As part of a health survey of New Zealand sea lions (Phocarctos hookeri) on Enderby Island, Auckland Islands (50°30’S, 166°17’E), neonatal mortality was continuously monitored at the Sandy Bay Beach rookery, from 1998/1999 to 2004/2005. The primary causes of death were categorised as trauma (35%), bacterial (24%) and hookworm (13%) infections, starvation (13%) and stillbirth (4%). During the 2001/2002 and 2002/2003 breeding seasons, bacterial epidemics caused by Klebsiella pneumoniae increased mortality by three times the mean in non-epidemic years. Uncinaria spp. from New Zealand sea lion (NZSL) pups was described for the first time using morphometric criteria. It differed from the two species already described in pinnipeds, Uncinaria lucasi and Uncinaria hamiltoni, suggesting the existence of a different morphotype in NZSLs. A study on the epidemiology of hookworm infection showed that all pups up to at least three months of age harboured adult hookworms in their intestines and transmammary transmission was identified as the route of infection of NZSL pups. Uncinariosis as a primary cause of mortality was generally associated with anaemia, haemorrhagic enteritis and frank blood in the lumen. The relationship between hookworm burden and clinical disease could not be clearly established. The 2001/2002 and 2002/2003 bacterial epidemics at Sandy Bay Beach rookery were caused by a clonal strain of Klebsiella pneumoniae as verified by pulse-field gel electrophoresis and antimicrobial testing. Suppurative arthritis was the most common post-mortem diagnosis during the two epidemic seasons. Internal lesions were consistent with septicaemia, which explained the wide range of organs from which the pathogen was grown in pure culture. A serological test investigating the exposure of NZSLs to Klebsiella spp. showed that the large majority of pups up to two months of age did not have any anti-Klebsiella antibodies, even after the epidemics, but that almost all the adults were seropositive. In addition, passive immunoglobulin (Ig) transfer from lactating females to neonates was examined by measuring IgG levels in pups and was very low compared to terrestrial mammals although similar to other pinniped neonates.

Eleven experiments examined two late-developing learning and memory systems in rats: fear-potentiated startle (FPS) and the contextual regulation of latent inhibition and extinction. The first study was based on three previous developmental findings on FPS: (1) FPS to an odour CS emerges at postnatal day (PN) 23; Rats conditioned at PN16 to an odour CS express freezing but not FPS when tested at PN23, and (3) FPS to an odour CS trained at PN16 is activated if rats are also trained to a difference odour at PN23 (Yap, Stapinski, & Richardson, 2005). Yap et al. (2005) hypothesised that the activation effect only occurs if rats are given training to the second odour at an age when FPS has emerged. Study 1 assessed this hypothesis and trained the second odour CS at either PN23 or PN20. Contrary to expectations, the results of this study showed the activation effect for both groups of rats. Surprisingly, the results also revealed a significant FPS effect to the odour CS trained at PN20. Subsequent experiments examined this unexpected result, and found that learning to odour 1 at PN16 facilitated the age of onset for FPS at PN20. The results of Study 1 are discussed in relation to past findings on enrichment, cumulative learning, and neurobiological models of conditioned fear. The second section of this thesis (Studies 2 and 3) examined the context-specificity of two memory interference paradigms, latent inhibition and extinction, in developing rats. The studies found that both phenomena were context-specific at PN23-25 but not at PN16-18. Moreover, the results suggest that the context-specificity of both latent inhibition depended on the age of the rat during the second phase of training, but not their age during the first phase of training or their age at test. The implications of these findings for theoretical and neural models of learning, as well as the occurrence of latent inhibition and extinction during development are discussed.

