioDAQ, Research Diets®), and showed no differences between the groups. On the other hand, the SL animals ingested more sweet food in response to the 1min. tail-pinch challenge and did not develop conditioned place preference to sweet food. In Experiment 3 we showed that the SL rats had increased VTA TH content but had no difference in this protein in response to a sweet food challenge, as the NL had. The SL rats also showed decreased levels of dopamine D2 receptors in the nucleus accumbens. Here we showed that early postnatal overfeeding was linked to an altered functioning of the mesolimbic dopamine pathway, which was associated with altered insulin signaling in the VTA, suggesting increased sensitivity, and expression of important proteins of the dopaminergic system.
Behavioural Brain Research 09/2014; · 3.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It has previously been reported that exposure to repeated restraint stress induces hyperalgesia in male rats, an effect that was not observed in females. The aim of the present study was to investigate the effects of chronic variable stress over 40days on nociception threshold indexed by tail-flick latency in male and female adult rats. The results showed different behavior in chronically stressed animals when compared to the control group: male rats showed a decrease in tail-flick latency while females presented an increase in this parameter. For female rats this effect was independent of the phase of the estrous cycle. Several sources of data indicate that behavioral and physiological responses to stress are sexually dimorphic, including in nociception, and the estrous cycle appears to be a factor that influences opioid analgesia in female. These effects are modulated by the strain and conditions of nociception assay. Additional studies concerning the mechanisms involved in the hyperalgesic response in males and the differences on nociceptive response in females chronically exposed to stress are needed.
[Show abstract][Hide abstract] ABSTRACT: Morphine exposure during the neonatal period can promote changes in pain signaling pathways that can be expressed as an increased nociceptive response in adult life. Glutamate is the major excitatory neurotransmitter in primary afferent terminals and plays a critical role in normal spinal excitatory synaptic transmission. Considering the importance of a better understanding of the mechanisms that underlie nociceptive changes throughout the life course, the aim of this study was investigate the effects of repeated morphine administration at postnatal days 8 (P8) to 14 (P14) on glutamate uptake in spinal synaptosomes at P30 and P60. The morphine group showed decreased [3H]-glutamate uptake as compared to control groups in both P30 and P60. These findings suggest that morphine exposure in early life leads to changes in glutamatergic signaling at least until the 60th day of age, which may lead to increased levels of glutamate in the spinal synaptic cleft and, consequently, an increased nociceptive response in adult life. Thus, this study highlights the importance of conducting research in this field to provide a comprehensive knowledge of the long-term effects of early-life morphine treatment on nociceptive pathways.
[Show abstract][Hide abstract] ABSTRACT: Early life events lead to a large number of behavioral and biochemical alterations in adulthood. The aim of this study is to verify whether the release of gonadal hormones during puberty affects parameters of oxidative stress observed in adulthood in cerebral cortex, striatum and hypothalamus of female rats subjected to neonatal handling. Rats were exposed or not to neonatal handling (10min/day, first 10 days of life). Between 21-28 post-natal days, females from each litter were divided into the following groups: ovariectomy, sham, and intact (no surgery) when adults, parameters of oxidative stress were analyzed. The groups subjected to surgery (ovx and sham), showed increased production of free radicals by the method of oxidation of dichlorodihydrofluorescein (DCFH) in cerebral cortex and striatum. Decreased catalase activity was observed in the cerebral cortex, in the same groups. No effects of neonatal manipulation were observed in these structures. We conclude that the period after weaning constitute a critical window for stressful interventions during development, leading to alterations in parameters of oxidative stress in adulthood, and these effects are not influenced by estradiol and neonatal handling.
Journal of Medicine and Medical Science. 03/2011; 2:741-749.
[Show abstract][Hide abstract] ABSTRACT: Previous studies have shown sex-specific oxidative changes in spinal cord of rats submitted to chronic stress, which may be due to gonadal hormones. Here, we assessed total radical-trapping potential (TRAP), superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities and lipid peroxidation (evaluated by the TBARS test) in the spinal cord of ovariectomized (OVX) female rats. Female rats were subjected to OVX, and half of the animals received estradiol replacement. Animals were subdivided into controls and chronically stressed (for 40 days). Our findings demonstrate that chronic stress decreased TRAP, and increased SOD activity in spinal cord homogenates from ovariectomized female rats and had no effect on GPx activity. On the other hand, groups receiving 17β-estradiol replacement presented a decreased GPx activity, but no alteration in TRAP and in SOD activity. No differences in the TBARS test were found in any of the groups analyzed. In conclusion, our results support the idea that chronic stress induces an imbalance between SOD and GPx activities, additionally decreasing TRAP. Estradiol replacement did not reverse the effects of chronic stress, but induced a decrease in GPx activity. Therefore, estradiol replacement in ovariectomized chronically stressed rats could make the spinal cord more susceptible to oxidative injury.
