Biomedical subjects

D O Souza

Publications and source records attributed to D O Souza.

At least 19 recordsLinked to original sources

PubMed2006

Methotrexate induces seizure and decreases glutamate uptake in brain slices: prevention by ionotropic glutamate receptors antagonists and adenosine.

Methotrexate (MTX)-induced neurotoxicity may occur after intrathecal or systemic administration at low, intermediate and high doses for the treatment of malignant or inflammatory diseases. The mechanisms of MTX neurotoxicity are not totally understood, and appear to be multifactorial. In this study we characterized a model of MTX-induced seizures in mice to evaluate the convulsive and toxic MTX properties. Additionally, the effect of MTX-induced seizures on the activity of glutamate transporters, as well as the anticonvulsant role of MK-801, DNQX and adenosine on glutamate uptake in brain slices was investigated . MTX induced tonic-clonic seizures in approximately 95% of animals and pre-treatment with MK-801, DNQX and adenosine prevented seizure in 80%, 62% and 50% of animals, respectively. Moreover, MTX leads 59% of mice to death, which was prevented in 100% and 94% when animals received MK-801 and DNQX, respectively. Glutamate uptake decreased by 20% to 30% in cortical slices after MTX-induced seizures. Interestingly, when seizures were prevented by MK-801, DNQX or adenosine, glutamate uptake activity remained at the same level as the control group. Thus, our results demonstrate the involvement of the glutamatergic system in MTX-induced seizures.

Adenosine↗

PubMed2006

Raised serum S100B protein levels in neuropsychiatric lupus.

OBJECTIVE: To test serum S100B protein levels in patients with and without neuropsychiatric systemic lupus erythematosus (NPSLE) and controls. METHODS: 87 patients with SLE, 23 with and 64 without neuropsychiatric involvement, and 25 control subjects were prospectively evaluated. NPSLE diagnosis was made according to the American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Serum S100B protein levels were determined with a luminescence immunoassay. Statistical analysis was performed using Mann-Whitney and Kruskal-Wallis tests. RESULTS: Among the patients with NPSLE, 9 presented psychosis; 4, cranial neuropathy; 3, cerebrovascular disease; 1, seizures; 1, chorea; 1, peripheral polyneuropathy; 1, multiplex mononeuropathy; 3, dementia. Serum concentrations of S100B protein were significantly higher in patients with NPSLE (median 0.164 ng/ml, interquartile range 0.113-0.332) than in non-NPSLE patients (0.062 ng/ml, 0.026-0.109) and controls (0.088 ng/ml, 0.013-0.124) (p<0.001). Patients with anti-dsDNA antibodies had higher S100B protein levels (p = 0.001). No significant associations were found of lupus activity (among non-NPSLE cases), antiphospholipid antibodies, and reduced complement levels with S100B concentration. CONCLUSIONS: Serum S100B protein level is raised in NPSLE, reflecting continuing neurological damage. The association of anti-dsDNA antibodies with higher S100B protein concentration deserves further study.

Adult↗

PubMed2005

Ebselen protects glutamate uptake inhibition caused by methyl mercury but does not by Hg2+.

Alterations of the neurotransmitter release systems in CNS have been reported in a variety of neuropathological processes associated with heavy metal toxicity. Neurotoxic effects of mercurials were investigated in vitro in cerebral cortex slices from young rats. The present study indicates that: (i) the environmental contaminants methylmercury (MeHg) and mercuric chloride (Hg2+) (50 microM) inhibited the glutamate net uptake from the cerebral cortex of 17-day-old rats; (ii) ebselen (10 microM) reverted the MeHg-induced inhibition of glutamate net uptake but did not protect the inhibition caused by Hg2+. At same time, we investigated another diorganochalcogenide, diphenyl diselenide (PhSe)2 and it was observed that this compound did not revert the action of MeHg or Hg2+; (iii) in addition, we observed that exposure of slices to 50 microM MeHg and Hg2+ for 30 min followed by Trypan blue exclusion assay resulted in 58.5 and 67.5% of staining cells, respectively, indicating a decrease in cell viability. Ebselen protected slices from the deleterious effects of MeHg, but not of Hg2+ on cell viability. Conversely, ebselen did not modify the reduction of MTT caused by MeHg and Hg2+; (iv) the protective effect of ebselen on MeHg-induced inhibition of glutamate net uptake seems to be related to its ability in maintaining cell viability.