Mammalian brain and behaviour are plastic, particularly early in development when offspring are under the care of their mothers. Adverse early life events, such as maternal and social deprivation, have short- and long-term consequences for neurobiology and consequently for behaviour. The purpose of this thesis was to investigate the effects of maternal and social deprivation, through artificial rearing (AR), on adult impulsive behaviour. Rats were raised in isolation from mothers and siblings (AR) or with their mothers and siblings in the nest [maternal rearing (MR)]. In addition, half of the AR rats were provided with replacement somatosensory stimulation designed to simulate mothers’ licking (see Gonzalez et al., 2001). As adults, rats were tested on impulsive action using the differential reinforcement of low rates (DRL) operant task and locomotor activity. Both male and female AR rats were more impulsive than MR rats; they made more responses and they were less efficient at earning rewards. In addition, they displayed greater levels of locomotor activity. These effects were partially reversed by replacement somatosensory stimulation. Furthermore, impulsivity was positively correlated with locomotor activity. Impulsive choice was then assessed using a delay discounting operant schedule. On this task, AR rats were less likely to discount the value of large-delayed reward, suggesting that they were better able to tolerate delays to large reward and were less impulsive. However, performance on a modified version of delay discounting revealed that AR rats were less efficient at switching their responses; that is, they displayed reduced behavioural flexibility. To address this finding, impulsive choice was next assessed in fixed consecutive chain operant schedule of reinforcement, but there were no differences between AR and MR animals. Finally, the relationship between impulsive action and a species-characteristic behaviour, maternal behaviour, was investigated. Consistent with the literature, AR rats were less maternal and more impulsive. Moreover, there was a negative correlation between impulsivity and maternal behaviour. Overall, this set of studies demonstrates that maternal and social deprivation produces an increase in impulsive action without an effect on impulsive choice. Furthermore, increased action impulsiveness is a significant moderator of disrupted maternal behaviour observed in artificially reared rats.

Mammalian brain and behaviour are plastic, particularly early in development when offspring are under the care of their mothers. Adverse early life events, such as maternal and social deprivation, have short- and long-term consequences for neurobiology and consequently for behaviour. The purpose of this thesis was to investigate the effects of maternal and social deprivation, through artificial rearing (AR), on adult impulsive behaviour. Rats were raised in isolation from mothers and siblings (AR) or with their mothers and siblings in the nest [maternal rearing (MR)]. In addition, half of the AR rats were provided with replacement somatosensory stimulation designed to simulate mothers’ licking (see Gonzalez et al., 2001). As adults, rats were tested on impulsive action using the differential reinforcement of low rates (DRL) operant task and locomotor activity. Both male and female AR rats were more impulsive than MR rats; they made more responses and they were less efficient at earning rewards. In addition, they displayed greater levels of locomotor activity. These effects were partially reversed by replacement somatosensory stimulation. Furthermore, impulsivity was positively correlated with locomotor activity. Impulsive choice was then assessed using a delay discounting operant schedule. On this task, AR rats were less likely to discount the value of large-delayed reward, suggesting that they were better able to tolerate delays to large reward and were less impulsive. However, performance on a modified version of delay discounting revealed that AR rats were less efficient at switching their responses; that is, they displayed reduced behavioural flexibility. To address this finding, impulsive choice was next assessed in fixed consecutive chain operant schedule of reinforcement, but there were no differences between AR and MR animals. Finally, the relationship between impulsive action and a species-characteristic behaviour, maternal behaviour, was investigated. Consistent with the literature, AR rats were less maternal and more impulsive. Moreover, there was a negative correlation between impulsivity and maternal behaviour. Overall, this set of studies demonstrates that maternal and social deprivation produces an increase in impulsive action without an effect on impulsive choice. Furthermore, increased action impulsiveness is a significant moderator of disrupted maternal behaviour observed in artificially reared rats.