Monosialoganglioside (GM1) is a component of most cell membranes and is thought to play a role in development, recognition and cellular differentiation. Furthermore, GM1 is a neuroprotective agent that has been reported to scavenge free radicals generated during reperfusion and to protect receptors and enzymes from oxidative damage. In the present study we investigate the effect of GM1 on the catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities, on the spontaneous chemiluminescence and total radical-trapping potential (TRAP) in cortex of rats ex vivo and in vitro. Systemic GM1 administration (50 mg/kg, i.p.; twice) reduced spontaneous chemiluminescence and increased CAT activity ex vivo. On the other hand, GM1 (103-104 nM) reduced CAT activity in vitro. The other parameters were not affected by GM1 administration. These findings agree with the view that the antioxidant action of GM1 is not due to an intrinsic antioxidant activity of this glycolipid, but due to a secondary decrease of reactive species generation and/or increase of antioxidant defenses. Moreover, we evaluated whether GM1 could have a neuroprotective action on the experimental model of glutaric acidemia, an inherited metabolic disorder characterized by glutaric acid (GA) accumulation and neurological dysfunction, as striatal degeneration and convulsion. The systemic GM1 administration (50 mg/kg, i.p. twice) protected against the convulsions, oxidative damage markers increase (total protein carbonylation and thiobarbituric acid-reactive substances - TBARS) production and Na+,K+-ATPase activity inhibition induced by GA (4 mol/ 2 l) in striatum of rats. Furthermore, convulsive episodes induced by GA strongly correlated with Na+,K+-ATPase activity inhibition in the injected striatum, but not with oxidative stress marker measures. In addition, GM1 (50-200 M) protected against Na+,K+-ATPase inhibition induced by GA (6 mM), but not against oxidative damage in vitro. Intrastriatal administration of muscimol (46 pmol/striatum), a GABAA receptor agonist, but not glutamatergic receptor antagonists MK-801 (3 nmol/striatum) and DNQX (8 nmol/striatum), prevented GA-induced convulsions and inhibition of Na+,K+-ATPase activity. The protection of GM1 and muscimol against GA-induced seizures strongly correlated with Na+,K+-ATPase activity maintenance in the injected striatum with GA. Since GM1 and muscimol prevented neurotoxic effects induced by GA, we investigated the GM1 action after intrastriatal administration of pentylenetetrazole (PTZ), a GABAA receptor antagonist. GM1 treatment prevented seizures, Na+,K+-ATPase inhibition, and increase of TBARS and protein carbonyl induced by PTZ (1.8 mol/striatum) in the rats striatum. Furthermore, these data suggest that Na+,K+-ATPase and GABAA receptor-mediated mechanisms may play important roles in GA-induced seizures and in their prevention by GM1. / O monossialogangliosídeo (GM1) é um componente natural de membrana plasmática que está envolvido no crescimento, reconhecimento e diferenciação celular, além de proteger o SNC da ação dos radicais livres. No presente estudo investigou-se o efeito do GM1 sobre a atividade das enzimas antioxidantes catalase (CAT), superóxido dismutase (SOD) e glutationa peroxidase (GPx), assim como na quimiluminescência e capacidade antioxidante total (TRAP) em córtex cerebral de ratos machos adultos ex vivo e in vitro. A administração sistêmica de GM1 (50 mg/kg, i.p.; duas doses: 24 horas e 30 minutos antes do sacrifício) reduziu a quimiluminescência e aumentou significativamente a atividade da CAT ex vivo. A adição