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Many studies suggest a protective role of phenolic compounds in mood disorders. We aimed to assess the effect of Euterpe oleracea (açaí) seed extract (ASE) on anxiety induced by periodic maternal separation (PMS) in adult male rats. Animals were divided into 6 groups: control, ASE, fluoxetine (FLU), PMS, PMS+ASE, and PMS+FLU. For PMS, pups were separated daily from the dam for 3 h between postnatal day (PN) 2 and PN21. ASE (200 mg·kg−1·day−1) and FLU (10 mg·kg−1·day−1) were administered by gavage for 34 days after stress induction, starting at PN76. At PN106 and PN108, the rats were submitted to open field (OF) and forced swim tests, respectively. At PN110, the rats were sacrificed by decapitation. ASE increased time spent in the center area in the OF test, glucocorticoid receptors in the hypothalamus, tropomyosin receptor kinase B (TRKB) levels in the hippocampus, and nitrite levels and antioxidant activity in the brain stem (PMS+ASE group compared with PMS group). ASE also reduced plasma corticotropin-releasing hormone levels, adrenal norepinephrine levels, and oxidative damage in the brain stem in adult male offspring submitted to PMS. In conclusion, ASE treatment has an anti-anxiety effect in rats submitted to PMS by reducing hypothalamic–pituitary–adrenal axis reactivity and increasing the nitric oxide (NO)–brain-derived neurotrophic factor (BDNF)–TRKB pathway and antioxidant defense in the central nervous system.Novelty ASE has anti-anxiety and antioxidant effects in early-life stress. ASE reduces hypothalamic–pituitary–adrenal axis reactivity. The anxiolytic effect of ASE may involve activation of the NO–BDNF–TRKB pathway in the central nervous system.

Many studies suggest a protective role of phenolic compounds in mood disorders. We aimed to assess the effect of

Breastfeeding is associated with obesity prevention. We showed previously that prolactin inhibition at the end of lactation causes hyperleptinemia at weaning (PN21) and programs for obesity, insulin resistance, dyslipidemia, and leptin resistance (PN180). Here, we evaluate the source of neonatal hyperleptinemia and how it develops during the nutritional transition from milk through solid food. Lactating rats were treated with bromocriptine (BRO), a prolactin inhibitor, 0.5 mg twice a day, or saline (CON) for the last 3 days of lactation. All parameters were studied at PN22 and PN30. At PN22, BRO-treated rats showed lower food intake, body mass, and body length. At PN30, only body length and mesenteric fat mass were lower. Despite normal plasma leptin levels at PN22, the adipose tissue leptin mRNA expression was lower, while plasma leptin was higher in PN30, possibly due to a higher adipose mesenteric tissue production. At PN22, the hypothalamus seems to be more sensitive to leptin, since OBR and STAT3 are higher. Conversely, at PN30 leptin signaling pathway is suggestive of leptin resistance with lower STAT3 and higher SOCS3 in hypothalamus and consequently higher NPY. Glycemia was lower at PN22 and higher at PN30, without changes in plasma insulin levels. At PN30, BRO-treated rats had other metabolic changes such as higher plasma cholesterol, lower HDL-c, higher hepatic cholesterol and AST, suggesting a liver dysfunction. Our data show that milk supply can exert a crucial role in the imprinting of a second leptin peak, which is important for survival adaptation to adverse nutritional conditions.

The most frequently used animal models of early weaning (EW) in rodents, maternal deprivation and pharmacological inhibition of lactation, present confounding factors, such as high stress or drug side effects, that can mask or interact with the effects of milk deprivation per se. Given these limitations, the development of new models of EW may provide useful information regarding the impact of a shortened period of breastfeeding on the endocrine and nervous systems, both during development and at adulthood. Using a model of EW in which lactating Wistar rat dams are wrapped with a bandage to block access to milk during the last three days of lactation, we have recently shown that the adult offspring presented higher body mass, hyperphagia, hyperleptinemia, leptin as well as insulin resistance, and higher adrenal catecholamine content at adulthood. Here, we used this EW model, which involves no pharmacological treatment or maternal separation, to analyze anxiety-like, novelty-seeking and memory/learning behavioral traits in the adult male offspring. To that end, animals were tested in the elevated plus maze, in the hole board arena and in the radial arm water maze. Except for an increased number of rearing events (a measure of vertical activity), no other behavioral differences were observed between EW and control animals. The contrasting behavioral results between the three EW models may be associated with differences in HPA axis function in the offspring at weaning, since it has been observed that bandaging does not affect corticosteronemia while maternal separation and pharmacological EW increase it.

Objective We have recently shown that maternal flaxseed supplementation during lactation induces insulin resistance in adult offspring. Here, we studied the effects of maternal dietary flaxseed during lactation on adipocyte morphology and leptin signaling in the hypothalamic-pituitary-thyroid axis as well as on behavioral traits in the adult progeny. Methods Lactating rats were fed a control (C) diet or a diet with 25% flaxseed (F). After weaning, pups received a standard diet until postnatal day (PN) 180. Male offspring were killed at PN21 and 180. Data were considered significant at P Results Weaned F rats presented a lower total and subcutaneous fat mass and higher subcutaneous adipocyte area (+48%), but at adulthood they presented higher subcutaneous and visceral adipocyte areas (+40% and 1.9-fold increase, respectively), with no change in body fat mass. At PN21, F pups had hyperleptinemia (+69%), lower T 3 (−33%), higher TSH (2.1-fold increase), higher pituitary leptin receptor (Ob-R, +11%), signal transducer and activator of transcription 3 (STAT3, +21%), and phosphorylated-STAT3 (p-STAT3, +77%) protein content. Adult F offspring only showed lower T 4 (−28%) and higher thyroid Ob-R (+52%) expression. Maternal flaxseed intake during lactation did not result in behavioral changes in the adult offspring. Conclusions Maternal flaxseed supplementation decreases offspring adiposity and increases pituitary leptin signaling at weaning, but it induces hypertrophic adipocytes and higher thyroid leptin receptor in adulthood. The present data suggest that extensive use of flaxseed during lactation is undesirable.