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Lead (Pb) is a toxic metal without biological function, which can cause various undesirable changes in organism. Developing animals are more sensitive to external aggressions, and exposure to Pb may cause pronounced and even irreversible damage. Studies show detoxifyng action by zinc chloride (ZnCl2) and N-acetylcysteine (NAC), suggesting same protective effect against intoxication with Pb. Therefore, we investigated the toxic effect of lead acetate (AcPb) on biochemical and behavioral parameters, in developing animals, and the possible protective effect of ZnCl2 and NAC. For this young Wistar rats received subcutaneously: saline, ZnCl2 (27 mg/kg), NAC (5 mg/kg) or more NAC ZnCl2 from the 3rd to 7 th; and AcPb (7 mg/kg) or saline from the 8th to 12th day of age. The animals were subjected to behavioral tasks: negative geotactismo, the tail immersion test beaker and open field to assess neurological damage and motors. They were sacrificed at 33 days and the biological samples were stored for further analysis. We assessed the body weight, the activity of porphobilinogen synthase (PBG synthase) in blood, acetylcholinesterase (AChE) in brain and cerebellum, hemoglobin (Hb) in whole blood, serum urea and creatinine, and blood, cerebrum and cerebellum levels. Pups exposed to AcPb presented a decrease of blood PBG-synthase activity, without changes in Hb content. ZnCl2 pre-exposure partially prevented the PBG-synthase inhibition. Pb caused a decrease in the activity of brain AChE, while the treatment with ZnCl2, NAC and ZnCl2 more NAC prevented this change. In addition, animals exposed to AcPb presented Pb accumulation in blood and brain; all preventive treatments decreased Pb levels. In summary, the results show that there was an accumulation of Pb and inhibition of the activity of two enzymes, which are important biomarkers of toxicity. As preventive treatments, the protector effect of ZnCl2 may related to its capacity of to induce the biosyntese of metal ligant proteins. As to NAC, it is probable that its protective effect is related to chelating effects. / O chumbo (Pb) é um metal tóxico, sem função biológica, o qual pode provocar várias alterações indesejadas no organismo. Animais em desenvolvimento apresentam maior sensibilidade à agressões externas, e a exposição ao Pb poderá provocar danos pronunciados e até mesmo irreversíveis. Alguns trabalhos sugerem que o cloreto zinco (ZnCl2) e a N-acetilcisteína (NAC) possuem ação detoxificante, podendo então, ter um efeito protetor frente a uma intoxicação com Pb. Sendo assim, buscamos investigar o efeito tóxico do acetato de chumbo (AcPb) em parâmetros bioquímicos e comportamentais, quando administrado em animais em desenvolvimento, e a possível ação protetora do ZnCl2 e da NAC sobre esta toxicidade. Para isso ratos Wistar jovens receberam subcutaneamente: salina, ZnCl2 (27 mg/kg), NAC (5 mg/kg) ou ZnCl2 mais NAC do 3o ao 7o; e AcPb (7 mg/kg) ou salina do 8o ao 12o dia de idade. Os animais foram submetidos às tarefas comportamentais: geotactismo negativo, imersão da cauda, teste do becker e campo aberto para avaliação de danos neurológicos e motores. Foram sacrificados aos 33 dias e as amostras biológicas foram guardadas para análises posteriores. Avaliou-se: o peso corporal; a atividade das enzimas porfibilinogênio-sintase (PBG-sintase) em sangue, acetilcolinesterase (AChE) em cérebro e cerebelo; níveis de hemoglobina (Hb) em sangue total, de ureia e creatinina em soro; níveis de metalotioneíanas (MT) em sangue, fígado e cérebro; dosagem de metais em sangue, cérebro e cerebelo. Filhotes expostos ao AcPb apresentaram diminuição da atividade da PBG-sintase de sangue, sem alterações no conteúdo de Hb. O ZnCl2 preveniu parcialmente a inibição PBG-sintase. O AcPb causou diminuição na atividade da AChE de cérebro, enquanto os tratamentos com ZnCl2, NAC e ZnCl2 mais NAC preveniram essa alteração. Além disso, os animais expostos ao AcPb apresentaram acúmulo de Pb em sangue e cérebro; todos os tratamentos preventivos diminuiram os níveis de Pb. Em resumo, os resultados mostram que houve um acúmulo de Pb nos tecidos onde houve inibição das enzimas, que são importantes biomarcadores de toxicidade; acredita-se que a inibição ocorra através da ligação do metal aos grupamentos tiois das enzimas. Quanto aos tratamentos preventivos, o efeito protetor do zinco pode estar ligado a indução de proteínas ligantes de metais. Ainda, sugere-se que a proteção exercida pela NAC está ligada a sua capacidade quelante.