de GM1 (103-104 nM) ao meio de incubação diminuiu a atividade da CAT in vitro. Estes resultados sugerem que o efeito neuroprotetor do GM1 não é devido à ação antioxidante intrínseca deste glicoesfingolipídeo, mas devido ao aumento secundário das defesas antioxidantes e/ou uma redução da geração de radicais livres. Além disso, avaliamos se o GM1 tinha efeito neuroprotetor em um modelo experimental da acidemia glutárica, um erro inato do metabolismo caracterizado pelo acúmulo tecidual de ácido glutárico (GA) e alterações neurológicas, como degeneração estriatal e convulsões. A administração de GM1 preveniu as convulsões, o aumento da produção dos marcadores do dano oxidativo (carbonilação protéica total e substâncias reativas do ácido tiobarbitúrico - TBARS) e a inibição da atividade da Na+,K+-ATPase induzidas pelo GA (4 mol/2 µl) em estriado de ratos. Além disso, os episódios convulsivos induzidos por GA apresentaram uma correlação significativa com a inibição da atividade da Na+,K+-ATPase no estriado injetado, mas não com os níveis dos marcadores do estresse oxidativo. A adição de GM1 (50 200  ao meio de incubação preveniu a inibição da Na+,K+-ATPase, mas não reduziu o dano oxidativo induzido por GA (6 mM) in vitro. A administração intraestriatal de muscimol (46 pmol/0,5 l), um agonista de receptor GABAA, mas não dos antagonistas de receptores glutamatérgicos, MK-801 (3 nmol/0,5 l) e DNQX (8 nmol/0,5 l), preveniu as convulsões e a inibição da atividade da Na+,K+-ATPase induzidas por GA. A proteção do GM1 e muscimol contra as convulsões induzidas por GA apresentou uma correlação significativa com a manutenção da atividade da Na+,K+-ATPase no estriado injetado com GA. Desde que o GM1 e o muscimol preveniram os efeitos neurotóxicos induzidos pelo GA, investigou-se a ação do GM1 após a administração intraestriatal de pentilenotetrazol (PTZ), um antagonista de receptores GABAA. O tratamento com GM1 preveniu as convulsões, o dano oxidativo e a inibição da atividade da Na+,K+-ATPase induzidas por PTZ (1,8 µmol/2 µl). Esses dados sugerem que a atividade da Na+,K+-ATPase e mecanismos mediados pela ativação de receptores GABAérgicos podem ser de grande importância para a atividade convulsiva induzida por GA, bem como nos mecanismos de neuroproteção induzidos pelo GM1.

Schizophrenia is a severe neuropsychiatric disorder characterized by positive, negative and cognitive symptoms with poor functional outcomes, placing an enormous burden on the individual, caregivers and society. Although deficits in cognition are an integral part of the disease and the best predictor of functional outcomes, there is as yet no established treatment addressing them. Avoidance of a hidden place on a continuously rotating arena (Carousel) requires cognitive control and is a rodent model of cognitive coordination of information from dissociated spatial frames, which is impaired in acute pharmacological and neurodevelopmental model of schizophrenia. Cognitive training on the Carousel during adolescence alleviates adult cognitive deficit in a neurodevelopmental model of schizophrenia and improves neural coordination (oscilations in the beta and gamma band), which is thought to be necessary for cognition. We examined if cognitive training during adolescence eliminates the deficit in neuronal coordination observed in adult rats after acute systemic NMDA receptor antagonist MK-801 (0.15 mg/kg). During adolescence, rats were either trained in spatial avoidance on Carousel or merely handled. As adults, rats received two 5-min exploration sessions in the same (A/A) or in two distinct...

