Publications by authors named "Ana Paula Ardais"

23 Publications

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Brief cognitive behavioral therapy in pregnant women at risk of postpartum depression: Pre-post therapy study in a city in southern Brazil.

J Affect Disord 2021 Jul 30;290:15-22. Epub 2021 Apr 30.

Catholic University of Pelotas, Brazil; PQ CNPq, Brazil.

Background: Postpartum depression (PPD) affects a high number of women, often the first manifestation of a mood disorder that will occur later in life, bringing serious consequences for the patient and her offspring. Depression today is the leading cause of disability worldwide. The aim of this study was to evaluate the effectiveness of a preventive cognitive behavioral therapy (CBT) for PPD.

Methods: Pre-post therapy study, as part of a population-based cohort study. Pregnant women without a diagnosis of depression participated, who were divided into two groups: risk of depression (CBT) and a control group (without therapy). The preventive therapy consisted of six sessions of CBT, administered weekly. The Outcome Questionnaire (OQ-45) was used in all sessions. The Mini International Neuropsychiatric Interview and Beck Depression Inventory-II were used on three occasions. The final statistical analyses were performed by Poisson regression.

Results: The prevalence of PPD in the risk group was 5.5% and in the control group 2.2%, with no difference between the groups (PR 1.66 95% CI 0.44-6.18). The OQ-45 averages gradually reduced during the therapy sessions, indicating therapeutic progress. Schooling was an associated factor, both with the manifestation of PPD and with the greater effectiveness of the therapy.

Limitations: Rate of 40.5% refusal to preventive treatment and absence of a group with similar characteristics in another therapy model.

Conclusions: Brief cognitive behavioral therapy applied by mental health professionals with basic training was effective in preventing the manifestation of PPD.
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http://dx.doi.org/10.1016/j.jad.2021.04.031DOI Listing
July 2021

Generalized Anxiety Disorder, Depressive Symptoms and the Occurrence of Stressors Events in a Probabilistic Sample of Pregnant Women.

Psychiatr Q 2021 03;92(1):123-133

Postgraduate Program in Health and Behavior, Catholic University of Pelotas (UCPel), Gonçalves Chaves, 377 - 411 C - 96015-560, Pelotas, RS, Brazil.

The aim of the study is to verify the association between GAD, the severity of depressive symptoms and stressors in pregnant women between the first and second trimester. Cross-sectional study, part of a cohort that followed 980 women during the gestational period of a city in southern Brazil. We performed bivariate analysis using the t-test and chi-square. The variables that presented p ≤ 0.20 were taken for multivariate analysis, through logistic regression, in order to control possible confounding factors. The Mini International Neuropsychiatric Interview Plus was used to evaluate GAD, the severity of depressive symptoms was investigated through the Beck Inventory of Depression II, and stress events according to the Social Readjustment Assessment Scale of Holmes e Rahe. The sample consisted of 980 women. Women with mild depression symptoms had 9.8 (IC95% 4.6;21.0) times more GAD, those with moderate symptoms had 27.5 (IC95% 12.5;60.0) times more GAD, and those with severe symptoms had 52.9 (IC95% 19.1;146.5) times more GAD when compared to pregnant women with no symptoms or minimal symptoms. Regarding the stressful events, the pregnant women who presented GAD had an increase of 1.0 (IC95% 1.0;1.1) point in the mean of occurrence of stressor events when compared to those without GAD. These findings highlight the need for prevention strategies and interventions to promote maternal mental health, which benefit the development of infants in the long term.
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http://dx.doi.org/10.1007/s11126-020-09763-0DOI Listing
March 2021

Temperament traits moderate the relationship between Childhood Trauma and Interleukin 1β profile in young adults.

Psychoneuroendocrinology 2020 06 16;116:104671. Epub 2020 Apr 16.

Programa de Pós-Graduação em Saúde e Comportamento, Universidade Católica de Pelotas, Pelotas, Brazil. Electronic address:

Early life stressors, such as childhood trauma, have been associated to alterations in immune response that can last until adulthood. In this context, interleukin 1β (IL-1β) emerges as a pro-inflammatory cytokine with a pivotal role. Also, considering the temperament differences in stress susceptibility, and even immune dysfunction, studies investigating the complex interaction between these factors are scarce. Thus, the aim of the present study was to evaluate the moderating role of temperament traits in the relationship between childhood trauma and serum IL-1β levels. This cross-sectional study consisted of 325 individuals, men and women, aged 18-35, enrolled from a population-based study in the city of Pelotas, Southern Brazil. Our main results indicate that higher serum levels of IL-1β were associated with trauma severity (p < 0.01), and the variance of anger could explain 29% of IL-1β increase in individuals who suffered severe trauma (p < 0.05). The effect of anger was considerably stronger in men than in women (46% and 25%, respectively). Moreover, the variance of sensitivity also explained 15% of IL-1β increase (p < 0.05) as well as the variance of volition explained 11% of IL-1β decrease (p < 0.05) in individuals who suffered severe trauma in the general population. Our results indicate that emotional individual differences can moderate the impact of childhood trauma on low-grade inflammation in young adults.
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http://dx.doi.org/10.1016/j.psyneuen.2020.104671DOI Listing
June 2020

The role of CACNA1C gene and childhood trauma interaction on bipolar disorder.