<p>Developing bat pups produce distinct vocalizations called isolation calls (I‐calls) that serve to attract the bat’s mother. How individual pups shift their vocalizations from I‐calls to downward frequency modulated (FM) sweeps during development remains unclear. By recording individual bat pups from the day of birth to twenty‐five days postnatal we observed behavioural and bioacoustic (temporal and spectral) changes in pup calls. Temporal characteristics examined were call duration and call rate; spectral characteristics were minimum frequency, maximum frequency, peak spectral frequency, total signal bandwidth, maximum frequency of the fundamental acoustic element and bandwidth of the fundamental. I‐calls were produced only until a certain point in development, after which pups change from emitting long‐duration, tonal I‐calls to downward FM signals and eventually short‐duration biosonar vocalizations. We discovered additional spectral changes in the harmonic structure of pup calls, with the number of harmonic elements decreasing with age. We also recorded pup vocalizations during prolonged separation from their mothers to determine if extended isolation alters the type, number or acoustic structure of emitted vocalizations. Rate of calling was influenced by prolonged separation; younger pups had higher calling rates and called longer than older pups. We also compared temporal and spectral characteristics of spontaneous and provoked calls. We found that provoked calls were more similar to vocalizations produced by younger pups. By documenting the vocal behaviour and acoustic structure of pups calling in different situations, this research provides groundwork for further studies on the ontogeny and development of FM vocalizations in bats and other mammals.</p> / Master of Science (MSc)

Vários estudos realizados com roedores permitem analisar, entre outros fatores, as respostas dos animais à novidade, a emocionalidade e locomoção dos animais. Para tal, vários testes tem sido empregados e um dos mais utilizados é o do campo aberto. O presente estudo visa analisar o papel da presença de um animal adulto da mesma espécie, ou de espécie diferente, no comportamento exploratório e na ocupação das áreas de um campo aberto por filhotes de rato, testados em duas condições: agrupados ou individualmente. Na primeira condição os testes de exploração foram feitos em um campo aberto. Em uma das paredes do campo aberto foi acoplada uma gaiola que em diferentes momentos continha uma fêmea da mesma espécie (Rattus norvegicus), um macho da mesma espécie (ambos não familiarizados com os filhotes), a própria ama-de-leite ou uma fêmea de outra espécie, no caso, uma cobaia (Cavia porcelus). As sessões experimentais foram realizadas no vigésimo quinto dia de vida dos filhotes. Os animais foram divididos em cinco ninhadas compostas por oito filhotes cada uma: quatro machos e quatro fêmeas., testados juntos em uma única sessão. O primeiro grupo foi testado no campo aberto sem qualquer tipo de estímulo na gaiola. Os outros grupos foram testados, respectivamente, na presença da ama-de-leite, de uma outra rata, de um rato macho ou de uma cobaia. Na segunda condição, os sujeitos de outras cinco ninhadas foram testados nas mesmas circunstâncias, porém individualmente. Os resultados mostraram que a presença de um animal adulto altera a preferência pela ocupação dos cantos mais estruturados por filhotes de rato em campo aberto. Quando o adulto presente é um co-especifico, a tendência dos filhotes é de se aproximar do local onde o animal se encontra (gaiola). Na presença de um animal de outra espécie, a tendência é, num primeiro momento, de aproximação e posteriormente de permanência nos locais mais estruturados do campo aberto, como as áreas de duas paredes, igual aos testados com a gaiola vazia. Os animais apresentaram diferenças de comportamento devidos ao agrupamento. Os filhotes agrupados frequentaram mais a periferia do campo aberto e passaram mais tempo nestas áreas que os testados individualmente, que por sua vez tendem a se aproximar mais do adulto do que os testados em grupo. Na idade em que foram testadas, as fêmeas mostraram-se menos ansiosas que os machos. De um modo geral, a principal conclusão é a de que filhotes de rato expostos a um campo aberto na presença de um adulto, exibem preferência pelas