The goal of this research was to describe the nature, occurrence and extent to which integration preceded normative and institutional transformation in the SANDF and therefore in its Military Police, thereby demonstrating how in its aftermath, integration has become a recipe for disaster, casting a spell on further transformation within the military. The research also aimed at bringing the reader face-to-face with the daily struggles of Africans in the SANDF, by focusing on one of the smallest divisions of the military, the Military Police Agency (MPA). The research project was limited to all reported interviews and questionnaire responses of eighty five participants of the Southern Military Police Region (S MPR), excluding the S MPR HQ as well as the MPA HQ. A total of eighty five respondents out of a total strength of 172 S MPR composition, took part in the sample. Seventy nine participated in the questionnaire, fifty one in the interview and a total of forty five participated in both. Interviews were used as follow-up sessions to respondents' questionnaire answers. While the questionnaire was structured, the interview was semi-structured, allowing members to comment, object, affirm or question the process of transformation both in the SANDF and in the MPA. In keeping with the qualitative research method, the semi-structured interview enabled the mapping of categories, trends and patterns in the responses. It was found that MK and APLA cadres who integrated into the ex-Naval MPs surpassed their counterparts in the ex-Army MPs, by far. The two groups are incomparable, in rank level, experience, training, attitude and knowledge of the organisation. It was further discovered that most practices that had taken place before 1999 at W CSC and still continued within the MPA, negate SANDF policy and are criminal. Prejudice, racism, obscene language and gender insensitivity were rife, forming part of institutional culture. It is recommended that Weitzer's proposed solution for the transformation of coercive institutions be considered. It is a thoroughgoing transformation of the security apparatus through a legal framework because civil control is not enough to guarantee the pre-eminence of the democratic forces. / Criminology / M.A (Criminology)

La greffe de cellules souches hématopoïétiques est parfois le seul traitement efficace contre les cancers hématologiques ainsi que plusieurs autres désordres reliés au système hématopoïétique. La greffe autologue est souvent le traitement de choix pour les patients atteints de lymphome ou de myélome. Dans ce cas, les cellules souches hématopoïétiques (CSH) du patient sont récoltées et congelées. Le patient subit ensuite des traitements de chimiothérapie et/ou radiothérapie qui éliminent les cellules malignes, mais détruisent aussi son système hématopoïétique. Ce dernier sera ensuite reconstitué par la greffe de CSH. Ces traitements ont pour conséquence de plonger le patient en état d’aplasie pour une période variant de 2 à 4 semaines. La thrombocytopénie (faible taux de plaquettes) est une complication majeure nécessitant des transfusions plaquettaires répétées et associée à une augmentation de la mortalité hémorragique post-transplantation. Il serait particulièrement intéressant de développer une thérapie accélérant la reconstitution des mégacaryocytes (MK), ce qui aurait pour effet de raccourcir la période de thrombopénie et donc de diminuer les besoins transfusionnels en plaquettes et potentiellement augmenter la survie. HOXB4 est un facteur de transcription qui a déjà démontré sa capacité à expandre les CSH et les progéniteurs multipotents (CFU-GEMM) donnant naissance aux MK. Il est donc un bon candidat pour l’expansion des progéniteurs MK. Comme la protéine HoxB4 a par contre une courte demi-vie (~1.1h), des protéines HoxB4 de deuxième génération avec une plus grande stabilité intracellulaire ont été créées (1423 (HoxB4L7A), 1426 (HoxB4Y23A) et 1427 (HoxB4Y28A)). Nous avons donc étudié la capacité d’HoxB4 sauvage et de deuxième génération à expandre les CSH, ainsi que les MK donnant naissance aux plaquettes. La surexpression rétrovirale de ces protéines HoxB4Y23A et HoxB4Y28A conduit à une expansion des progéniteurs MK murins in vitro supérieure à HoxB4-wt, 1423 et au contrôle GFP. La reconstitution plaquettaire in vivo dans un modèle murin a ensuite été évaluée par des transplantations primaires et secondaires. Les résultats révèlent que la surexpression rétrovirale des différents HoxB4 n’apporte pas de bénéfice significatif à la reconstitution plaquettaire des souris. Lorsque cultivées dans un milieu favorisant la différenciation mégacaryocytaire, le traitement de cellules CD34+ dérivées du sang de cordon ombilical avec les protéines recombinantes TATHoxB4WT ou de seconde génération n’a pas augmenté la production plaquettaire. Par contre, de manière intéressante, les cellules CD34+ provenant de sang mobilisé de patients atteints de myélome et mises en culture dans un milieu favorisant l’expansion des CSH ont montré des différences significatives dans la différenciation des progéniteurs MK en présence de la protéine recombinante TATHoxB4. La protéine HOXB4 possède