Neurochemical Research 11/2010; 35(11):1700-7. · 2.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Early life events lead to behavioral and neurochemical changes in adulthood. The aim of this study is to verify the effects of neonatal handling on spatial memory, nitric oxide (NO) production, antioxidant enzymatic activities and DNA breaks in the hippocampus of male and female adult rats. Litters of rats were non-handled or handled (10 min/day, days 1-10 after birth). In adulthood they were subjected to a Morris water maze or used for biochemical evaluations. Female handled rats showed impairment in spatial learning. They also showed decreased NO production, while no effects were observed in these parameters in male rats. No effects were observed on the number of hippocampal NADPH diaphorase positive cells. In the Comet Assay, male handled rats showed increased DNA breaks index when compared to non-handled ones. We conclude that neonatal handling impairs learning performance in a sex-specific manner, what may be related to NO decreased levels.
Neurochemical Research 04/2010; 35(7):1083-91. · 2.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Neurochemical Research 09/2008; 34(3):499-507. · 2.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report a chemically-induced model of maple syrup urine disease (MSUD) in 10- and 30-day-old rats produced by subcutaneous administration of a branched-chain amino acids (BCAA) pool along with the analyses of plasma and brain amino acid levels by HPLC at 0-120 min after administration. We observed an increase of plasma leucine (Leu), isoleucine (Ile) and valine (Val) concentrations in both 10- and 30-day-old rats. These increases were accompanied by a concomitant reduction of plasma concentrations of methionine (Met), phenylalanine (Phe), tyrosine (Tyr), histidine (His), alanine (Ala), lysine (Lys), and ornithine (Orn) in 10-day-old rats and of Met, Phe, Tyr, tryptophan (Trp), and Orn in 30-day-old rats. These results are similar to those observed in MSUD patients during crises, when plasma levels of large neutral amino acids (LNAA) are also reduced when BCAA concentrations are increased. In the brain, increased concentrations of Leu, Ile and Val were achieved in 10-day-old rats at all times after injection. In contrast, no differences in cerebral concentrations of BCAA were observed in 30-day-old rats. In conclusion, the present MSUD model, using 10- rather than 30-day-old rats, has a similar amino acid profile to that of MSUD untreated patients and is suitable to investigate the mechanisms of brain damage characteristic of this disorder.
Journal of Neuroscience Methods 10/2006; 155(2):224-30. · 2.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: Adenosine acting on A(1) receptors has been related with neuroprotective and neuromodulatory actions, protection against oxidative stress and decrease of anxiety and nociceptive signaling. Previous studies demonstrated an inhibition of the enzymes that hydrolyze ATP to adenosine in the rat central nervous system after hyperthyroidism induction. Manifestations of hyperthyroidism include increased anxiety, nervousness, high O(2) consumption and physical hyperactivity. Here, we investigated the effects of administration of a specific agonist of adenosine A(1) receptor (N(6)-cyclopentyladenosine; CPA) on nociception, anxiety, exploratory response, locomotion and brain oxidative stress of hyperthyroid rats. Hyperthyroidism was induced by daily intraperitoneal injections of l-thyroxine (T4) for 14 days. Nociception was assessed with a tail-flick apparatus and exploratory behavior, locomotion and anxiety were analyzed by open-field and plus-maze tests. We verified the total antioxidant reactivity (TAR), lipid peroxide levels by the thiobarbituric acid reactive species (TBARS) reaction and the free radicals content by the DCF test. Our results demonstrated that CPA reverted the hyperalgesia induced by hyperthyroidism and decreased the exploratory behavior, locomotion and anxiety in hyperthyroid rats. Furthermore, CPA decreased lipid peroxidation in hippocampus and cerebral cortex of control rats and in cerebral cortex of hyperthyroid rats. CPA also increased the total antioxidant reactivity in hippocampus and cerebral cortex of control and hyperthyroid rats, but the production of free radicals verified by the DCF test was changed only in cerebral cortex. These results suggest that some of the hyperthyroidism effects are subjected to regulation by adenosine A(1) receptor, demonstrating the involvement of the adenosinergic system in this pathology.
Behavioural Brain Research 03/2006; 167(2):287-94. · 3.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purinergic system exerts a significant influence on the modulation of pain pathways at the spinal site. Adenosine has antinociceptive properties in experimental and clinical situations, while ATP exerts pronociceptive actions in different pain models. In this study we investigated the hydrolysis of ATP to adenosine in synaptosomes from spinal cord in parallel with the nociceptive response of rats at different ages after hypothyroidism induction. Hypothyroidism elicited a significant increase in AMP hydrolysis to adenosine in synaptosomes from spinal cord of rats subjected to neonatal hypothyroidism and in 420-day-old rats submitted to thyroidectomy. Accordingly, these rats presented an analgesic response as a consequence of hypothyroidism. In contrast, the ATP hydrolysis was decreased in the spinal cord of 60-day-old hypothyroid rats in parallel with a significant increase in nociceptive response. These results indicate the involvement of adenine nucleotides in the control of the hypothyroidism-induced nociceptive response during development.