Prog Neuropsychopharmacol Biol Psychiatry 2020 07 10;101:109915. Epub 2020 Mar 10.

Laboratory of Clinical Neuroscience, Post-graduation Program in Health and Behavior, Catholic University of Pelotas, Pelotas, Rio Grande do Sul, Brazil. Electronic address:

Studies on gene x environment interaction (GxE) have provided vital information for uncovering the origins of complex diseases. When considering the etiology of bipolar disorder (BD), the role of such interactions is unknown. Here, we tested whether trauma during childhood could modify the effect of two polymorphisms in the CACNA1C gene (rs1006737 and rs4765913) in terms of susceptibility to BD. The study enrolled 878 Caucasian young adults in a cross-sectional population-based survey. BD diagnosis was performed using a clinical interview MINI 5.0, and trauma was assessed with the childhood trauma questionnaire (CTQ). Binary logistic regression models were employed to test the main effects of polymorphisms, haplotypes, and GxE interactions using sex as a confounder. We did not observe an association between the polymorphisms and diagnosis of BD. However, we noted that childhood trauma modified the effect of the rs4765913 polymorphism (p = .018) and the AA haplotype (rs1006737 - rs4765913) (p = .018) on BD susceptibility. A allele carriers of the rs4765913 polymorphism or the AA haplotype exposed to childhood trauma are more likely to develop BD compared to the individuals without a genetic risk. Thus, this study showed that the risk of developing BD in individuals exposed to childhood trauma was influenced by the individual's genetic background, varying according to the CACNA1C genotypes.
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http://dx.doi.org/10.1016/j.pnpbp.2020.109915DOI Listing
July 2020

Inosine prevents hyperlocomotion in a ketamine-induced model of mania in rats.

Brain Res 2020 04 8;1733:146721. Epub 2020 Feb 8.

Postgraduate Program in Health and Behavior, Catholic University of Pelotas, Rio Grande do Sul, Brazil. Electronic address:

Bipolar Disorder is a disorder characterized by alternating episodes of depression, mania or hypomania, or even mixed episodes. The treatment consists on the use of mood stabilizers, which imply serious adverse effects. Therefore, it is necessary to identify new therapeutic targets to prevent or avoid new episodes. Evidence shows that individuals in manic episodes present a purinergic system dysfunction. In this scenario, inosine is a purine nucleoside known to act as an agonist of A and A adenosine receptors. Thus, we aimed to elucidate the preventive effect of inosine on locomotor activity, changes in purine levels, and adenosine receptors density in a ketamine-induced model of mania in rats. Inosine pretreatment (25 mg/kg, oral route) prevented the hyperlocomotion induced by ketamine (25 mg/kg, intraperitoneal route) in the open-field test; however, there was no difference in hippocampal density of A and A receptors, where ketamine, as well as inosine, were not able to promote changes in immunocontent of the adenosine receptors. Likewise, no effects of inosine pretreatments or ketamine treatment were observed for purine and metabolic residue levels evaluated. In this sense, we suggest further investigation of signaling pathways involving purinergic receptors, using pharmacological strategies to better elucidate the action mechanisms of inosine on bipolar disorder. Despite the limitations, inosine administration could be a promising candidate for bipolar disorder treatment, especially by attenuating maniac phase symptoms, once it was able to prevent the hyperlocomotion induced by ketamine in rats.
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http://dx.doi.org/10.1016/j.brainres.2020.146721DOI Listing
April 2020

Leptin polymorphism rs3828942: risk for anxiety disorders?

Eur Arch Psychiatry Clin Neurosci 2019 Aug 16. Epub 2019 Aug 16.

Institute of Health Sciences, Department of Health and Behavior, Catholic University of Pelotas - UCPel, Rua Gonçalves Chaves 373, Sala 324, Pelotas, RS, 96010-280, Brazil.

Leptin is an anorexigenic hormone well recognized by its role in mediating energy homeostasis. Recently, leptin has been associated with psychiatric disorders and interestingly, leptin treatment has shown antidepressant and anxiolytic effects. We examined the association of leptin levels and leptin (LEP) gene rs3828942 polymorphism with anxiety disorders considering sex differences. A cross-sectional population-based study, including 1067 young adults, of whom 291 presented anxiety disorders diagnosed by the Mini International Neuropsychiatric Interview (MINI 5.0). The rs3828942 polymorphism was genotyped by real-time PCR and ELISA measured leptin levels. Leptin levels were not associated with anxiety disorders after adjusting for sex and body mass index (BMI) [ß = - 0.009 (- 0.090-0.072); p = 0.832]. The distribution of rs3828942 genotypes was not associated with anxiety disorders. However, in a sex-stratified sample, the A-allele of rs3828942 polymorphism was associated with risk for GAD in women even when adjusting for confounding variables [OR = 1.87 (1.17-2.98); p = 0.008]. In a subsample of 202 individuals with GAD and control matched by sex and BMI, results suggest an interaction between genotypes and GAD diagnosis based on leptin levels only in the male group [F (1, 54) = 6.464; p = 0.0139]. Leptin is suggested to be related with the neurobiology of anxiety disorders in a sex-dependent manner since women carrying the A-allele of LEP rs3828942 present a higher risk for GAD, while leptin levels seem to be lower in men with GAD carrying A-allele. Studies on the relationship between leptin polymorphisms and levels are scarce and, therefore, further research is necessary.
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http://dx.doi.org/10.1007/s00406-019-01051-8DOI Listing
August 2019

Impact of genetic variations in ADORA2A gene on depression and symptoms: a cross-sectional population-based study.