Maternal hypoprolactinemia at the end of lactation in rats reduces milk production and is associated with offspring's malnutrition. Since malnutrition during development is also known to have long lasting effects on cognition and emotion, in the present study we tested the hypothesis that maternal hypoprolactinemia, induced by bromocriptine treatment, at the end of the lactating period affects memory/learning, novelty-seeking and anxiety-like behaviors in adult male Wistar rats using, respectively, the radial arm water maze (RAWM), the hole board (HB) arena and the elevated plus-maze (EPM). We also analyzed serum corticosterone and thyroid hormone levels at postnatal day (PN) 21. Lactating dams were treated with bromocriptine (BRO, 1 mg twice a day, inhibiting prolactin) or saline from PN19 to 21 (the last 3 days of lactation). BRO offspring had hypercorticosteronemia and hypothyroidism at PN21. In the RAWM, reductions in latency observed in CON rats were initially more accentuated than in BRO ones. By the end of the testing period, latencies became similar between groups. No difference was observed between groups regarding the number of nose-pokes in the HB. In the EPM, BRO rats stayed less time in and had fewer entries into the open-arms than CON ones. This pattern of results indicates that maternal bromocriptine treatment at the end of the lactating period results in poorer memory/learning performance and in higher levels of anxiety-like behavior in the adult offspring, demonstrating that even a relatively short period of malnutrition during development can have long lasting detrimental effects regarding cognition and emotion.

Previously, we demonstrated that maternal prolactin inhibition at the end of lactation, using bromocriptine (BRO), leads to an increase in leptin transfer via milk and induces the adult progeny to present hypothyroidism, leptin resistance and metabolic syndrome (obesity, hyperglycemia, hypertriglyceridemia, lower HDL). To test if these alterations are due to direct BRO action on the pups, in the present study we evaluated the long-term effects of direct injection of BRO (0.1μg/once daily) in male Wistar rats from postnatal (PN) day 1 to 10 (early treatment) or from PN11 to 20 (late treatment) on: food intake, body mass, cardiovascular parameters, hormone profile, hypothalamic leptin signaling, glucose homeostasis and thyroid hormone-dependent proteins. The respective controls were injected with methanol-saline. Offspring were killed at adulthood (PN180). Adult PN1-10 BRO-treated animals had lower food intake, hypoprolactinemia, lower leptin action (lower OBR-b, STAT-3 and SOCS-3 mRNA levels in the arcuate nucleus), lower TRH-TSH-thyroid axis as well as lower thyroid hormone markers. On the other hand, adult animals that were BRO-treated during the PN11-20 period showed hyperphagia, higher blood pressure, higher prolactinemia and OBR-b, higher TRH and plasma T3, hypercorticosteronemia as well as higher Dio2 and UCP1 mRNA expression in the brown adipose tissue. Glucose homeostasis was not changed treatment in either period. Our data show that early and late dopamine overexposure during lactation induces diverse metabolic disturbances later in life, increasing the risk of thyroid dysfunction and, consequently, changes in prolactinemia.

In humans, bromocriptine (BRO) is used as a treatment for many disorders, such as prolactinomas, even during pregnancy and lactation. Previously we demonstrated that maternal BRO treatment at the end of lactation programs offspring for obesity and several endocrine dysfunctions. Here, we studied the long-term effects of direct BRO injection in neonatal Wistar rats on their dopaminergic pathway, anxiety-like behavior and locomotor activity at adulthood. Male pups were either s.c. injected with BRO (0.1μg/once daily) from postnatal day (PN) 1 to 10 or from PN11 to 20. Controls were injected with methanol-saline. Body mass, food intake, neuropeptides, dopamine pathway parameters, anxiety-like behavior and locomotor activity were analyzed. The dopamine pathway was analyzed in the ventral tegmental area (VTA), nucleus accumbens (NAc) and dorsal striatum (DS) at PN180. PN1-10 BRO-treated animals had normal body mass and adiposity but lower food intake and plasma prolactin (PRL). This group had higher POMC in the arcuate nucleus (ARC), higher tyrosine hydroxylase (TH) in the VTA, higher dopa decarboxylase (DDc), higher D2R and μu-opioid receptor in the NAc. Concerning behavior in elevated plus maze (EPM), BRO-treated animals displayed more anxiety-like behaviors. PN11-20 BRO-treated showed normal body mass and adiposity but higher food intake and plasma PRL. This group had lower POMC in the ARC, lower TH in the VTA and lower DAT in the NAc. BRO-treated animals showed less anxiety-like behaviors in the EPM. Thus, neonatal BRO injection, depending on the time of treatment, leads to different long-term dysfunctions in the dopaminergic reward system, food intake behavior and anxiety levels, findings that could be partially due to PRL and POMC changes.