proximidades do adulto quando este é um co-específico, tendendo a permanecer nas áreas mais estruturadas quando o animal presente é de outra espécie. / Several studies with rodents allow us to analyze, among other factors, the responses of animals to novelty, emotionality and locomotion of animals. For this, several tests have been used and one of the most frequently used is the open-field. The present study aims at examining the role of the presence of an adult animal of the same species, or of a different species, in the exploratory behavior and the occupation of areas of an open-field by rat pups, tested in two conditions: grouped and individually. In the first condition, exploration tests were done in an open-field. In one wall of the open-field a cage was connected which, in different occasions, contained a female of the same species (Rattus norvegicus), a male of the same species (both unfamiliar to the pups), the dam or a female of another species, in this case, a guinea-pig (Cavia porcelus). The experimental sessions occurred at the twenty-fifth day of life of the of pups. The animals were divided into five eight-pup litters with four males and four females, which were tested together in a single session. The first group was tested in the open-field without any kind of stimulus in the cage. The other groups were tested, respectively, in the presence of the dam, another female, a male or a female guinea-pig. In the second condition, all subjects in a litter were tested under the same circumstances, but individually. The results showed that the presence of an adult animal changes the preference for the occupation of the more structured corners by rat pups in the open-field. When the animal in the cage was an adult co-specific, the tendency of the subjects was to approach the place where the adult animal was (the cage). In the presence of an animal of another species, the trend was, at first, to approach and subsequently to spent more time in the most structured corners of the open-field, areas with two walls. The animals showed behavioral differences due to grouping. The grouped pups went more often to the periphery of the open-field and spent more time in these areas than those tested individually, which, in turn, tended to be close to the adult longer than the grouped subjects. At the age they were tested, female infants were less anxious than males. In general, the main conclusion is that rat pups exposed to an open-field in the presence of an adult, exhibit a preference for the vicinity of the adult when it is a co-specific, tending to remain in the more structured areas when the cage was empty or when the animal in the cage belonged to another species.

Studying the reintroduction of hand-raised wolves may embrace several interests such as deepening knowledge on wolf biology and allowing a controlled release in isolated populations in need of genetic influx. Studies on hand-raised wild animals, showing successful reintroduction, suggested that young released wolves might be able to survive in the wild without previous fastidious training. Most of their survival behaviours would be instinctive. In this study, nine young wolves were reintroduced in Tver region (Russia) and followed in order to evaluate their fear of humans, their movement patterns, thanks to GPS-Argos collars fitted to three of the animals, and assess their diet via four methods of scats analysis. We analyzed 46 wolf scats collected from August 2010 to January 2011. We determined the frequency of occurrences of items per scats and per items, and used the Relative Estimated Bulk to estimate the biomass of prey species consumed. Statistics were conducted to test for significance of method comparisons. The results showed that half of the wolves remained near the enclosure weeks to months after release, occasionally leaving the vicinity. The individual wolves behaved differently, they adopted various movement patterns and had diverse home ranges (from 15 km2 to 40 km2). Released wolves preyed more on ungulates, especially moose and on other wild mammals such as mountain hare. They also sporadically hunted domestic animals and regularly consumed vegetal matter along with smaller animals as alternative prey. Finally, all scat-analysis methods significantly assessed (p &lt; 0.01) the relative importance of the main food types.