Animals↗

PubMed2005

Hematological changes in rats chronically exposed to oral aluminum.

This study was aimed to investigate the effects of the long-term oral exposure to aluminum sulfate on hematological parameters in rats. For this purpose, 24 adult female Wistar rats were divided in three groups with 8 animals each (control, citrate, and citrate plus aluminum groups). Rats from control and citrate groups had free access to tap water and to a sodium citrate solution (35 mM), respectively. Rats from citrate plus aluminum group received, as unique source of liquid, an aluminum sulfate solution (30 mM) diluted in the above-mentioned sodium citrate solution, ad libitum. After the treatment period (18 months), aluminum-exposed rats showed a significant decrease in the number of red blood cells, blood hemoglobin concentration and hematocrit when compared to rats from the control group. Serum iron levels were also significantly lower in citrate plus aluminum group, whereas total iron binding capacity did not change after citrate plus aluminum exposure. Erythrocyte thiobarbituric acid-reactive substances (TBARS) and nonprotein thiols (NPSH) levels, erythrocyte osmotic fragility and hepatic delta-aminolevulinic acid dehydratase (delta-ALA-D) activity did not change after treatment with citrate plus aluminum. Conversely, aluminum exposure increased delta-ALA-D activity in bone marrow. The present results indicate that long-term oral exposure to low doses of aluminum sulfate promotes alterations on erythrocyte parameters in rats, probably as a consequence of alterations in the iron status. In addition, although the details of the underlying mechanism remain unclear, our study reports, for the first time, a stimulatory effect of chronic aluminum exposure on bone marrow delta-ALA-D activity.

Administration, Oral↗

PubMed2005

Hypoxic-ischemic insult decreases glutamate uptake by hippocampal slices from neonatal rats: prevention by guanosine.

Brain injury secondary to hypoxic-ischemic disease is the predominant form of damage encountered in the perinatal period. The impact of neonatal hypoxia-ischemia (HI) in 7-day-old pups on the high-affinity [3H] glutamate uptake into hippocampal slices at different times after insult was examined. Immediately following, and 1 day after the insult there was no effect. But at 3 to 5 days after the HI insult, glutamate uptake into the hippocampus was markedly reduced; however, after 30 or 60 days the glutamate uptake into hippocampal slices returned to control levels. Also, this study demonstrated the effect of the nucleoside guanosine (Guo) on the [3H] glutamate uptake in neonatal HI injury, maintaining the [3H] glutamate uptake at control levels when injected before and after insult HI. We conclude that neonatal HI influences glutamate uptake a few days following insult, and that guanosine prevents this action.

Analysis of Variance↗

PubMed2005

Effect of subchronic caffeine treatment on MK-801-induced changes in locomotion, cognition and ataxia in mice.

N-Methyl-D-aspartate (NMDA) receptor antagonists cause hyperlocomotion and cognitive deficits in rodents, and caffeine-tolerant mice show diminished locomotor response to NMDA receptor antagonists. The aim of this study was to evaluate the effect of subchronic caffeine treatment on MK-801-induced hyperlocomotion, ataxia and cognitive deficits, as well as amphetamine-induced hyperlocomotion in mice. Mice were treated subchronically with caffeine (0, 0.1, 0.3 and 1 mg/ml and 1, 3 and 7 days) and evaluated for locomotor activity, working memory (delayed alternation test), long-term memory (inhibitory avoidance task) and ataxia. Hyperlocomotion induced by MK-801 (0.25 mg/kg i.p.) was diminished after 3 days and almost abolished after 7 days of caffeine treatment at the 1 mg/ml dose, and this effect was also dose-dependent. Ataxia induced by 0.5 mg/kg MK-801 was not affected by caffeine treatment, but a short-lived hyperlocomotor effect was observed. Performance deficit in the inhibitory avoidance task induced by MK-801 (0.01 mg/kg) was prevented in mice treated with caffeine for 7 days at 1 mg/ml, and perseverative errors in the T-maze by MK-801 (0.4 mg/kg) were attenuated. The locomotor effect of amphetamine (5 mg/kg) was unaffected by subchronic caffeine treatment. The findings that hyperlocomotion and cognitive effects induced by MK-801 can be specifically influenced by reduced adenosinergic activity agree with a model of adenosine hypofunction in schizophrenia, since NMDA receptor antagonists are pharmacological models for this disorder.