donc un avenir prometteur quant à une amélioration de l’état thrombocytopénique chez les patients. / Haematopoietic stem cell (HSC) transplantation is the most efficient treatment against a number of cancers or other disorders of the hematologic system. Prior to HSC transplantation, patients are exposed to high doses of radiotherapy and/or chemotherapy to eliminate malignant cells. However, these treatments result in a state of aplasia, particularly in thrombocytopenia, which is characterised by very low blood platelet counts. Platelets produced by megakaryocytes (MK) are essential components of the blood system and play a critical role in the prevention of bleeding. Thus a low platelet blood level is a major complication and contributes significantly to transplant related mortality. At present, regular infusion of platelets isolated from healthy donors is the treatment of choice for thrombocytopenia. However, this is cumbersome for patients as well as donors and, in many instances results in platelet refractoriness due to the generation of auto-antibodies against disparate HLA molecules expressed on donor platelets. Therefore, the development of strategies to accelerate MK production and thus platelet reconstitution post HSC transplant would represent a major advance. It has already been shown that HoxB4 expands HSC and multipotent progenitors (CFU-GEMM) that give rise to megakaryocytes (MK). Thus HoxB4 is a great candidate for in vitro MK progenitor expansion. However, the short half-life of HoxB4 protein prompted us to generate a second generation of HoxB4 proteins with greater intracellular stability. We therefore studied the capacity of wild type (WT) and HoxB4 with 3 substitutions (1423 (HoxB4L7A), 1426 (HoxB4Y23A) and 1427 (HoxB4Y28A) resulting in a longer protein half-life to expand HSC as well as MK progenitors. Retroviral-mediated expression of HoxB4Y23A and HoxB4Y28A proteins showed a greater expansion of murine MK progenitors, in comparison with HoxB4WT or HoxB4L7A proteins or GFP control. We also evaluated the ability of HSC expressing second generation HoxB4 to generate platelets in a murine model. Our results show that retroviral-mediated transduction of second generation HoxB4 in murine HSC does not provide a significant advantage over HoxB4WT in platelet reconstitution in mice. Interestingly, treatment of CD34+ cells derived from cord blood showed only marginal effect of HoxB4WT or second generation HoxB4 soluble recombinant proteins when cultured under conditions optimized for megakaryocyte differentiation. Unexpectedly, CD34+ cells derived from mobilized peripheral blood of myeloma patients showed a significant increase in MK progenitor differentiation in the presence of TAT-HoxB4WT when cultured in expansion medium for HSC. Thus, HoxB4 holds promise in autologous HSC transplantation for the treatment of thrombocytopenic patients.

De plus en plus d’études montrent un lien entre la teneur en vitamine K (VK) dans l’organisme et la cognition. Certaines études effectuées in vitro on montré l’effet de la VK au niveau moléculaire, mais très peu in vivo. Une étude récente de Tamadon-Nejad a montré qu’un traitement de 14mg/kg/jr de warfarine, un antagoniste de la VK, administré simultanément à des injections sous-cutanées de 85mg/kg/jr de phylloquinone entrainait une diminution significative de la concentration de MK-4 du cerveau, résultant en une diminution significative du statut vitaminique K au cerveau, une altération de la cognition, du comportement exploratoire et de la locomotion [1]. Dans la présente étude, le traitement de Tamadon-Nejad a été modifié et les doses de phylloquinone ont été augmentées à 120mg/kg/jr (WVK) ce qui a maintenu une diminution significative de la concentration de la concentration de MK-4 dans le cerveau, mais a entrainé une surcompensation par la phylloquinone, résultant en une augmentation significative du statut vitaminique K au cerveau. Ce statut a été associé à une mémoire de reconnaissance intacte et corrélé à une amélioration de la mémoire spatiale des rats WVK. Le traitement a aussi été associé à une augmentation significative de l’anxiété et au rétablissement du comportement exploratoire et de la locomotion des rats WVK comparativement à l’étude de Tamadon-Nejad [1]. Dans l’hippocampe des rats WVK, l’amélioration de la cognition et le rehaussement du statut vitaminique K du cerveau n'ont pas induit de variation significative de l’activation des protéines dépendantes de la VK Gas6 et Protéine S, mais ont été associés à une augmentation significative de l’activation de la voie MAPK, à une inhibition de l’apoptose et à une présence accrue de la microglie. En somme, cette étude confirme le rôle modulateur de la VK dans le cerveau sur la cognition et la survie cellulaire. / There is growing evidence that vitamin K (VK) plays a role in cognition. Some in vitro studies have shown how VK affects different molecular pathways in brain cells, but few in vivo studies have been conducted. Recently, a study from Tamadon- Nejad showed that a treatment of 14mg/kg/d of warfarine, a VK antagonist, given simultaneously with subcutaneous injections of 85mg/kg/d lead to a significant