Vários estudos realizados com roedores permitem analisar, entre outros fatores, as respostas dos animais à novidade, a emocionalidade e locomoção dos animais. Para tal, vários testes tem sido empregados e um dos mais utilizados é o do campo aberto. O presente estudo visa analisar o papel da presença de um animal adulto da mesma espécie, ou de espécie diferente, no comportamento exploratório e na ocupação das áreas de um campo aberto por filhotes de rato, testados em duas condições: agrupados ou individualmente. Na primeira condição os testes de exploração foram feitos em um campo aberto. Em uma das paredes do campo aberto foi acoplada uma gaiola que em diferentes momentos continha uma fêmea da mesma espécie (Rattus norvegicus), um macho da mesma espécie (ambos não familiarizados com os filhotes), a própria ama-de-leite ou uma fêmea de outra espécie, no caso, uma cobaia (Cavia porcelus). As sessões experimentais foram realizadas no vigésimo quinto dia de vida dos filhotes. Os animais foram divididos em cinco ninhadas compostas por oito filhotes cada uma: quatro machos e quatro fêmeas., testados juntos em uma única sessão. O primeiro grupo foi testado no campo aberto sem qualquer tipo de estímulo na gaiola. Os outros grupos foram testados, respectivamente, na presença da ama-de-leite, de uma outra rata, de um rato macho ou de uma cobaia. Na segunda condição, os sujeitos de outras cinco ninhadas foram testados nas mesmas circunstâncias, porém individualmente. Os resultados mostraram que a presença de um animal adulto altera a preferência pela ocupação dos cantos mais estruturados por filhotes de rato em campo aberto. Quando o adulto presente é um co-especifico, a tendência dos filhotes é de se aproximar do local onde o animal se encontra (gaiola). Na presença de um animal de outra espécie, a tendência é, num primeiro momento, de aproximação e posteriormente de permanência nos locais mais estruturados do campo aberto, como as áreas de duas paredes, igual aos testados com a gaiola vazia. Os animais apresentaram diferenças de comportamento devidos ao agrupamento. Os filhotes agrupados frequentaram mais a periferia do campo aberto e passaram mais tempo nestas áreas que os testados individualmente, que por sua vez tendem a se aproximar mais do adulto do que os testados em grupo. Na idade em que foram testadas, as fêmeas mostraram-se menos ansiosas que os machos. De um modo geral, a principal conclusão é a de que filhotes de rato expostos a um campo aberto na presença de um adulto, exibem preferência pelas proximidades do adulto quando este é um co-específico, tendendo a permanecer nas áreas mais estruturadas quando o animal presente é de outra espécie. / Several studies with rodents allow us to analyze, among other factors, the responses of animals to novelty, emotionality and locomotion of animals. For this, several tests have been used and one of the most frequently used is the open-field. The present study aims at examining the role of the presence of an adult animal of the same species, or of a different species, in the exploratory behavior and the occupation of areas of an open-field by rat pups, tested in two conditions: grouped and individually. In the first condition, exploration tests were done in an open-field. In one wall of the open-field a cage was connected which, in different occasions, contained a female of the same species (Rattus norvegicus), a male of the same species (both unfamiliar to the pups), the dam or a female of another species, in this case, a guinea-pig (Cavia porcelus). The experimental sessions occurred at the twenty-fifth day of life of the of pups. The animals were divided into five eight-pup litters with four males and four females, which were tested together in a single session. The first group was tested in the open-field without any kind of stimulus in the cage. The other groups were tested, respectively, in the presence of the dam, another female, a male or a female guinea-pig. In the second condition, all subjects in a litter were tested under the same circumstances, but individually. The results showed that the presence of an adult animal changes the preference for the occupation of the more structured corners by rat pups in the open-field. When the animal in the cage was an adult co-specific, the tendency of the subjects was to approach the place where the adult animal was (the cage). In the presence of an animal of another species, the trend was, at first, to approach and subsequently to spent more time in the most structured corners of the open-field, areas with two walls. The animals showed behavioral differences due to grouping. The grouped pups went more often to the periphery of the open-field and spent more time in these areas than those tested individually, which, in turn, tended to be close to the adult longer than the grouped subjects. At the age they were tested, female infants were less anxious than males. In general, the main conclusion is that rat pups exposed to an open-field in the presence of an adult, exhibit a preference for the vicinity of the adult when it is a co-specific, tending to remain in the more structured areas when the cage was empty or when the animal in the cage belonged to another species.