Nicotine exposure causes the release of dopamine from the ventral tegmental area (VTA) to the nucleus accumbens (NAc). We have previously shown that maternal exposure to nicotine during lactation causes hyperleptinemia in dams and pups, and leptin is known to decrease dopamine release from the VTA. Here we evaluated whether maternal exposure to nicotine during lactation causes changes in dopamine and leptin signaling pathways at the end of exposure and after 5 days of withdrawal in the: VTA, NAc, arcuate nucleus (ARC) and dorsal striatum (DS). On postnatal day (PN) 2, lactating Wistar rats were implanted with minipumps releasing nicotine (NIC; 6 mg/kg/day, s.c.) or saline (C) for 14 days. Offspring were tested in the elevated plus maze (EPM) and open field on PN14 or PN20, and euthanized on PN15 or PN21. Entries into the open arms and head dips in the EPM were reduced in NIC pups at P20. At weaning (PN21), NIC dams had: lower tyrosine hydroxylase (TH), higher OBRb and SOCS3 contents in VTA; lower TH, higher D1R, D2R and DAT contents in NAc; higher TH content in DS; and higher D2R and SOCS3 contents in ARC. On PN15, NIC offspring had higher D1R, D2R and lower DAT contents in NAc, while on PN21, they had lower DAT in DS, and lower pSTAT3 content in ARC. We evidenced that postnatal nicotine exposure induces relevant changes in the brain reward system of dams and pups, possibly associated with changes in leptinemia and increased offspring anxiety-like behavior.

Children from pregnant smokers are more susceptible to become obese adults and to become drug or food addicts. Drugs and food activate the mesolimbic reward pathway, causing a sense of pleasure that induces further consumption. Here, we studied the relationship between tobacco smoke exposure during lactation with feeding, behavior and brain dopaminergic reward system parameters at adulthood. Nursing Wistar rats and their pups were divided into two groups: tobacco smoke-exposed (S: 4times/day, from the 3rd to the 21th day of lactation), and ambient air-exposed (C). On PN175, both offspring groups were subdivided for a food challenge: S and C that received standard chow (SC) or that chose between high-fat (HFD) and high-sucrose diets (HSDs). Food intake was recorded after 30min and 12h. Offspring were tested in the elevated plus maze and open field on PN178-179; they were euthanized for dopaminergic analysis on PN180. SSD (self-selected diet) animals presented a higher food intake compared to SC ones. S-SSD animals ate more than C-SSD ones at 30min and 12h. Both groups preferred the HFD. However, S-SSD animals consumed relatively more HFD than C-SSD at 30min. No behavioral differences were observed between groups. S animals presented lower tyrosine hydroxylase (TH) content in the ventral tegmental area, lower TH, dopaminergic receptor 2, higher dopaminergic receptor 1 contents in the nucleus accumbens and lower OBRb in hypothalamic arcuate nucleus. Tobacco-smoke exposure during lactation increases preference for fat in the adult progeny possibly due to alterations in the dopaminergic system.

The mesolimbic reward pathway is activated by drugs of abuse and palatable food, causing a sense of pleasure, which promotes further consumption of these substances. Children whose parents smoke are more vulnerable to present addictive-like behavior to drugs and food.We evaluated the association between maternal nicotine exposure during lactation with changes in feeding, behavior and in the dopaminergic reward system. On postnatal day (PN) 2,Wistar rat dams were implanted with minipumps releasing nicotine (N; 6 mg/kg/day, s.c.) or saline (C) for 14 days. On PN150 and PN160, offspring were divided into 4 groups for a food challenge: N and C that received standard chow(SC); and N and C that could freely self-select (SSD) between high-fat and high-sugar diets (HFD and HSD, respectively). Offspring were tested in the elevated plus maze (EPM) and open field (OF) arena on PN152–153. On PN170, offspring were euthanized for central dopaminergic analysis. SSD animals showed an increased food intake compared to SC ones and a preference for HFD. However, N-SSD animals consumed relatively more HSD than C-SSD ones. Regarding behavior, N animals showed an increase in the time spent in the EPM center and a reduction in relative activity in the OF center. N offspring presented lower dopamine receptor (D2R) and transporter (DAT) contents in the nucleus accumbens, and lower D2R in the arcuate nucleus. Postnatal exposure to nicotine increases preference for sugar and anxiety levels in the adult progeny possibly due to a decrease in dopaminergic action in the nucleus accumbens and arcuate nucleus.