decrease in MK-4 concentration in brain, resulting in a significant decrease of VK status in brain, and perturbation in cognition, exploratory behaviour and locomotion [1]. In the present study, we modified the treatment used in Tamadon-Nejad and increased the phylloquinone doses to 120mg/kg/d which maintained the significant decrease in MK-4 concentration in brain, but lead to an overcompensation of phylloquinone that resulted in an increase of VK status in brain. This status was associated with an intact recognition memory and correlated with an improvement in spatial memory of WVK rats. The treatment was also associated with a significant increase in anxiety and recovery of exploratory behavior and locomotion compared to rats in the Tamadon-Nejad study [1]. In WVK rat hippocampi, cognition improvement and increased VK status were not associated with significant variation in VK dependant proteins (VKDP) Gas6 and Protein S activation, but were associated with an increase in the MAPK activation pathway, an inhibition of apoptosis and, an increased presence of microglia. In summary, this study confirms the modulatory role of VK in brain in cognition and cell survival.

Microelectronics has shaped the world beyond what was thought possible at the time of its advent. One area of current research in this field is on the solid-state Si:P-based quantum computer (QC). In this machine, each qubit requires an individually addressed fast control-pulse for non-adiabatic drive and measure operations. Additionally, it is increasingly becoming important to be able to interface nanoelectronics with complementary metal-oxide-semiconductor (CMOS) technology. In this work, I have designed and demonstrated full-custom mixed-mode and full-digital fast control-pulse generators fabricated in a silicon-on-sapphire (SOS) CMOS commercial foundry process ?? a radio-frequency (RF) CMOS technology. These circuits are, fundamentally, fast monostable multivibrators. Initially, after the design specifications were decided upon, I characterized NFET and PFET devices and a n+-diffusion resistor from 500 nm and 250 nm commercial SOS-CMOS processes. Measuring their conductance curves at 300 300 K, 4.2 2 K, and sub-K (30 30 mK base to 1000 1000 mK) showed that they function with desirable behaviour although exhibiting some deviations from their 300 300 K characteristics. The mixed-mode first generation control-pulse generator was demonstrated showing that it produced dwell-time adjustable pulses with 100 100 ps rise-times at 300 K, 4.2 2 K, and sub-K with a power dissipation of 12 12 uW at 100 100 MHz. The full-digital second generation control-pulse generator was demonstrated showing accurately adjustable dwell-times settable via a control-word streamed synchronously to a shift-register. The design was based on a ripple-counter with provisions for internal or external clocking. This research has demonstrated that SOS-CMOS technology is highly feasible for the fabrication of control microelectronics for a Si:P-based QC. I have demonstrated full-custom SOS-CMOS mixed-mode and full-digital control circuits at 300 300 K, 4.2 2 K, and sub-K which suitable for qubit control.

Microelectronics has shaped the world beyond what was thought possible at the time of its advent. One area of current research in this field is on the solid-state Si:P-based quantum computer (QC). In this machine, each qubit requires an individually addressed fast control-pulse for non-adiabatic drive and measure operations. Additionally, it is increasingly becoming important to be able to interface nanoelectronics with complementary metal-oxide-semiconductor (CMOS) technology. In this work, I have designed and demonstrated full-custom mixed-mode and full-digital fast control-pulse generators fabricated in a silicon-on-sapphire (SOS) CMOS commercial foundry process ?? a radio-frequency (RF) CMOS technology. These circuits are, fundamentally, fast monostable multivibrators. Initially, after the design specifications were decided upon, I characterized NFET and PFET devices and a n+-diffusion resistor from 500 nm and 250 nm commercial SOS-CMOS processes. Measuring their conductance curves at 300 300 K, 4.2 2 K, and sub-K (30 30 mK base to 1000 1000 mK) showed that they function with desirable behaviour although exhibiting some deviations from their 300 300 K characteristics. The mixed-mode first generation control-pulse generator was demonstrated showing that it produced dwell-time adjustable pulses with 100 100 ps rise-times at 300 K, 4.2 2 K, and sub-K with a power dissipation of 12 12 uW at 100 100 MHz. The full-digital second generation control-pulse generator was demonstrated showing accurately adjustable dwell-times settable via a control-word streamed synchronously to a shift-register. The design was based on a ripple-counter with provisions for internal or external clocking. This research has demonstrated that SOS-CMOS technology is highly feasible for the fabrication of control microelectronics for a Si:P-based QC. I have demonstrated full-custom SOS-CMOS mixed-mode and full-digital control circuits at 300 300 K, 4.2 2 K, and sub-K which suitable for qubit control.