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / In recent years have been identifical numerous pharmacological properties of a selenium compound, diphenyl diselenide [(PhSe)2]. Consequently, it is important the investigation of its toxic effect for a safe application in pharmacological studies. It is known that babies, in particular, have many physiological and biochemical changes related to development, which increase the susceptibility to toxic effects of drugs. Thus, the article 1 investigated the appearance of seizure episodes induced by (PhSe)2 when administered orally at doses of 5 to 500 mg/kg in rat pups (pos natal day 12-14) and the possible glutamatergic (article 2) and GABAergic (article 3) mechanisms involved in this process. Some studies using different experimental models have demonstrated the most different pharmacological and toxicodynamics properties of (PhSe)2. However, little is known about the toxicokinetic disposition of this compound. Therefore, the aim of article 4 was to determine and quantify the plasma levels of (PhSe)2 in adult mice and rats after oral (p.o.) administration of 500 mg/kg (PhSe)2; to verify the involvement of different routes of administration, vehicle and animal species in plasma levels of (PhSe)2 and in the onset of the first seizure episode induced by it. In article 5, it was determined and quantified the levels of (PhSe)2 in plasma, liver and brain of rat pups and these levels were correlated to the latency for the onset of the first seizure episode. To obtain more information about the compound, which were to supplement the data obtained, we carried out in vitro kinetic models. The manuscript 1 investigated the drug-like properties of (PhSe)2 in regards to stability, solubility, absorption and plasma protein binding (PPB) in vitro. In manuscript 2, it was conducted an in vitro study in order to identify possible metabolic pathways responsible for the biotransformation of (PhSe)2 in the body. Results of article 1 showed that administration of (PhSe)2 caused toxicity in rat pups, evidenced by the appearance of seizures. These were dose dependent and were, at least in part, related to oxidative stress. Among the mechanisms involved in the convulsive effect of (PhSe)2 were the interaction with: glutamatergic system by stimulating the inotropic glutamatergic receptors NMDA and by inhibiting the uptake of glutamate (Article 2); GABAergic system by antagonize the GABAA receptor, stimulating GABA transaminase enzyme and increasing GABA uptake (Article 3). The article 4 revealed that the maximum concentration of (PhSe)2 in the plasma of adult rats and mice occurred 30 minutes after p.o administration of the compound and remained detectable up to 8 hours after administration. The use of different routes of administration (intraperitoneal (i.p.), p.o., subcutaneous (s.c.)) or vehicle (canola oil or dimethyl sulfoxide (DMSO)) in rats and mice indicated that the onset of the first seizure episode and plasma levels are dependent on the route of administration (i.p. > p.o. > s.c.), vehicle (DMSO > canola oil) and animal species (mouse > rat). In article 5, it was observed that rat pups showed seizures even presenting lower plasma values of (PhSe)2 as compared to adults. This result demonstrated that rat pups are more sensitive to the toxic effects of (PhSe)2 than adult rats. Levels of (PhSe)2 in the liver and brain of rat pups showed a negative correlation with the latency to the first seizure episode. The manuscript 1 showed that (PhSe)2 has chemical and biological stability. However, the compound has a low solubility in water, a high partition coefficient octanol-water and an extensive plasma protein binding. Manuscript 2 indicated that (PhSe)2 is not biotranformed by Phase I reactions, catalyzed by cytochrome P450. It reacted chemically with reduced glutathione (GSH) and N-acetylcysteine (NAC) to form adducts or reacts with protein SH groups. The presence of GSH or NAC in the incubation medium decreased the binding of (PhSe)2 protein. Finally, it was observed