Neurochemical Research 10/2005; 30(9):1155-61. · 2.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It has been reported that animals submitted to repeated restraint stress present various adaptation responses which are dependent on the sex. These adaptations include changes in nociception and adenine nucleotide hydrolysis. In this study, we report the effect of chronic administration of a gonadal steroid (17beta-estradiol) on ATP, ADP and AMP hydrolysis in spinal cord synaptosomes of adult ovariectomized (OVX) Wistar rats submitted to repeated restraint stress over 40 days. We also measured nociceptive threshold in these animals using the tail-flick test. The results show that tail-flick latencies were decreased in both stressed groups, OVX and OVX rats receiving estradiol replacement therapy, indicating reduced nociceptive threshold after exposure to repeated stress. Repeated restraint stress caused no effect on ATPase or ADPase activities. On the other hand, AMP hydrolysis in spinal cord synaptosomes from repeatedly stressed rats was decreased in OVX rats compared to non-stressed OVX ones, indicating reduced extracellular adenosine production; this effect was reversed by hormonal replacement. These observations suggest that nociceptive sensitivity to noxious stimuli is affected by repeated stress and that modulation of neurotransmission by adenine nucleotides in spinal cord may be altered by the interaction of sexual hormones and psychological factors, such as exposure to stress.
[Show abstract][Hide abstract] ABSTRACT: 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.
Brain Research Bulletin 06/2005; 65(5):443-50. · 2.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It has been shown that emotional stress may induce oxidative damage, and considerably change the balance between pro-oxidant and antioxidant factors in the brain. The aim of this study was to verify the effect of repeated restraint stress (RRS; 1 h/day during 40 days) on several parameters of oxidative stress in the hippocampus of adult Wistar rats. We evaluated the lipid peroxide levels (assessed by TBARS levels), the production of free radicals (evaluated by the DCF test), the total radical-trapping potential (TRAP) and the total antioxidant reactivity (TAR) levels, and antioxidant enzyme activities (SOD, GPx and CAT) in hippocampus of rats. The results showed that RRS induced an increase in TBARS levels and in GPx activity, while TAR was reduced. We concluded that RRS induces oxidative stress in the rat hippocampus, and that these alterations may contribute to the deleterious effects observed after prolonged stress.
Neurochemical Research 02/2005; 30(1):105-11. · 2.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Comparative Biochemistry and Physiology - Part A Molecular & Integrative Physiology 02/2005; 140(1):111-6. · 2.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Neurochemical Research 11/2004; 29(10):1923-30. · 2.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Glutamatergic mechanisms are thought to be involved in stress-induced changes of brain function, especially in the hippocampus. We hypothesized that alterations caused by the hormonal changes associated with chronic and acute stress may affect glutamate uptake and release from hippocampal synaptosomes in Wistar rats. It was found that [3H]glutamate uptake and release by hippocampal nerve endings, when measured 24 h after 1 h of acute restraint, presented no significant difference. The exposure to repeated restraint stress for 40 days increased neuronal presynaptic [3H]glutamate uptake as well as basal and K+-stimulated glutamate release when measured 24 h after the last stress session. Chronic treatment also caused a significant decrease in [3H]glutamate binding to hippocampal membranes. We suggest that changes in the glutamatergic system are likely to take part in the mechanisms involved in nervous system plasticity following repeated stress exposure.
Neurochemical Research 10/2004; 29(9):1703-9. · 2.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Pharmacology Biochemistry and Behavior 07/2004; 78(2):341-7. · 2.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Exposure to stress induces a cluster of physiological and behavioral changes in an effort to maintain the homeostasis of the organism. Long-term exposure to stress, however, has detrimental effects on several cell functions such as the impairment of antioxidant defenses leading to oxidative damage. Oxidative stress is a central feature of many diseases. The lungs are particularly susceptible to lesions by free radicals and pulmonary antioxidant defenses are extensively distributed and include both enzymatic and non-enzymatic systems. The aim of the present study was to determine lipid peroxidation and total radical-trapping potential (TRAP) changes in lungs of rats submitted to different models of chronic stress. Adult male Wistar rats weighing 180-230 g were submitted to different stressors (variable stress, N = 7) or repeated restraint stress for 15 (N = 10) or 40 days (N = 6) and compared to control groups (N = 10 each). Lipid peroxidation levels were assessed by thiobarbituric acid reactive substances (TBARS), and TRAP was measured by the decrease in luminescence using the 2-2'-azo-bis(2-amidinopropane)-luminol system. Chronic variable stress induced a 51% increase in oxidative stress in lungs (control group: 0.037 +/- 0.002; variable stress: 0.056 +/- 0.007, P < 0.01). No difference in TBARS was observed after chronic restraint stress, but a significant 57% increase in TRAP was presented by the group repeatedly restrained for 15 days (control group: 2.48 +/- 0.42; stressed: 3.65 +/- 0.16, P < 0.05). We conclude that different stressors induce different effects on the oxidative status of the organism.
Brazilian Journal of Medical and Biological Research 02/2004; 37(2):185-92. · 1.14 Impact Factor