Adenosine↗

PubMed2004

Maternal milk as methylmercury source for suckling mice: neurotoxic effects involved with the cerebellar glutamatergic system.

Methylmercury (MeHg) is a highly neurotoxic compound and several studies have reported intoxication signs in children whose mothers were exposed to this environmental toxicant. Although it is well established that the in utero exposure to MeHg causes neurological deficits in animals and humans, there is no evidence of the exclusive contribution of lactational exposure to MeHg as a possible cause of neurotoxicity in the offspring. In this study, we investigated the exclusive contribution of MeHg exposure through maternal milk on biochemical parameters related to the glutamatergic homeostasis (glutamate uptake by slices) and to the oxidative stress (total and nonprotein sulfhydryl groups, nonprotein hydroperoxides, glutathione peroxidase and catalase activities) in the cerebellum of suckling mice (Swiss albino). The same parameters were also evaluated in the cerebellum of mothers. Our results showed, for the first time, that lactational exposure to MeHg caused a high percent of inhibition (50%) on glutamate uptake by cerebellar slices in pups. Contrarily, this effect was not observed in mothers, which were submitted to a direct oral exposure to MeHg (15 mg/l in drinking water). In addition, behavioral/functional changes were observed in the weaning mice exposed to MeHg. It was observed an increase in the levels of nonprotein hydroperoxides in cerebellum, and this increase was negatively correlated to the glutamate uptake by cerebellar slices. This study indicates that (1) the exposure of lactating mice to MeHg causes inhibition of the glutamate uptake by cerebellar slices in the offspring; (2) this inhibitory effect seems to be related to increased levels of hydroperoxide.

Animals↗

PubMed2004

Additive pro-oxidative effects of methylmercury and ebselen in liver from suckling rat pups.

Oxidative stress has been pointed as an important molecular mechanism for liver injury in methylmercury (MeHg) poisoning. Ebselen, a seleno-organic compound that possesses anti-oxidant properties, is a useful therapeutic agent used in clinical situations involving oxidative stress. Here, we examined the possible in vivo protective effect of ebselen against the pro-oxidative effects of MeHg in liver from suckling rat pups. The effects of MeHg exposure (subcutaneous injections of methylmercury chloride: 2 mg/kg) on the hepatic levels of thiobarbituric acid reactive substances (TBARS) and non-ptotein thiols (NPSH), and on liver glutathione peroxidase (GSHPx) activity, as well as the possible antagonist effect of ebselen (10 mg/kg; subcutaneously) against MeHg effects, were evaluated during the post-natal period. In addition, the possible in vitro interaction between ebselen, glutathione (GSH) and MeHg was investigated by light/UV spectroscopy, with particular attention to the formation of complexes involving ebselen selenol intermediate and MeHg. After in vivo exposure, MeHg and ebselen alone increased hepatic TBARS levels. Moreover, simultaneous treatment with both compounds caused a higher increase in hepatic TBARS levels when compared to the treatments with individual compounds. Liver NPSH decreased after treatments with MeHg and ebselen alone. A significant negative correlation between hepatic TBARS and NPSH was observed. MeHg alone decreased liver GSHPx activity and ebselen, which did not affect this variable per se, reverted this inhibitory effect of MeHg. Light/UV spectroscopy showed that ebselen and GSH form a chemical intermediate that regenerates ebselen after MeHg addition. The presented results show that ebselen abolished the MeHg-induced inhibition on liver GSHPx activity, but did not prevent the oxidative effects of MeHg on liver lipids and NPSH. MeHg affects the in vitro interaction between ebselen and GSH and this phenomenon seems to be responsible for its inhibitory effect toward thiol-peroxidase activity. Additionally, ebselen presents pro-oxidative effects on rat liver, pointing to thiol depletion as a molecular mechanism related to ebselen-induced hepatotoxicity.

Animals↗

PubMed2004

Two-dimensional polyacrylamide gel electrophoresis of bovine seminal plasma proteins and their relation with semen freezability.