Purinergic Signal 2019 03 3;15(1):37-44. Epub 2018 Dec 3.

Department of Life and Health Sciences, Catholic University of Pelotas, Pelotas, Rio Grande do Sul, Brazil.

Genetic variants involved in adenosine metabolism and its receptors were associated with increased risk for psychiatric disorders, including anxiety, depression, and schizophrenia. Here, we examined an association between a single nucleotide polymorphism in A receptor gene (ADORA2A, rs2298383 SNP) with current depressive episode and symptom profile. A total of 1253 individuals from a cross-sectional population-based study were analyzed by the Mini International Neuropsychiatric Interview 5.0. Our data showed that the TT genotype of ADORA2A rs2298383 SNP was associated with reduced risk for depression when compared to the CC/CT genotypes (p = 0.020). This association remained significant after adjusting for confounding variables such as smoking, gender, socioeconomic class, and ethnicity (OR = 0.631 (95% CI 0.425-0.937); p = 0.022). Regarding the symptoms associated with depression, we evaluated the impact of the ADORA2A SNP in the occurrence of sad/discouraged mood, anhedonia, appetite changes, sleep disturbances, motion changes, energy loss, feelings of worthless or guilty, difficulty in concentrating, and presence of bad thoughts. Notably, the TT genotype was independently associated with reduced sleep disturbances (OR = 0.438 (95% CI 0.258-0.743); p = 0.002) and less difficulty in concentrating (OR = 0.534 (95% CI 0.316-0.901; p = 0.019). The cross-sectional design cannot evaluate the cause-effect relationship and did not evaluate the functional consequences of this polymorphism. Our data support an important role for ADORA2A rs2298383 SNP in clinical heterogeneity associated with depression. The presence of the TT genotype was associated with decrease risk for current depression and disturbances in sleep and attention, two of the most common symptoms associated with this disorder.
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http://dx.doi.org/10.1007/s11302-018-9635-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439088PMC
March 2019

Different effects of caffeine on behavioral neurophenotypes of two zebrafish populations.

Pharmacol Biochem Behav 2018 02 12;165:1-8. Epub 2017 Dec 12.

Laboratory of Experimental Neuropsychobiology, Department of Biochemistry and Molecular Biology, Natural and Exact Sciences Center, Federal University of Santa Maria, 1000 Roraima Avenue, Santa Maria, RS 97105-900, Brazil; Graduate Program in Biological Sciences: Toxicological Biochemistry, Federal University of Santa Maria, 1000 Roraima Avenue, Santa Maria, RS 97105-900, Brazil; The International Zebrafish Neuroscience Research Consortium (ZNRC), 309 Palmer Court, Slidell, LA 70458, USA. Electronic address:

Caffeine is a substance present in several foods and drinks of common western diet. Although high caffeine concentrations induce anxiogenic properties in various species, the influence of the different baselines of anxiety levels on caffeine-mediated responses is poorly understood. The short-fin wild-type (WT) and leopard (leo) zebrafish populations present significant behavioral differences, in which leo shows exacerbated anxiety-like responses. Since behavioral neurophenotyping may be easily assessed in adult zebrafish by associating temporal and spatial three-dimensional reconstructions of locomotion, we investigated the effects of caffeine on exploration and anxiety-like behavior of WT and leo zebrafish. Moreover, the whole-body cortisol content was assessed in the absence and presence of caffeine. For this purpose, animals were acutely exposed to caffeine (25, 50, 100 and 200mg/L) for 15min and further tested in the novel tank. Endpoint data and 3D reconstruction plots revealed that caffeine was anxiogenic in both WT and leo populations by altering vertical swimming, freezing, and erratic movements depending on the concentration. Prominent anxiogenic effects during habituation to novelty were observed in WT, suggesting a fundamental role of the phenotype in caffeine-mediated neurobehavioral responses. Although untreated leo showed higher baseline cortisol levels than control WT, caffeine increased whole-body cortisol in both populations. Moreover, caffeine induced aberrant swimming profiles in WT and leo following 200mg/L exposure, which could reflect nonspecific toxicity and/or seizure-like behaviors. Collectively, our novel findings show that caffeine effects in zebrafish differ in a population-dependent manner.
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http://dx.doi.org/10.1016/j.pbb.2017.12.002DOI Listing
February 2018

Sex differences in the effects of pre- and postnatal caffeine exposure on behavior and synaptic proteins in pubescent rats.

Prog Neuropsychopharmacol Biol Psychiatry 2018 Feb 19;81:416-425. Epub 2017 Aug 19.

Laboratório de Estudos sobre o Sistema Purinérgico, Universidade Federal Rio Grande do Sul, Instituto de Ciências Básicas da Saúde, Departamento de Bioquímica, 90035-003 Porto Alegre, RS, Brazil.