that (PhSe)2 reduced the activity of cytochrome P450. Together, the data presented showed that the intensity of toxic effects caused by (PhSe)2 are directly related to its toxicokinetic. / Nos últimos anos, têm sido identificadas inúmeras propriedades farmacológicas do composto de selênio disseleneto de difenila [(PhSe)2]. Assim, a pesquisa dos efeitos tóxicos deste composto torna-se importante para a segurança na aplicação farmacológica. Sabe-se que os bebês, em particular, apresentam muitas mudanças fisiológicas e bioquímicas relacionadas ao desenvolvimento, que aumentam a suscetibilidade aos efeitos tóxicos de drogas. Desta forma, no artigo 1 investigou-se o aparecimento de convulsões induzida pelo (PhSe)2, quando administrado pela via oral (p.o), nas doses de 5 à 500 mg/kg em ratos bebês (12-14 dias de vida) bem como os possíveis mecanismos glutamatérgicos (Artigo 2) e GABAérgicos (Artigo 3) envolvidos em tal processo. Vários estudos, utilizando diferentes modelos experimentais demonstraram as mais diferentes propriedades farmacológicas e toxicodinâmicas do (PhSe)2 no entanto, pouco se conhece sobre a toxicodinâmica deste composto. Por isso, o objetivo do artigo 4 foi determinar e quantificar os níveis plasmáticos de (PhSe)2 em ratos e camundongos adultos após a administração p.o. de (PhSe)2 na dose de 500 mg/kg; bem como verificar o envolvimento de diferentes vias de administração, veículos e espécie animal nos níveis plasmáticos do composto e no aparecimento de convulsões induzidas pelo mesmo. No artigo 5, determinou-se e quantificou-se os níveis de (PhSe)2 no plasma, fígado e cérebro de ratos bebês e correlacionou-se estes níveis à latência para o aparecimento de convulsões. Devido a necessidade de obter mais informações sobre o composto, que viessem a complementar os dados obtidos, realizou-se modelos cinéticos in vitro. O manuscrito 1 investigou parâmetros relacionados a estabilidade, solubilidade, absorção e ligação às proteínas plasmáticas do (PhSe)2 in vitro. No manuscrito 2 realizou-se um estudo in vitro para identificar as vias metabólicas responsáveis pela biotransformação do (PhSe)2 no organismo. Os resultados do artigo 1 demonstraram que a administração de (PhSe)2 causou toxicidade em ratos bebês, evidenciada pelo aparecimento de convulsões. Estas são dependentes da dose utilizada e estão, pelo menos em parte, relacionadas ao estresse oxidativo. Dentre os mecanismos neuroquímicos envolvidos no efeito convulsivante do (PhSe)2 estão a interação com o sistema glutamatérgico, por estimular os receptores glutamatérgicos ionotrópicos do tipo NMDA e por inibir a captação de glutamato (Artigo 2); e com o sistema GABAérgico, por antagonizar os receptores GABAégicos do tipo GABAA, estimulando a enzima GABA transaminase e estimulando a captação de GABA (Artigo 3). O artigo 4 demonstrou que concentração máxima de (PhSe)2 no plasma de ratos e camundongos adultos ocorreu 30 minutos após a administração pela via oral do composto e permaneceu detectável até 8 horas após sua administração. O uso de diferentes vias de administração (intraperitonial (i.p); p.o; subcutânea (s.c)) e veículo (óleo de canola ou dimetil sulfóxido (DMSO)) em ratos e camundongos indicou que o aparecimento de convulsões e os níveis plasmáticos de (PhSe)2 são dependentes da via de administração (i.p > p.o > s.c), do veículo (DMSO > óleo de canola) e da espécie animal (camundongo > rato). No artigo 5 observou-se ainda que os ratos bebês convulsionaram mesmo apresentando níveis plasmáticos menores de composto que os adultos, o que nos leva a crer que estes são mais sensíveis aos feitos tóxicos do (PhSe)2. Os níveis de (PhSe)2 no fígado e no cérebro de ratos bebês no momento do episódio convulsivo apresentaram uma correlação negativa com a latência para o primeiro episódio convulsivo. O manuscrito 1 revelou que o (PhSe)2 apresenta estabilidade química e biológica. No entanto, o composto apresenta uma baixa solubilidade em água, um alto coeficiente de partição octanol-água e uma extensa ligação às proteínas plasmáticas. O manuscrito 2 indicou que o (PhSe)2 não é biotransformado por reações de fase I catalizadas pelo citocromo P450. O composto reage quimicamente com a glutationa reduzida (GSH) e a N-acetilciateína (NAC), formando adutos ou ainda reage com grupos SH de proteínas. A presença de GSH ou NAC no meio de incubação diminuiu a ligação do (PhSe)2 às proteínas. Por fim, foi observado que o (PhSe)2 reduziu a atividade das enzimas do citocromo P450. Em conjunto, os resultados desta tese demonstraram que a intensidade dos efeitos tóxicos causados pelo (PhSe)2 estão diretamente relacionados a sua toxicocinética.