The objective of this study was to evaluate the low weight (10-30 kDa) protein profile of bovine seminal plasma using two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and to determine if any of these proteins was associated with semen freezability. Seminal plasma was collected from 16 bulls of high or low semen freezability. Twelve protein spots were identified from the 2D gel (15%); six of these were present in all samples. Of the 12 proteins found, three spots, present in all samples, 3 (15-16 kDa), 5 (16-17 kDa), and 7 (10-12 kDa) had nonsignificant variation among bulls, regardless of their freezability classification. Four proteins were more abundant (P<0.05) in seminal plasma samples collected from bulls with high semen freezability than in samples of bulls with low semen freezability: the spots 3 (15-16 kDa, pI 4.7-5.2), 7 (11-12 kDa, pI 4.8-4.9), 11 (13-14 kDa, pI 4.0-4.5), and 23 (20-22 kDa, pI 4.8-5.2). On the other hand, spot 25 (25-26 kDa, pI 6.0-6.5) was more abundant (P<0.05) on seminal plasma samples from bulls with low semen freezability. The N-terminus sequence of protein 7 was identical to the acidic seminal fluid protein (aSFP). Protein 23 (after trypsin digestion) had structural similarity to bovine clusterin. We concluded that there were differences in the seminal plasma protein profile from bulls with low and high semen freezability; aSFP, clusterin, proteins 3 and 11 may be used as semen freezability markers; and protein 25 was related to low semen freezability.

Amino Acid Sequence↗

PubMed2004

Dehydroepiandrosterone increases synaptosomal glutamate release and improves the performance in inhibitory avoidance task.

Dehydroepiandrosterone (DHEA) exerts multiple effects in the rodent central nervous system (CNS), mediated through its nongenomic actions on several neurotransmitter systems, increasing neuronal excitability, modulating neuronal plasticity and presenting neuroprotective properties. It has been demonstrated that DHEA is a potent modulator of GABA(A), NMDA and Sigma receptors. In the present study, we investigated the effect of DHEA on (i) basal- and K(+)-stimulated l-[(3)H]glutamate release from synaptosomes (both in vitro and ex vivo), (ii) synaptosomal l-[(3)H]glutamate uptake (in vitro), and (iii) an inhibitory avoidance task (in vivo). The results indicated that DHEA in vitro increased glutamate release by 57%, and its intracerebroventricular infusion increased the basal-[(3)H]glutamate release by 15%. After 30 min of intraperitoneal administration, DHEA levels in the serum or CSF increased 33 and 21 times, respectively. Additionally, DHEA, intraperitoneally administrated 30 min before training, improved memory for inhibitory avoidance task. Concluding, DHEA could improve memory on an inhibitory avoidance task, perhaps due to its ability to physiologically strength the glutamatergic tonus by increasing glutamate release.

Animals↗

PubMed2004

3-hydroxyglutaric acid enhances glutamate uptake into astrocytes from cerebral cortex of young rats.

A predominantly neurological presentation is common in patients with glutaric acidemia type I (GA-I). 3-hydroxyglutaric acid (3-OHGA), which accumulates in affected patients, has recently been demonstrated to play a central role in the neuropathogenesis of this disease. In the present study, we investigated the in vitro effects of 3-OHGA at concentrations ranging from 10 to 1000 microM on various parameters of the glutamatergic system, such as the basal and potassium-induced release of [3H]glutamate by synaptosomes, as well as on Na+-dependent [3H]glutamate uptake by synaptosomes and astrocytes and Na+-independent [3H]glutamate uptake by synaptic vesicles from cerebral cortex of 30-day-old Wistar rats. First, we observed that exposure of cultured astrocytes to 3-OHGA for 20 h did not reduce their viability. Furthermore, 3-OHGA significantly increased Na+-dependent [3H]glutamate uptake by astrocytes by up to 80% in a dose-dependent manner at doses as low as 30 microM. This effect was not dependent on the presence of the metabolite during the uptake assay, since it occurred even when 3-OHGA was withdrawn from the medium after cultured cells had been exposed to the acid for approximately 1 h. All other parameters investigated were not influenced by this organic acid, indicating a selective action of 3-OHGA on astrocyte transporters. Although the exact mechanisms involved in 3-OHGA-stimulatory effect on astrocyte glutamate uptake are unknown, the present findings contribute to the understanding of the pathophysiology of GA-I, suggesting that astrocytes may protect neurons against excitotoxic damage caused by 3-OHGA by increasing glutamate uptake and therefore reducing the concentration of this excitatory neurotransmitter in the synaptic cleft.

Animals↗

PubMed2004

Modulation of glutamatergic and GABAergic neurotransmission in glutaryl-CoA dehydrogenase deficiency.