Submitted by Boris Flegr (boris@uerj.br) on 2021-01-06T20:54:43Z No. of bitstreams: 1 MCF.pdf: 1186824 bytes, checksum: 8d7d9b8599dfce641d462602fd4eb0de (MD5) Made available in DSpace on 2021-01-06T20:54:43Z (GMT). No. of bitstreams: 1 MCF.pdf: 1186824 bytes, checksum: 8d7d9b8599dfce641d462602fd4eb0de (MD5) Previous issue date: 2009-08-27 Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro A considerable association exists between variations in nutritional, hormonal and environmental parameters during early life, particularly in the gestational and lactation periods, and the appearance of chronic diseases in adult life, such as obesity, diabetes, cardiovascular diseases, anxiety and depression. In the present study, the cognitive and behavioral effects of leptin injection (8μg/100g/day, sc) during the first 10 days of lactation were evaluated in adult male Wistar rats. In the first part of the study, leptin was injected directly in the offspring. In the second part of the study, leptin was injected in the lactation dams. Memory and learning, levels of anxiety-like behavior and levels of novelty-seeking behavior were evaluated by testing animals in, respectively, the radial-arm water maze, the elevated plus maze and the hole board arena. In the first model (offspring injection), high levels of anxiety and of novelty-seeking behavior were observed. Memory/learning and locomotor activity were unaffected. In the second model (dam injection), reduced levels of anxiety and better memory/learning performance were observed. Conversely, novelty-seeking and locomotor behavior were unaffected. Differences between models regarding somatic, endocrine and metabolic parameters are also observed. The first model presents hyperphagia, higher lean body mass, hyperleptinemia, hyperthyroidism, hipertrigliceridemia, hiperinsulinemia and hypoadiponectinemia, hypertension, increased levels of catecholamines and corticosterone, and hypothalamic leptin resistance. The second model induces hyperphagia, higher body mass, thou by accumulation of fat, hyperleptinemia, hyperglycemia, euthyroidism, normoinsulinemia and central mechanism of leptin resistance. The following possibilities may explain the cognitive-behavioral differences observed between models in the present study: 1) differences in somatic, endocrine and metabolic parameters; 2) modifications of the relationship between dams and their offspring, since leptin injection in the dams may reduce their anxiety levels; 3) different routes of leptin injection, since leptin transfer via milk may cause secondary alterations. Existe uma grande associação entre alterações em parâmetros nutricionais, hormonais ou ambientais durante estágios iniciais da vida, particularmente durante os períodos gestacional e de lactação, e o surgimento de doenças crônicas na vida adulta tais como obesidade, diabetes, doenças cardiovasculares, ansiedade e depressão. Neste trabalho, foram avaliados os efeitos cognitivo-comportamentais, em ratos Wistar adultos, da administração de leptina (8μg/100g, dia, sc) durante os primeiros 10 dias de lactação: 1) diretamente nos filhotes; 2) nas progenitoras. A memória e o aprendizado, os níveis de comportamento associados à ansiedade e à busca pela novidade foram avaliados em animais adultos através, respectivamente, dos seguintes testes comportamentais: labirinto aquático radial de 8 braços, labirinto em cruz elevado e campo vazado. No primeiro modelo (injeção nos filhotes), foram observados altos níveis de ansiedade e de busca por novos estímulos, enquanto que a memória e aprendizagem e atividade locomotora não foram afetados. No segundo modelo (injeção nas progenitoras), foram detectados redução dos níveis de ansiedade e melhora no desempenho associado à memória e ao aprendizado. Porém, não houve diferença nos níveis de busca por novos estímulos e no nível de atividade locomotora. Também são observadas diferenças em parâmetros somáticos, endócrinos e metabólicos entre modelos. O primeiro modelo resulta em hiperfagia, maior peso corporal por aumento de massa magra, hiperleptinemia, hipertireoidismo, hipertrigliceridemia, hiperinsulinemia e hipoadiponectinemia, hipertensão, aumento de catecolamina e de corticosterona, além de resistência hipotalâmica à leptina. O segundo modelo induz hiperfagia e maior peso corporal por acúmulo de gordura, hiperleptinemia, hiperglicemia, eutireoidismo, normoinsulinemia e resistência central à leptina. As seguintes possibilidades podem explicar as diferenças cognitivos-comportamentais observadas entre os modelos estudados: 1) diferentes perfis somáticos, endócrinos e metabólicos; 2) modificações na relação mãe-prole, já que a leptina injetada na mãe pode reduzir seu nível de ansiedade; 3) diferenças entre as vias de administração da leptina, já que sua transferência pelo leite pode causar alterações secundárias.