The goal of this research was to describe the nature, occurrence and extent to which integration preceded normative and institutional transformation in the SANDF and therefore in its Military Police, thereby demonstrating how in its aftermath, integration has become a recipe for disaster, casting a spell on further transformation within the military. The research also aimed at bringing the reader face-to-face with the daily struggles of Africans in the SANDF, by focusing on one of the smallest divisions of the military, the Military Police Agency (MPA). The research project was limited to all reported interviews and questionnaire responses of eighty five participants of the Southern Military Police Region (S MPR), excluding the S MPR HQ as well as the MPA HQ. A total of eighty five respondents out of a total strength of 172 S MPR composition, took part in the sample. Seventy nine participated in the questionnaire, fifty one in the interview and a total of forty five participated in both. Interviews were used as follow-up sessions to respondents' questionnaire answers. While the questionnaire was structured, the interview was semi-structured, allowing members to comment, object, affirm or question the process of transformation both in the SANDF and in the MPA. In keeping with the qualitative research method, the semi-structured interview enabled the mapping of categories, trends and patterns in the responses. It was found that MK and APLA cadres who integrated into the ex-Naval MPs surpassed their counterparts in the ex-Army MPs, by far. The two groups are incomparable, in rank level, experience, training, attitude and knowledge of the organisation. It was further discovered that most practices that had taken place before 1999 at W CSC and still continued within the MPA, negate SANDF policy and are criminal. Prejudice, racism, obscene language and gender insensitivity were rife, forming part of institutional culture. It is recommended that Weitzer's proposed solution for the transformation of coercive institutions be considered. It is a thoroughgoing transformation of the security apparatus through a legal framework because civil control is not enough to guarantee the pre-eminence of the democratic forces. / Criminology and Security Science / M.A (Criminology)

Nos últimos anos, houve um aumento significativo no uso abusivo dos Esteróides Anabólicos Andrógenos (EAAs). Um dos efeitos comportamentais mais marcantes da administração crônica de EAAs como o Decanoato de Nandrolona (DN) é a indução do comportamento agressivo exacerbado. Atualmente o sistema glutamatérgico tem sido associado ao comportamento agressivo induzido pelos EAAs, principalmente no que se refere à modulação dos receptores N-Methyl-D-Aspartato NMDA (NMDAr). Nós investigamos os efeitos centrais e periféricos da administração do DN ao longo do tempo (4, 11 e 19 dias consecutivos de administração), e a participação de mecanismos glutamatérgicos. Para isso, camundongos CF-1 tratados com DN foram avaliados em relação ao comportamento agressivo pelo teste do intruso. Além disso, investigamos a captação de glutamato, o imunoconteúdo de GLT-1, os níveis de glutamato no líquido extracelular, e a participação dos NMDAr na manifestação do comportamento agressivo. O fenótipo agressivo foi evidenciado somente no longo tempo de exposição à DN (19 dias). Na mesma janela temporal que os animais apresentaram o fenótipo agressivo houve redução significativa de captação de glutamato em fatias cerebrais de córtex e hipocampo, como também a redução do imunoconteúdo do transportador astrocitário GLT-1 nas mesmas estruturas cerebrais. A administração de antagonistas de NMDAr como MK-801 e memantina antes do teste do intruso diminuiu o comportamento agressivo dos animais tratados cronicamente com DN a níveis iguais aos do grupo controle. Ainda, o comportamento agressivo induzido pela administração crônica de DN diminuiu a remoção do glutamato da fenda sináptica, culminando com o aumento do glutamato