Although the precise mechanisms underlying the CNS degeneration of patients with glutaryl-CoA dehydrogenase (GCDH) deficiency are still the subject of intense debate, many studies have highlighted that excitotoxicity plays a fundamental role in the neuropathology of this disease, particularly involving the N-methyl-D-aspartate receptor subtype of ionotropic glutamate receptors. Modulation of the glutamatergic system by these compounds involves an inhibition of glutamate uptake into synaptosomes and synaptic vesicles, and a decrease in glutamate binding. Furthermore, glutaric and 3-hydroxyglutaric acids inhibit glutamate decarboxylase, the key enzyme of GABA synthesis, and striatal GABAergic medium-spiny neurons are highly vulnerable to 3-hydroxyglutaric acid-induced neurotoxicity. In conclusion, glutaric acid and 3-hydroxyglutaric acid induce an imbalance in glutamatergic and GABAergic neurotransmission.

Amino Acid Metabolism, Inborn Errors↗

PubMed2003

Methylmercury increases glutamate release from brain synaptosomes and glutamate uptake by cortical slices from suckling rat pups: modulatory effect of ebselen.

During the early postnatal period the brain is extremely sensitive to external agents. Here, we examined the effect of subcutaneous injections of methylmercury (MeHg; 2 mg/kg) during the suckling period (postnatal days [PND] 3-10, 3-17, or 3-24) on glutamate release from brain synaptosomal preparations and on glutamate uptake by brain cortical slices of rat pups. The possible antagonist effect of ebselen against MeHg effect was also examined at PND 24. MeHg increased the basal (but not K+-stimulated) glutamate release and glutamate uptake at PND 24. A strong tendency of increase in the basal glutamate release from synaptosomes (p= 0.088) was observed at PND 17. Ebselen, which did not affect glutamate release and uptake per se, prevented both effects of MeHg. This study indicates that (1) the effect of MeHg on glutamate release could be involved in its toxicity; (2) the increase in the glutamate uptake could represent a pathophysiological response to MeHg-induced glutamate release; (3) the inhibitory effect of ebselen on MeHg-induced glutamate release could be related to its reported neuroprotective effects.

Aging↗

PubMed2003

Mechanisms of the inhibitory effects of selenium and mercury on the activity of delta-aminolevulinate dehydratase from mouse liver, kidney and brain.

Mercury is known to interact with selenite and when the two are co-administered, one reduces the toxicity of the other. The main goal of this study was to investigate the simultaneous in vitro effects of sodium selenite (Se(4+)) and mercuric chloride (Hg(2+)) on the activity of hepatic, renal and cerebral delta-aminolevulinate dehydratase (delta-ALA-D) of adult male mice (Swiss albino). Hg(2+) inhibited delta-ALA-D from tissue supernatants and the IC(50) values for hepatic, renal and cerebral enzyme inhibition were 38+/-4.2, 67.5+/-4.3 and 46.2+/-3.7 microM, respectively. Se(4+) displayed a higher inhibitory action toward delta-ALA-D activity than Hg(2+). Simultaneous addition of Se(4+) and Hg(2+) to the delta-ALA-D assay increased the inhibition of the enzyme. Se(4+) and Hg(2+) oxidized total -SH groups from hepatic, renal and cerebral supernatants, although the effect of Se(4+) decreased in the presence of increasing concentrations of Hg(2+). The oxidation of -SH groups from a dithiol (DTT), a monothiol glutathione (GSH) and a protein (albumin) increased in the presence of Hg(2+). Only DTT was oxidized by Se(4+) and the oxidation decreased in the presence of Hg(2+), suggesting the formation of a chemical complex. This complex did not inhibit delta-ALA-D. These results suggest a similar inhibitory mechanism of Se(4+) and Hg(2+) on delta-ALA-D in which oxidation of sulfhydryl groups located at the active site of the enzyme is an essential step. Furthermore, decreasing oxidative effects of selenite on sulfhydryl groups from DTT in the presence of mercury are believed to occur as the result of the formation of an inactive ternary complex of the thiol-Hg-Se type, which does not inhibit delta-ALA-D.

Animals↗

PubMed2003

Interictal serum S100B levels in chronic neurocysticercosis and idiopathic epilepsy.