Few studies have addressed the effects of caffeine in the puberty and/or adolescence in a sex dependent manner. Considering that caffeine intake has increased in this population, we investigated the behavioral and synaptic proteins changes in pubescent male and female rats after maternal consumption of caffeine. Adult female Wistar rats started to receive water or caffeine (0.1 and 0.3g/L in drinking water; low and moderate dose, respectively) during the active cycle at weekdays, two weeks before mating. The treatment lasted up to weaning and the offspring received caffeine until the onset of puberty (30-34days old). Behavioral tasks were performed to evaluate locomotor activity (open field task), anxious-like behavior (elevated plus maze task) and recognition memory (object recognition task) and synaptic proteins levels (proBDNF, BDNF, GFAP and SNAP-25) were verified in the hippocampus and cerebral cortex. While hyperlocomotion was observed in both sexes after caffeine treatment, anxiety-related behavior was attenuated by caffeine (0.3g/L) only in females. While moderate caffeine worsened recognition memory in females, an improvement in the long-term memory was observed in male rats for both doses. Coincident with memory improvement in males, caffeine increased pro- and BDNF in the hippocampus and cortex. Females presented increased proBDNF levels in both brain regions, with no effects of caffeine. While GFAP was not altered, moderate caffeine intake increased SNAP-25 in the cortex of female rats. Our findings revealed that caffeine promoted cognitive benefits in males associated with increased BDNF levels, while females showed less anxiety. Our findings revealed that caffeine promotes distinct behavioral outcomes and alterations in synaptic proteins during brain development in a sex dependent manner.
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http://dx.doi.org/10.1016/j.pnpbp.2017.08.015DOI Listing
February 2018

Caffeine Reverts Memory But Not Mood Impairment in a Depression-Prone Mouse Strain with Up-Regulated Adenosine A Receptor in Hippocampal Glutamate Synapses.

Mol Neurobiol 2017 03 9;54(2):1552-1563. Epub 2016 Feb 9.

CNC-Center for Neurosciences and Cell Biology, University of Coimbra, 3004-517, Coimbra, Portugal.

Caffeine prophylactically prevents mood and memory impairments through adenosine A receptor (AR) antagonism. AR antagonists also therapeutically revert mood and memory impairments, but it is not known if caffeine is also therapeutically or only prophylactically effective. Since depression is accompanied by mood and memory alterations, we now explored if chronic (4 weeks) caffeine consumption (0.3 g/L) reverts mood and memory impairment in helpless mice (HM, 12 weeks old), a bred-based model of depression. HM displayed higher immobility in the tail suspension and forced swimming tests, greater anxiety in the elevated plus maze, and poorer memory performance (modified Y-maze and object recognition). HM also had reduced density of synaptic (synaptophysin, SNAP-25), namely, glutamatergic (vGluT1; -22 ± 7 %) and GABAergic (vGAT; -23 ± 8 %) markers in the hippocampus. HM displayed higher AR density (72 ± 6 %) in hippocampal synapses, an enhanced facilitation of hippocampal glutamate release by the AR agonist, CGS21680 (30 nM), and a larger LTP amplitude (54 ± 8 % vs. 21 ± 5 % in controls) that was restored to control levels (30 ± 10 %) by the AR antagonist, SCH58261 (50 nM). Notably, caffeine intake reverted memory deficits and reverted the loss of hippocampal synaptic markers but did not affect helpless or anxiety behavior. These results reinforce the validity of HM as an animal model of depression by showing that they also display reference memory deficits. Furthermore, caffeine intake selectively reverted memory but not mood deficits displayed by HM, which are associated with an increased density and functional impact of hippocampal AR controlling synaptic glutamatergic function.
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http://dx.doi.org/10.1007/s12035-016-9774-9DOI Listing
March 2017

Caffeine exposure during rat brain development causes memory impairment in a sex selective manner that is offset by caffeine consumption throughout life.

Behav Brain Res 2016 Apr 13;303:76-84. Epub 2016 Jan 13.

Laboratório de Estudos sobre o Sistema Purinérgico, Universidade Federal Rio Grande do Sul, Instituto de Ciências Básicas da Saúde, Departamento de Bioquímica, 90035-003 Porto Alegre, RS, Brazil. Electronic address:

Caffeine is the psychostimulant most consumed worldwide. In moderate doses, it affords a beneficial effect in adults and upon aging, but has a deleterious effect during brain development. We now tested if caffeine consumption by rats (0.1, 0.3, 1.0 g/L in the drinking water, only during active cycle and weekdays) during adulthood could revert the potentially negative effects of caffeine during early life. Thus, we compared caffeine intake starting 15 days before mating and lasting either up to weaning (development) or up to adulthood, on behavior and synaptic proteins in male and female rats. Recognition memory was impaired only in female rats receiving caffeine (0.3 and 1.0 g/L) during development, coincident with increased proBDNF and unchanged BDNF levels in the hippocampus. Caffeine in both treatment regimens caused hyperlocomotion only in male rats, whereas anxiety-related behavior was attenuated in both sexes by caffeine (1.0 g/L) throughout life. Both caffeine treatment regimens decreased GFAP (as an astrocyte marker) and SNAP-25 (as a nerve terminals marker) in the hippocampus from male rats. TrkB receptor was decreased in the hippocampus from both sexes and treatment regimens. These findings revealed that caffeine intake during a specific time window of brain development promotes sex-dependent behavioral outcomes related to modification in BDNF signaling. Furthermore, caffeine throughout life can overcome the deleterious effects of caffeine on recognition memory during brain development in female rats.
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http://dx.doi.org/10.1016/j.bbr.2016.01.026DOI Listing
April 2016

Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress.