Submitted by Boris INFORMAT (boris@uerj.br) on 2021-04-26T01:10:13Z No. of bitstreams: 1 Juliana de Oliveira Silva Tese completa.pdf: 1273660 bytes, checksum: ac083758918cb65850e9567bfbbf8a41 (MD5) Made available in DSpace on 2021-04-26T01:10:13Z (GMT). No. of bitstreams: 1 Juliana de Oliveira Silva Tese completa.pdf: 1273660 bytes, checksum: ac083758918cb65850e9567bfbbf8a41 (MD5) Previous issue date: 2017-03-31 Conselho Nacional de Desenvolvimento Científico e Tecnológico Environmental enrichment (EE) consists of an experimental model in which animals are exposed to an environment that provides a variety of cognitive, sensory and motor stimuli. Research in mice has shown that the EE can stimulate neurogenesis, for example in the hippocampus, throughout life. These structural changes result in improved cognitive function, which is observed, for example, through improvements in tasks involving memory and learning. The EE also has behavioral benefits regarding the modulation of mood and social contact. EE exposure during development can have an impact on the neurophysiological responses to drugs of abuse due to its action on the reward system of the brain. Studies have suggested that EE is a new possibility of neurocomportamental approach to changes in the function of the central nervous system, particularly in relation to its role both in prevention and in the reversal of the effects of addiction to various drugs of abuse. In fact, the EE has been assigned a protective role regarding the development of this dependency. Here, our goal was to evaluate, in adolescent (postnatal day - PN - 45) and adult (PN75) Swiss mice, the impact of prior exposure to the enriched environment during childhood on the effects derived from treatment with nicotine during adolescence on the following behavioral parameters: locomotor activity, search for new stimuli and anxiety. Also studied were the contents of dopamine, DOPAC and norepinephrine. From PN15 to PN30 (childhood), experimental litters were separated into two groups: those exposed to the EE and those exposed to the control environment (CONT). From PN30 to PN45 (adolescence), animals were either treated with nicotine (NIC; osmotic minipumps s.c.) or saline (SAL). Four experimental groups were thus used: CONT-SAL, CONT-NIC, EE-SAL and EE-NIC. The animals were evaluated, at PN45 (adolescence) or at PN75 (adulthood), initially in the open field (CA) and, 2 hours later, in the hole board arena (CV). In the CA, EE exposure increased locomotor activity of adolescent females. At adulthood, males treated with nicotine also showed an increase in locomotor activity. In the CV, EE exposure reversed the effects of nicotine on the number of explored holes both in adult females and males. EE exposure reduced the concentration of dopamine in the cortex of adult males, while the content of DOPAC was reduced in adult males exposed to EE and treated with nicotine. Besides, EE exposure increased the concentration of cortical noradrenaline in both adult females and males. Our results indicate a clear influence of the enriched environment exposure on animal behavior, modulating or even reversing the effects of subsequent nicotine in a sex-dependent manner. O enriquecimento ambiental (AE) consiste em um modelo experimental no qual os animais são expostos a um ambiente que fornece uma variedade de estímulos cognitivos, sensoriais e motores. Pesquisas em ratos mostraram que o AE pode estimular a neurogênese, no hipocampo por exemplo, ao longo de toda a vida. Essas modificações estruturais resultam em aprimoramento da função cognitiva, que pode ser observada através da melhora em tarefas envolvendo memória e aprendizagem. O AE traz também benefícios comportamentais na modulação do humor e no contato social. A exposição ao AE durante o desenvolvimento pode ter impacto sobre as respostas neurofisiológicas às drogas de abuso devido à sua ação sobre o sistema de recompensa do cérebro. Estudos tem proposto que o AE é uma nova possibilidade na abordagem neurocomportamental de diferentes alterações na função do sistema nervoso central, particularmente em relação ao seu papel tanto na prevenção como na reversão dos efeitos da dependência a diferentes drogas de abuso. De fato, atribui-se ao AE um papel protetor contra o desenvolvimento desta dependência. No presente estudo, nosso objetivo foi o de avaliar, em camundongos Suíços, o impacto da exposição prévia ao AE na infância sobre os efeitos derivados do tratamento com nicotina durante a adolescência em parâmetros comportamentais relacionados à atividade locomotora, à busca por novos estímulos e à ansiedade, bem como sobre o conteúdo cerebral de dopamina, DOPAC e noradrenalina, em dois momentos do desenvolvimento do animal, na adolescência, no 45o dia de vida pós-natal (PN) e na idade adulta (PN75). Para tanto, de PN15 a PN30 (infância), as ninhadas experimentais foram separadas em dois grupos: as expostas ao AE e as expostas ao ambiente controle (CONT). De PN30 a PN45 (adolescência), os animais foram tratados com nicotina (NIC; minibomba osmótica s.c.) ou salina (SAL). Formaram-se, então, 4 grupos experimentais: CONT-SAL, CONT-NIC, AE-SAL e AE-NIC. Os animais foram avaliados, em PN45 (adolescentes) ou em PN75 (adultos), inicialmente no campo aberto (CA) e, 2 h, depois, no campo vazado (CV). No CA, a exposição ao AE aumentou a atividade locomotora das fêmeas adolescentes. Na idade adulta, os machos tratados com nicotina também apresentaram um aumento na atividade locomotora. No CV, a exposição ao AE reverteu os efeitos da nicotina sobre o número de orifícios explorados tanto nas fêmeas como nos machos adultos. A exposição ao AE reduziu a concentração de dopamina no córtex dos machos adultos, enquanto que o conteúdo de DOPAC foi reduzido nos machos adultos expostos ao AE e tratados com nicotina. Além disso a exposição ao AE aumentou a concentração de noradrenalina cortical tanto em fêmeas como em machos adultos. Nossos resultados indicam a clara influência da exposição ao ambiente enriquecido no comportamento dos animais, podendo modular ou até mesmo reverter efeitos causados pelo tratamento com a nicotina de forma sexo-dependente.