OBJECTIVE: To assess whether serum S100B levels could reflect a glial response in patients with epilepsy secondary to neurocysticercosis (NCC) and with idiopathic epilepsy. SUBJECTS AND METHODS: Serum S100B levels were measured using an immunoluminometric assay in 20 patients with focal epilepsy related to chronic NCC (NCC group), and 19 patients with focal epilepsy (EPI group), matched by epidemiological and clinical data. Epileptic patients were compared with 20 healthy controls (CON group) matched by age and sex. RESULTS: No difference was observed in S100B levels among NCC, EPI and CON groups (P>0.39). Serum S100B levels were not affected by antiepileptic drugs, frequency and type of seizures. Preliminarily, significantly higher levels of S100B were observed in patients with bilateral electroencephalographic (EEG) findings than in patients with unilateral and normal EEG findings (P<0.05). CONCLUSION: Serum S100B is normal in patients with focal epilepsy related or not to chronic NCC.

Acute Disease↗

PubMed2002

Guanine based purines inhibit [(3)H]glutamate and [(3)H]AMPA binding at postsynaptic densities from cerebral cortex of rats.

Extracellular guanine-based purines (GBPs) have been implicated in neuroprotective effects against glutamate toxicity by modulating the glutamatergic system through mechanisms without the involvement of G proteins. Accordingly, GBPs have been shown to inhibit the binding of glutamate and its analogs in different brain membrane preparations. However, brain membrane preparations used for these studies are comprised of both post- and pre-neuronal and glial synaptic components. In this study we investigated the ability of GBPs to displaced glutamate and AMPA binding at postsynaptic densities (PSDs). PSDs are markedly prominent in glutamatergic synapses and retains the native apposition of membrane components and post synaptic receptors. The PSD fraction was prepared from cerebral cortex of Wistar rats and it was characterized as PSDs by electron microscopy and by an enrichment of PSD-95, a protein marker of PSDs (90% of immunodetection). Moreover, we detected an enrichment of glutamate receptors subunits that including NR1 subunit of NMDA receptors and GluR1 subunit of AMPA receptors. GppNp (poor hydrolyzable GTP analog) and GMP displaced 40 and 36% of glutamate binding, respectively, and guanosine only 23%. AMPA binding was not affected by guanosine and was inhibited 21 and 25% by GppNp and GMP, respectively. Hence, this study demonstrates that guanine based purines inhibited glutamate and AMPA binding at postsynaptic membrane preparations, contributing for a better understanding of the mechanisms by which GBPs antagonize glutamatergic neurotoxicicity, e.g. the possible involvement of glutamatergic postsynaptic receptors in their neuroprotective roles.

Animals↗

PubMed2002

Elevated serum S100B protein in drug-free bipolar patients during first manic episode: a pilot study.

S100B protein is a calcium-binding protein mostly derived from glial cells, which exerts trophic or toxic effects on neural cells depending on its concentration. Since serum S100B levels has been tested as a potential marker in neuropsychiatric disorders, and structural abnormalities on glial cells have been recently associated with bipolar disorder patients, we conducted this preliminary study to examine if S100B serum levels are altered during first manic episode. We quantitated S100B in serum of 40 subjects (20 unmedicated patients during manic episode and 20 healthy matched controls). The mean+/-S.D. values for S100B for bipolar subjects were 0.065+/-0.068 microg/l and 0.018+/-0.029 microg/l for healthy controls. Increased levels of S100B in bipolar mania was statistically significant (Wilcoxon signed ranks test, Z=-2.45, P=0.01). These preliminary findings suggest that mania may increase the levels of S100B in serum of bipolar disorder patients, which could be related to adaptative neural mechanisms in bipolar mania.

Adult↗

PubMed2002

Purinergic dysfunction in mania: an integrative model.

The purinergic system, which includes the anticonvulsant and antikindling neuromodulator adenosine and the neurotransmitter ATP, modulates second messenger systems, neurotransmitters, energy metabolism and different behaviors, such as sleep, motor activity, cognition, memory, aggressive behavior and social interaction. At the same time, mania is characterized by similar behavioral changes and a molecular basis to explain the pathological activation observed during manic episodes has been also associated with second messenger systems dysfunction and kindling. This hypothesis put forward an integrative model of neuronal communication, associating a reduced adenosinergic activity, mostly at A1 receptors, with the complex network of changes on neurotransmitters pathways related to manic behavior.

Adenosine↗