Proc Natl Acad Sci U S A 2015 Jun 8;112(25):7833-8. Epub 2015 Jun 8.

CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal

The consumption of caffeine (an adenosine receptor antagonist) correlates inversely with depression and memory deterioration, and adenosine A2A receptor (A2AR) antagonists emerge as candidate therapeutic targets because they control aberrant synaptic plasticity and afford neuroprotection. Therefore we tested the ability of A2AR to control the behavioral, electrophysiological, and neurochemical modifications caused by chronic unpredictable stress (CUS), which alters hippocampal circuits, dampens mood and memory performance, and enhances susceptibility to depression. CUS for 3 wk in adult mice induced anxiogenic and helpless-like behavior and decreased memory performance. These behavioral changes were accompanied by synaptic alterations, typified by a decrease in synaptic plasticity and a reduced density of synaptic proteins (synaptosomal-associated protein 25, syntaxin, and vesicular glutamate transporter type 1), together with an increased density of A2AR in glutamatergic terminals in the hippocampus. Except for anxiety, for which results were mixed, CUS-induced behavioral and synaptic alterations were prevented by (i) caffeine (1 g/L in the drinking water, starting 3 wk before and continued throughout CUS); (ii) the selective A2AR antagonist KW6002 (3 mg/kg, p.o.); (iii) global A2AR deletion; and (iv) selective A2AR deletion in forebrain neurons. Notably, A2AR blockade was not only prophylactic but also therapeutically efficacious, because a 3-wk treatment with the A2AR antagonist SCH58261 (0.1 mg/kg, i.p.) reversed the mood and synaptic dysfunction caused by CUS. These results herald a key role for synaptic A2AR in the control of chronic stress-induced modifications and suggest A2AR as candidate targets to alleviate the consequences of chronic stress on brain function.
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http://dx.doi.org/10.1073/pnas.1423088112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485143PMC
June 2015

Chronic caffeine prevents changes in inhibitory avoidance memory and hippocampal BDNF immunocontent in middle-aged rats.

Neuropharmacology 2013 Jan 27;64:153-9. Epub 2012 Jul 27.

Laboratory of Studies on the Purinergic System, Department of Biochemistry, Health and Basic Sciences Institute, Federal University of Rio Grande do Sul, Rua Ramiro Barcelos, 2600-anexo, Porto Alegre, RS 90035 003, Brazil.

Beneficial effects of caffeine on memory processes have been observed in animal models relevant to neurodegenerative diseases and aging, although the underlying mechanisms remain unknown. Because brain-derived neurotrophic factor (BDNF) is associated with memory formation and BDNF's actions are modulated by adenosine receptors, the molecular targets for the psychostimulant actions of caffeine, we here compare the effects of chronic caffeine (1 mg/mL drinking solution for 30 days) on short- and long term memory and on levels of hippocampal proBDNF, mature BDNF, TrkB and CREB in young (3 month old) and middle-aged (12 month old) rats. Caffeine treatment substantially reduced i) age-related impairments in the two types of memory in an inhibitory avoidance paradigm, and ii) parallel increases in hippocampal BDNF levels. In addition, chronic caffeine increased proBDNF and CREB concentrations, and decreased TrkB levels, in hippocampus regardless of age. These data provide new evidence in favor of the hypothesis that modifications in BDNF and related proteins in the hippocampus contribute to the pro-cognitive effects of caffeine on age-associated losses in memory encoding. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
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http://dx.doi.org/10.1016/j.neuropharm.2012.07.010DOI Listing
January 2013

Treadmill running frequency on anxiety and hippocampal adenosine receptors density in adult and middle-aged rats.

Prog Neuropsychopharmacol Biol Psychiatry 2012 Jan 28;36(1):198-204. Epub 2011 Oct 28.

Laboratory of Studies on the Purinergic System, Graduation Program in Biological Sciences/Biochemistry, Federal University of Rio Grande do Sul, Health and Basic Sciences Institute, Department of Biochemistry, Porto Alegre/RS 90035-003, Brazil.

Physical exercise protocols have varied widely across studies raising the question of whether there is an optimal intensity, duration and frequency that would produce maximal benefits in attenuating symptoms related to anxiety disorders. Although physical exercise causes modifications in neurotransmission systems, the involvement of neuromodulators such as adenosine has not been investigated after chronic exercise training. Anxiety-related behavior was assessed in the elevated plus-maze in adult and middle-aged rats submitted to 8 weeks of treadmill running 1, 3 or 7 days/week. The speed of running was weekly adjusted to maintain moderate intensity. The hippocampal adenosine A1 and A2A receptors densities were also assessed. Treadmill running protocol was efficient in increasing physical exercise capacity in adult and middle-aged rats. All frequencies of treadmill running equally decreased the time spent in the open arms in adult animals. Middle-aged treadmill control rats presented lower time spent in the open arms than adult treadmill control rats. However, treadmill running one day/week reversed this age effect. Adenosine A1 receptor was not changed between groups, but treadmill running counteracted the age-related increase in adenosine A2A receptors. Although treadmill running, independent from frequency, triggered anxiety in adult rats and treadmill running one day/week reversed the age-related anxiety, no consistent relationship was found with hippocampal adenosine receptors densities. Thus, our data suggest that as a complementary therapy in the management of mental disturbances, the frequency and intensity of physical exercise should be taken into account according to age. Besides, this is the first study reporting the modulation of adenosine receptors after chronic physical exercise, which could be important to prevent neurological disorders associated to increase in adenosine A2A receptors.
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http://dx.doi.org/10.1016/j.pnpbp.2011.10.015DOI Listing
January 2012

Cd modifies hepatic Zn deposition and modulates δ-ALA-D activity and MT levels by distinct mechanisms.