Submitted by Boris Flegr (boris@uerj.br) on 2021-01-06T20:54:19Z No. of bitstreams: 1 Sylvio Claudio Neto Tese completa.pdf: 4544754 bytes, checksum: 18e36467dcf0b434797a6c02339012ac (MD5) Made available in DSpace on 2021-01-06T20:54:19Z (GMT). No. of bitstreams: 1 Sylvio Claudio Neto Tese completa.pdf: 4544754 bytes, checksum: 18e36467dcf0b434797a6c02339012ac (MD5) Previous issue date: 2016-09-16 Conselho Nacional de Desenvolvimento Científico e Tecnológico Nicotine is the main pharmacologically active substance in cigarettes responsible for dependency. It has been shown that teenagers that are exposed to nicotine, have increased risks of acquiring long lasting dependence. Strategies to facilitate the interruption of nicotine use have been developed, but little is known about the effects of nicotine exposure during adolescence and even less of the short and long-term effects of the treatments available for the reversal of the dependency. The objective of this work was to analyze behavior, in the Elevated Plus Maze test (LCE) and in the Open Field test (CA), of mice exposed to nicotine during adolescence and then treated with bupropion or varenicline. From post-natal day 30 (PN30) to PN45, 899 male Swiss mice were exposed to a 2% saccharine solution containing 50 µg/ml of nicotine (NIC) or to a 2% saccharine solution (SAC) in standard plastic bottles. From PN46 to PN56, the animals were treated orally (gavage) with one of the following drugs: a) 0.1 mg/kg varenicline (VAR1); b) 1.0 mg/kg varenicline (VAR2); c) 30 mg/kg bupropion (BUP1); d) 60 mg/kg bupropion (BUP2). In addition to the above treatments, two other treatments were performed: a) animals received nicotine (NIC) in accordance with the method used during the exposure period, receiving additionally vehicle solution by gavage; b) animals receiving nicotine (NIC) and who received, by gavage, VAR1. The following experimental groups were then formed (exposure-treatment): 1) SAC-VEH; 2) SAC-NIC; 3) SAC-VAR1; 4) SAC-VAR2; 5) SAC-NICVAR1; 6) SAC-BUP1; 7) SAC-BUP2; 8) NIC-VEH; 9) NIC-NIC; 10) NIC-VAR1; 11) NIC-VAR2; 12) NIC-NICVAR1; 13) NIC-BUP1; 14) NIC-BUP2. The animals were behaviorally tested in one of three different periods: a) During treatment (LCE in PN54 and CA in PN55); (b) with 5 days of termination of treatment (LCE in PN61 and CA in PN62); c) with 10 days of termination of treatment (LCE in PN66 and CA in PN67). Different animals were used in each period. Regarding the LCE, our main findings indicate that, during treatment, bupropion partially reversed the ansiogenic effect of the exposure to nicotine, while varenicline did not present a consistent improvement in the results. With 5 days of termination, no effects on anxiety associated with bupropion were observed, but the combined treatment of nicotine with varenicline was markedly anxiolytic. With 10 days of termination, the lower dose of bupropion normalized the levels of anxiety-like behavior. In this same period, the combined treatment with varenicline and nicotine normalized the anxiolytic behavior from exposure to nicotine, while treatment only with varenicline (either dose) presented an anxiolytic effect. No effects of exposure or treatment were observed on the locomotor activity. Our results suggest that treatment with bupropion and varenicline, in combination or not with nicotine, have a safe profile for use during adolescence. A nicotina é a principal substância farmacologicamente ativa no cigarro responsável pela dependência. Tem sido demonstrado que os adolescentes, ao serem expostos à nicotina, aumentam os riscos de adquirir dependência duradoura. Estratégias para facilitar a interrupção do seu uso têm sido desenvolvidas, porém pouco se sabe sobre os efeitos da exposição à nicotina na adolescência e menos ainda dos efeitos de curto e longo prazos dos tratamentos disponíveis para a reversão da dependência. O objetivo desse trabalho foi analisar o comportamento no teste do Labirinto em Cruz Elevado (LCE) e no Campo Aberto (CA) de camundongos expostos à nicotina na adolescência e em seguida tratados com vareniclina ou bupropiona. Do dia pós-natal 30 (PN30) a PN45, 899 camundongos Suíços de ambos os sexos foram expostos a uma solução de sacarina a 2% contendo 50µg/ml de nicotina (NIC) ou uma solução de sacarina a 2% (SAC) em garrafas plásticas padrão. De PN46 a PN56, os animais foram tratados por via oral (gavagem) com um dos seguintes fármacos: a) vareniclina a 0,1 mg/kg (VAR1); b) vareniclina a 1,0 mg/kg (VAR2); c) bupropiona a 30 mg/kg (BUP1); d) bupropiona a 60 mg/kg (BUP2). Além dos tratamentos citados acima, dois outros tratamentos foram realizados: a) animais receberam nicotina (NIC) na conforme o método utilizado no período de exposição, recebendo adicionalmente gavagem de solução veículo; b) animais que receberam nicotina (NIC) e que receberam, por gavagem, VAR1. Os seguintes grupos experimentais foram formados (exposição - tratamento): 1) SAC-VEH; 2) SAC-NIC; 3) SAC-VAR1; 4) SAC-VAR2; 5) SAC-NICVAR1; 6) SAC-BUP1; 7) SAC-BUP2; 8) NIC-VEH; 9) NIC-NIC; 10) NIC-VAR1; 11) NIC-VAR2; 12) NIC-NICVAR1; 13) NIC-BUP1; 14) NIC-BUP2. Os animais foram comportamentalmente testados em um de três períodos diferentes: a) durante a vigência do tratamento (LCE em PN54 e CA em PN55); b) com 5 dias de encerramento do tratamento (LCE em PN61 e CA em PN62); c) com 10 dias de encerramento do tratamento (LCE em PN66 e CA em PN67). Animais diferentes foram utilizados em cada período. Em relação ao EPM, nossos principais resultados indicam que, durante a vigência, a bupropiona reverteu parcialmente o efeito ansiogênico da exposição à nicotina enquanto que a vareniclina não apresentou uma melhora consistente nos resultados. Com 5 dias de retirada, não foram observados efeitos sobre a ansiedade associadas à bupropiona, mas o tratamento combinado de nicotina com vareniclina foi marcadamente ansiolítico. Com 10 dias de retirada da bupropiona, a dose menor deste fármaco normalizou os níveis de comportamento associado à ansiedade dos animais expostos à nicotina. Neste mesmo período, o tratamento combinado de nicotina com vareniclina normalizou o comportamento ansiolítico da exposição à nicotina enquanto que o tratamento só com vareniclina (qualquer das doses) apresentou um efeito ansiolítico. Não foram observados efeitos da exposição ou tratamento sobre a atividade locomotora total dos animais. Os nossos resultados sugerem que tanto o tratamento com bupropiona quanto com vareniclina, em combinação ou não com a nicotina, apresentam um padrão seguro de uso ainda durante a adolescência.