J Appl Toxicol 2012 Jan 24;32(1):20-5. Epub 2011 Feb 24.

Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.

Cadmium (Cd) is a pollutant that is harmful to human and animals. The liver is a target for Cd accumulation and it can disrupt Zn homeostasis. Here we examined the interaction of Zn and Cd to determine how these two metals could affect δ-aminolevulinate-dehydratase (δ-ALA-D) and metallothionein (MT), two potential molecular endpoints for Cd hepatotoxicity. Cd exposure (0.25 and 1 mg kg1 body weight, i.p., for 10 days) caused a marked increase in hepatic Zn deposition, which was not modified by treatment with Zn (2 mg kg1 , i.p.). Cd caused a dose-dependent increase in hepatic Cd content that was not modified by Zn. Zn and/or Cd treatment increased hepatic δ-ALA-D activity, although the increase caused by Cd was less marked. Reactivation index of δ-ALA-D by DTT was decreased by Zn and Cd exposure, which indicates that Zn protects enzyme from oxidation. Hepatic MT was increased only after exposure to 1 mg kg(-1) Cd and Zn reduced the stimulation of MT synthesis. The results presented here indicate that Cd can redistribute Zn from non-hepatic tissues to liver and the increase in hepatic Zn deposition can account for the increase in hepatic δ-ALA-D activity after Cd exposure. However, Zn blocked the increase in hepatic MT levels caused by Cd. Thus, the modulation of the two molecular endpoints of Cd toxicity used here was distinct, which indicates that the mechanism(s) involved in Zn and Cd distribution, δ-ALA-D and MT regulation are not coincident.
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http://dx.doi.org/10.1002/jat.1648DOI Listing
January 2012

Blockade of adenosine A(1) receptors prevents methylphenidate-induced impairment of object recognition task in adult mice.

Prog Neuropsychopharmacol Biol Psychiatry 2011 Jan 31;35(1):169-76. Epub 2010 Oct 31.

Department of Biochemistry, Laboratory of Studies on the Purinergic System, Federal University of Rio Grande do Sul, Health and Basic Sciences Institute, Porto Alegre/RS, Brazil.

Methylphenidate (MPH) is the preferred treatment used for attention-deficit/hyperactivity disorder (ADHD). Recently, misuse for MPH due to its apparent cognitive enhancer properties has been reported. Adenosine is a neuromodulator known to exert influence on the dopaminergic neurotransmission, which is the main pharmacological target of MPH. We have reported that an overdosage of MPH up-regulates adenosine A(1) receptors in the frontal cortex, but this receptor was not involved in its anxiolytic effects. In this study, the role of adenosine A(1) receptor was investigated on MPH-induced effects on aversive and recognition memory in adult mice. Adult mice received acute and chronic (15 days) administration of methylphenidate (5mg/kg, i.p.), or an acute overdosage (50mg/kg, i.p) in order to model misuse. Memory was assessed in the inhibitory avoidance and object recognition task. Acute administration 5mg/kg improved whereas 50mg/kg disrupted recognition memory and decreased performance in the inhibitory avoidance task. Chronic administration did not cause any effect on memory, but decreased adenosine A(1) receptors immunocontent in the frontal cortex. The selective adenosine A(1) receptor antagonist, (DPCPX 1mg/kg, i.p.), prevented methylphenidate-triggered recognition memory impairment. Our findings showed that recognition memory rather than aversive memory was differently affected by acute administration at both doses. Memory recognition was fully impaired by the overdosage, suggesting that misuse can be harmful for cognitive functions. The adenosinergic system via A(1) receptors may play a role in the methylphenidate actions probably by interfering with dopamine-enhancing properties of this drug.
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http://dx.doi.org/10.1016/j.pnpbp.2010.10.022DOI Listing
January 2011

Adenosine A1 receptors are modified by acute treatment with methylphenidate in adult mice.

Brain Res 2010 Oct 7;1357:62-9. Epub 2010 Aug 7.

Department of Biochemistry, Laboratory of Studies on the Purinergic System, Graduation Program in Biological Sciences-Biochemistry, Federal University of Rio Grande do Sul, Health and Basic Sciences Institute, Bairro Santana, Brazil.

In recent years misuse of methylphenidate (MPH) has been reported. The main pharmacological target of methylphenidate is the dopaminergic system. Adenosine is a neuromodulator that influences the dopaminergic neurotransmission, but studies on MPH and adenosine are still lacking. In this study, adult mice were acutely treated with MPH (5mg/kg, i.p.) and to model misuse, they received an acute overdosage (50mg/kg, i.p). The involvement of adenosine A(1) receptors in anxiety-related behavior and locomotor and exploratory activity was examined. The administration of methylphenidate (5 and 50mg/kg) 30 min before the exposure to open field arena did not modify locomotor activity. The anxiolytic-like behavior was observed with both doses of MPH as revealed by the increase on the number of entries and the time spent in the open arms in the elevated plus-maze. Pre treatment with selective adenosine A(1) receptor antagonist (DPCPX 1mg/kg, i.p.) did not prevent anxiolytic effect caused by MPH 50mg/kg. Immunoblotting of frontal cortex and hippocampal extracts revealed that MPH 50mg/kg increased 88% adenosine A(1) receptor density in the frontal cortex. Extracts from hippocampus did not reveal any differences in the adenosine A(1) receptor density. Our findings ruled out the participation of adenosine A(1) receptors on the MPH-triggered anxiolytic effects. However, the density of adenosine A(1) receptors increased in a brain area strictly involved in the MPH-mediated effects. Thus, the adenosinergic system may play a role in the methylphenidate actions in the central nervous system.
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http://dx.doi.org/10.1016/j.brainres.2010.08.004DOI Listing
October 2010

Caffeine prevents disruption of memory consolidation in the inhibitory avoidance and novel object recognition tasks by scopolamine in adult mice.

Behav Brain Res 2010 Dec 27;214(2):254-9. Epub 2010 May 27.

Laboratory of Studies on the Purinergic System, Graduation Program in Biological Sciences/Biochemistry, Federal University of Rio Grande do Sul, Health and Basic Sciences Institute, Department of Biochemistry, Porto Alegre/RS 90035-003, Brazil.

Caffeine is a psychostimulant with positive effects on cognition. Recent studies have suggested the participation of the cholinergic system in the effects of caffeine on wakefulness. However, there are few studies assessing the contribution of cholinergic system in the cognitive enhancer properties of caffeine. In the present study, the effects of a dose and schedule of administration of caffeine that improved memory recognition were investigated on scopolamine-induced impairment of memory in adult mice. Inhibitory avoidance and novel object recognition tasks were used to assess learning and memory. Caffeine (10mg/kg, i.p.) was administered during 4 consecutive days, and the treatment was interrupted 24h before scopolamine administration (2mg/kg, i.p.). Scopolamine was administered prior to or immediately after training. Short-term and long-term memory was evaluated in both tasks. In the novel object recognition task, pre treatment with caffeine prevented the disruption of short- and long-term memory by scopolamine. In the inhibitory avoidance task, caffeine prevented short- but not long-term memory disruption by pre training administration of scopolamine. Caffeine prevented short- and long-term memory disruption by post training administration of scopolamine. Both treatments did not affect locomotor activity of the animals. These findings suggest that acute treatment with caffeine followed by its withdrawal may be effective against cholinergic-induced disruption of memory assessed in an aversive and non-aversive task. Finally, our results revealed that the cholinergic system is involved in the positive effects of caffeine on cognitive functions.
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http://dx.doi.org/10.1016/j.bbr.2010.05.034DOI Listing
December 2010

Diphenyl diselenide and diphenyl ditelluride: neurotoxic effect in brain of young rats, in vitro.

Mol Cell Biochem 2010 Jul 24;340(1-2):179-85. Epub 2010 Feb 24.

Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, RS CEP 97105-900, Brazil.

This study examined whether maturity of rat brain may be relevant for the sensitivity to diphenyl diselenide (PhSe)(2) and diphenyl ditelluride (PhTe)(2) on [(3)H]glutamate uptake and release, in vitro. Brain synaptosomes were isolated from young (14- and 30-day-old) and adult rats and incubated at different concentrations of (PhSe)(2) or (PhTe)(2). The results demonstrated that the highest concentration (100 microM) of (PhSe)(2) and (PhTe)(2) inhibited the [(3)H]glutamate uptake by synaptosomes of brain at all ages. In the adult brain, (PhSe)(2) did not inhibit the [(3)H]glutamate uptake at the lowest concentration (10 microM). The highest concentration of (PhTe)(2) inhibited the [(3)H]glutamate uptake more in the 14-day-old than in the 30-day-old rats or adult rats. In the 30-day-old animals, the highest concentration of (PhSe)(2), and the lowest concentration of (PhTe)(2), increased the basal [(3)H]glutamate release. At the highest concentration, (PhTe)(2) increased the basal and K(+)-stimulated glutamate release on all ages evaluated. The results suggest that (PhSe)(2) and (PhTe)(2) caused alterations on the homeostasis of the glutamatergic system at the pre-synaptic level. These alterations were age-, concentration-, and compound-dependent. The maturity of rat brain is relevant for the glutamatergic system sensitivity to (PhSe)(2) and (PhTe)(2) .
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http://dx.doi.org/10.1007/s11010-010-0416-7DOI Listing
July 2010

Influence of environmental enrichment on an object recognition task in CF1 mice.

Physiol Behav 2010 Jan;99(1):17-21

Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, 90035 003, Brazil.