Submitted by Boris Flegr (boris@uerj.br) on 2021-01-06T20:59:07Z No. of bitstreams: 1 Dayse Gomes Correa de Almeda Dissertacao completa.pdf: 2070551 bytes, checksum: ac0a85be3726dd293e927a72bcfd1dc0 (MD5) Made available in DSpace on 2021-01-06T20:59:07Z (GMT). No. of bitstreams: 1 Dayse Gomes Correa de Almeda Dissertacao completa.pdf: 2070551 bytes, checksum: ac0a85be3726dd293e927a72bcfd1dc0 (MD5) Previous issue date: 2014-12-15 There is an important association between nutritional, hormonal and environmental parameters during early life (pregnancy and lactation periods) and development of chronic diseases during adult life such as: cardiovascular diseases, obesity, diabetes, anxiety and depression. Previously we demonstrated that rats treated with leptin injections (8µg/100g/day, sc) during the first 10 days of lactation presented increase of anxiety, exploratory activity, hyperleptinemia, overweight, leptin resistance, hyperinsulemia, hypercorticosteronemia and hypertrigliceridemia at adulthood. We propose to investigate, trough longitudinal study, behavioral and metabolic-endocrine programming caused by hyperleptinemia exposure during the first 10 days of lactation and evaluate if these changes can be prevented by exposure to enriched environment during adolescence period. Initially were obtained 2 experimental groups treated during the first 10 days of lactation (PN1-PN10) with: Saline (50µL/day, sc) or leptin (8µg/100g/day, sc). At PN30, some litters were allocated at new environment conditions (enriched environment cage), while other litters remained in a standard cage. Litters were subdivided into 4 groups: 1) C Group: Neonatal exposure to saline; 2) L Group: Neonatal exposure to leptin; 3) CEE Group: Neonatal exposure to saline and adolescent exposure to an enriched environment (PN30-PN45); 4) LEE Group: Neonatal exposure to leptin and adolescent exposure to an enriched environment. We evaluated the metabolic endocrine profile as well as anxiety-like and novelty-seeking behaviors using Elevated Plus Maze (EPM) and Hole Board (HB), respectively, before and after to enriched environment exposure. Regarding anxiety, it was initially observed an anxiolytic effect of leptin on PN21 and PN30, which was lost during development and contradictorily resulted in higher anxiety on PN150. Was observed a higher exploratory activity in PN30 and PN150. Behavioral disorders in adulthood were acompained by metabolic-endocrine dysfunction, such as: hyperleptinemia, overweight, leptin resistance, hypertrigliceridemia, hypercorticosteronemia and increase of free T4, which were prevented by enriched environment exposure during adolescence. Therefore, it was demonstrated that enriched environment exposure for 15 days during adolescence, showed itself a promising non-farmacologic treatment strategy in prevention of long-lasting behavioral and metabolic endocrine disorders induced by neonatal hyperletinemia. Há uma associação importante entre alterações em parâmetros nutricionais, hormonais ou ambientais no inicio da vida (gestação e lactação) e o surgimento de doenças crônicas na vida adulta tais como doenças cardiovasculares, obesidade, diabetes, ansiedade e depressão. Previamente demonstramos que ratos tratados com injeções de leptina (8μg/100g, dia, sc) nos 10 primeiros dias de lactação apresentaram aumento da ansiedade e da atividade exploratória, hiperleptinemia, sobrepeso, resistência a leptina, hiperinsulinemia, hipercorticosteronemia e hipertrigliceridemia quando adultos. Propomos então investigar, através de estudo longitudinal, as alterações comportamentais e endócrino-metabólicas ocasionadas pela programação pela hiperleptinemia nos 10 primeiros dias de vida e avaliar se estas alterações podem ser prevenidas pela exposição ao ambiente enriquecido durante a adolescência. Inicialmente foram obtidos 2 grupos experimentais que foram tratados durante os 10 primeiros dias da lactação (PN1-PN10) com: salina (50 µL, dia, sc) ou leptina (8μg/100g, dia, sc). Em PN30, parte das ninhadas foi alocada em novas condições de habitação (gaiola de ambiente enriquecido), enquanto outra parte permaneceu em gaiola padrão. As ninhadas foram subdivididas em 4 grupos: 1) Grupo C: exposto a salina no período neonatal; 2) Grupo L: exposto a leptina no período neonatal; 3) Grupo CAE: exposto a salina no período neonatal e ao ambiente enriquecido na adolescência (PN30 PN45); 4) Grupo LAE: exposto a leptina no período neonatal e ao ambiente enriquecido na adolescência. Avaliamos o perfil endócrino-metabólico e os comportamentos associados à ansiedade e à busca pela novidade através do labirinto em cruz elevado (LCE) e campo vazado (CV), respectivamente, antes e após a exposição ao ambiente enriquecido. Em relação aos níveis de ansiedade, foi observado inicialmente um efeito ansiolítico da leptina em PN21 e PN30 o qual foi perdido ao longo do desenvolvimento, e contraditoriamente resultou em maior ansiedade em PN150. Foi observado aumento da atividade exploratória em PN30 e PN150. Os prejuízos comportamentais na idade adulta foram acompanhados disfunções endócrino-metabólicas, como: hiperleptinemia, sobrepeso, resistência a leptina, hipertrigliceridemia, hipercorticosteronemia e aumento de T4 livre, os quais foram prevenidos pela exposição ao ambiente enriquecido durante a adolescência. Assim, evidenciamos que a exposição ao ambiente enriquecido por 15 dias no período da adolescência, se mostrou uma estratégia de tratamento não-farmacológica promissora na prevenção de alterações comportamentais e endócrino-metabólicas a longo prazo induzidas pela hiperleptinemia neonatal.

Submitted by Boris Flegr (boris@uerj.br) on 2021-01-06T20:57:44Z No. of bitstreams: 1 Sylvio Claudio Neto Dissertacao completa.pdf: 560025 bytes, checksum: 57c205c341dd148d601ab3b78e8a199b (MD5) Made available in DSpace on 2021-01-06T20:57:44Z (GMT). No. of bitstreams: 1 Sylvio Claudio Neto Dissertacao completa.pdf: 560025 bytes, checksum: 57c205c341dd148d601ab3b78e8a199b (MD5) Previous issue date: 2011-09-30 Conselho Nacional de Desenvolvimento Científico e Tecnológico Maternal nicotine exposure during lactation in rats rogrammes for hyperleptinemia and hypothyroidism in the adult offspring. Changes in the levels of these hormones are known to affect behavior. Hence, here we investigated the short- and long-term behavioral effects of neonatal nicotine exposure in Wistar rats. Lactating rats implanted with minipumps either containing nicotine (NIC=6mg/Kg/day) or a solution with equivalent concentration of saline (C) during the second postnatal day to the nineteenth postnatal (PN) days. Sixty two NIC and 48 C rats were tested according to the following protocol: 1) Either at PN30 or PN75, anxiety levels were assessed in elevated plus-maze (EPM). Entries into each area of the maze (open and closed arms and centre square) were recorded over a period of 10 min; 2) One hour, animals were tested in the hole board arena (HB) in order to assess novelty-seeking behavior. Animals were allowed 10 min to explore. The number of explored holes was noted; 3) Either at PN31 or PN76, learning/memory was assessed in the radial arm water maze (RAWM). Each animal was tested 4 times a day for 5 consecutive days. On the 5th day, the platform was moved to the arm located in the opposite side. They were allowed 2 min to find the hidden escape platform. The latency to find the platform was noted. The percentage of time spent in the open arms of the EPM by PN30 NIC animals (6.4±1.1 %) was significantly (ANOVA: P=0.024) lower than that of PN30 C ones (9.9±1.4 %). The percentage of entries into the open arms was also significantly lower (ANOVA: P0.1). No differences (ANOVA: P>0.1) were observed between groups regarding the number of closed arm entries at both ages. As for the HB test, no differences were observed between groups at both ages (ANOVA: P>0.1). In the RAWM, PN75 NIC animals (274±24 s) displayed a significantly (ANOVA: P0.1). Neonatal nicotine programming results in a short term effect on anxiety-like behavior, observed by a high anxiety levels during adolescence. No difference was observed regarding novelty-seeking behavior. However, neonatal nicotine programming causes a long-term late emerging effect on cognitive-behavior, observed by a better performance in learning\memory task at adulthood. A exposição materna à nicotina durante a lactação em ratos programa para hiperleptinemia e hipotireoidismo na prole adulta. Alterações nos níveis desses hormônios alteram o comportamento. Por isso, resolvemos investigar os efeitos comportamentais a curto e a longo prazo da programação neonatal pela nicotina em ratos Wistar. Foram implantadas minibombas em ratas lactantes contendo nicotina (NIC = 6mg/Kg/Dia) ou uma solução com uma concentração equivalente de solução salina (CON) do 2o dia ao 19o dia de vida pós natal. Sessenta e dois ratos NIC e 48 CON foram testados de acordo com o seguinte protocolo: 1) Em PN30 ou PN75 foram avaliados os níveis de ansiedade no labirinto em cruz elevado (LCE). Entradas em cada área do labirinto (braços abertos e fechados e centro) foram gravadas por um período de 10 minutos; 2) Uma hora após, os animais foram testados no campo vazado (CV) para analisarmos o comportamento de busca por novos estímulos. Os animais tinham 10 minutos para explorar o aparelho. O número de orifícios explorados foi anotado. 3) Em PN31-35 ou PN76-80 o animal foi submetido ao labirinto aquático radial de oito braços (LAROB) para avaliarmos a memória e o aprendizado. Cada animal foi testado 4 vezes por dia durante 5 dias consecutivos sendo a plataforma mantida no mesmo braço durante os 4 primeiros dias e trocada no quinto dia. Eles tinham 2 minutos para encontrar a plataforma de escape. A latência para encontrar a plataforma foi anotada. O percentual de tempo gasto no braço aberto no LCE para os animais NIC em PN30 (6,4±1,1 %) foi significativamente (ANOVA: P=0,024) menor que o grupo controle PN30 (9,9±1,4 %). O percentual de entradas no braço aberto foi significativamente menor (ANOVA: P=0,04) para os animais do grupo NIC em PN30 (32,4±2,9 %) quando comparados com o grupo controle PN30 (38,5±1,8 %). Não foi observada diferença (ANOVA: P>0,1) entre os grupos no número de entradas no braço fechado para as duas idades. Para o CV não houve diferença entre os grupos para as duas idades (ANOVA: P>0,1). No LAROB, os animais PN75 NIC (274±24 s) tiveram uma diminuição significativa (ANOVA: P0,1). A programação neonatal pela nicotina resultou em um efeito a curto prazo no aumento dos níveis de ansiedade na adolescência. Não foi observada diferença no comportamento de busca por novos estímulos. Entretanto a programação neonatal por nicotina resultou em um efeito a longo prazo no comportamento-cognitivo observado pelo melhor desempenho na memória/aprendizado quando adulto.