Environmental enrichment (EE) is an experimental model for studying neuroplasticity. EE is used to investigate behavioral modifications associated with gene-environmental interaction. The object recognition task (ORT) evaluates animals' ability to learn about their environment, which depends on their innate instinct. By using young CF1 mice, the present study evaluated the effect of 8 weeks of EE on the ORT. Our results indicate that EE decreased the time the animals spent exploring familiar and unfamiliar objects and total time spent exploring both objects, without affecting the capacity of discrimination of objects. These findings indicate a more propitious behavior for species survival in animals subjected to EE, including rapid exploration and learning about the environment.
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http://dx.doi.org/10.1016/j.physbeh.2009.10.003DOI Listing
January 2010

Passive smoke exposure induces oxidative damage in brains of rat pups: Protective role of diphenyl diselenide.

Inhal Toxicol 2009 Aug;21(10):868-74

Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Brazil.

The protective effect of diphenyl diselenide, (PhSe)(2), on oxidative stress induced by cigarette smoke exposure in brains of rat pups was evaluated. Animals were exposed to passive cigarette smoke (15 min/day) in two different experimental protocols: P1 (1, 2, and 3 cigarettes) and P2 (4, 5, and 6 cigarettes) for 3 weeks. Before each period of smoke exposure, animals received an oral administration of (PhSe)(2) (0.5 mg/kg). A number of toxicological parameters in the brain were examined, such as lipid peroxidation, delta-aminolevulinate dehydratase (delta-ALA-D) activity, and components of enzymatic (superoxide dismutase and catalase activities) and non-enzymatic antioxidant defenses (ascorbic acid and non-protein thiol levels). In P1, smoke exposure induced an inhibition of catalase activity and an increase of ascorbic acid levels. (PhSe)(2) treatment was able to protect catalase activity but not ascorbic acid levels. In P2, an augmentation of lipid peroxidation, a reduction of enzymatic and non-enzymatic antioxidant status, and an inhibition of delta-ALA-D activity caused by smoke exposure were found. (PhSe)(2) protected the brains of rat pups against oxidative damage induced by smoke exposure. The results are consistent with the antioxidant effect of (PhSe)(2) demonstrated by the reduction of oxidative changes caused by smoke exposure in the brains of pups.
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http://dx.doi.org/10.1080/08958370802526881DOI Listing
August 2009

Exposure to diphenyl ditelluride, via maternal milk, causes oxidative stress in cerebral cortex, hippocampus and striatum of young rats.

Arch Toxicol 2009 May 3;83(5):485-91. Epub 2008 Dec 3.

Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, RS, Brazil.

The present study evaluated the effect of diphenyl ditelluride [(PhTe)(2)] exposure to mothers on the cerebral oxidative status of their offspring. The dams received (PhTe)(2) or canola oil via subcutaneous injection once daily during the first 14 days of lactational period. At post natal day 28, biochemical parameters of oxidative stress were evaluated in cerebral structures-cortex, hippocampus and striatum-of young rats. Exposure to (PhTe)(2) increased lipid peroxidation levels and inhibited delta-ALA-D, catalase and SOD activities in hippocampus and striatum of young rats. (PhTe)(2) induced changes in the levels of non-enzymatic antioxidant defenses in cortex and striatum of young rats. The exposure to (PhTe)(2), via maternal milk, caused oxidative stress in cerebral structures of young rats. Thus, the possible role of disrupted prooxidant/antioxidant balance in (PhTe)(2) toxicity was demonstrated. These results highlighted a possible molecular mechanism involved in toxicity caused by (PhTe)(2).
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http://dx.doi.org/10.1007/s00204-008-0392-9DOI Listing
May 2009

Caffeine improves adult mice performance in the object recognition task and increases BDNF and TrkB independent on phospho-CREB immunocontent in the hippocampus.

Neurochem Int 2008 Sep 24;53(3-4):89-94. Epub 2008 Jun 24.

Department of Biochemistry, Laboratory of Studies on the Purinergic System, Graduation Program in Biological Sciences/Biochemistry, Federal University of Rio Grande do Sul, Health and Basic Sciences Institute, Porto Alegre, RS, Brazil.

Caffeine is one of the most psychostimulants consumed all over the world that usually presents positive effects on cognition. In this study, effects of caffeine on mice performance in the object recognition task were tested in different intertrial intervals. In addition, it was analyzed the effects of caffeine on brain derived neurotrophic factor (BDNF) and its receptor, TrkB, immunocontent to try to establish a connection between the behavioral finding and BDNF, one of the neurotrophins strictly involved in memory and learning process. CF1 mice were treated during 4 consecutive days with saline (0.9g%, i.p.) or caffeine (10mg/kg, i.p., equivalent dose corresponding to 2-3 cups of coffee). Caffeine treatment was interrupted 24h before the object recognition task analysis. In the test session performed 15min after training session, caffeine-treated mice recognized more efficiently both the familiar and the novel object. In the test session performed 90min and 24h after training session, caffeine did not change the time spent in the familiar object but increased the object recognition index, when compared to control group. Western blotting analysis of hippocampus from caffeine-treated mice revealed an increase in BDNF and TrkB immunocontent, compared to their saline-matched controls. Phospho-CREB immunocontent did not change with caffeine treatment. Our results suggest that acute treatment with caffeine improves recognition memory, and this effect may be related to an increase of the BDNF and TrkB immunocontent in the hippocampus.
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http://dx.doi.org/10.1016/j.neuint.2008.06.006DOI Listing
September 2008