extracelular no SNC, o que resultou na hiperexcitabilidade dos NMDAr. Este trabalho enfatiza o papel da comunicação entre astrócitos e neurônios e a relevância da hiperstimulação de NMDAr na manifestação do comportamento agressivo. / Nandrolone decanoate (ND), an anabolic androgenic steroid (AAS), induces an aggressive phenotype by mechanisms involving glutamate-induced N-methyl-d-aspartate receptor (NMDAr) hyperexcitability. The astrocytic glutamate transporters remove excessive glutamate surrounding the synapse. However, the impact of supraphysiological doses of ND on glutamate transporters activity remains elusive. We investigated whether ND-induced aggressive behavior is correlated with GLT-1 activity, glutamate levels and abnormal NMDAr responses. Two-month-old untreated male mice (CF1, n=20) were tested for baseline aggressive behavior in the resident-intruder test. Another group of mice (n=188) was injected with ND (15mg/kg) or vehicle for 4, 11 and 19 days (short-, mid- and long-term endpoints, respectively) and was evaluated in the resident-intruder test. Each endpoint was assessed for GLT-1 expression and glutamate uptake activity in the frontoparietal cortex and hippocampal tissues. Only the long-term ND endpoint significantly decreased the latency to first attack and increased the number of attacks, which was associated with decreased GLT-1 expression and glutamate uptake activity in both brain areas. These alterations may affect extracellular glutamate levels and receptor excitability. Resident males were assessed for hippocampal glutamate levels via microdialysis both prior to, and following, the introduction of intruders. Long-term ND mice displayed significant increases in the microdialysate glutamate levels only after exposure to intruders. A single intraperitoneal dose of NMDAr antagonists, memantine or MK-801, shortly before the intruder test, decreased aggressive behavior. In summary, long-term ND-induced aggressive behavior is associated with decreased extracellular glutamate clearance and NMDAr hyperexcitability, emphasizing the role of this receptor in mediating aggression mechanisms.

Nos últimos anos, houve um aumento significativo no uso abusivo dos Esteróides Anabólicos Andrógenos (EAAs). Um dos efeitos comportamentais mais marcantes da administração crônica de EAAs como o Decanoato de Nandrolona (DN) é a indução do comportamento agressivo exacerbado. Atualmente o sistema glutamatérgico tem sido associado ao comportamento agressivo induzido pelos EAAs, principalmente no que se refere à modulação dos receptores N-Methyl-D-Aspartato NMDA (NMDAr). Nós investigamos os efeitos centrais e periféricos da administração do DN ao longo do tempo (4, 11 e 19 dias consecutivos de administração), e a participação de mecanismos glutamatérgicos. Para isso, camundongos CF-1 tratados com DN foram avaliados em relação ao comportamento agressivo pelo teste do intruso. Além disso, investigamos a captação de glutamato, o imunoconteúdo de GLT-1, os níveis de glutamato no líquido extracelular, e a participação dos NMDAr na manifestação do comportamento agressivo. O fenótipo agressivo foi evidenciado somente no longo tempo de exposição à DN (19 dias). Na mesma janela temporal que os animais apresentaram o fenótipo agressivo houve redução significativa de captação de glutamato em fatias cerebrais de córtex e hipocampo, como também a redução do imunoconteúdo do transportador astrocitário GLT-1 nas mesmas estruturas cerebrais. A administração de antagonistas de NMDAr como MK-801 e memantina antes do teste do intruso diminuiu o comportamento agressivo dos animais tratados cronicamente com DN a níveis iguais aos do grupo controle. Ainda, o comportamento agressivo induzido pela administração crônica de DN diminuiu a remoção do glutamato da fenda sináptica, culminando com o aumento do glutamato extracelular no SNC, o que resultou na hiperexcitabilidade dos NMDAr. Este trabalho enfatiza o papel da comunicação entre astrócitos e neurônios e a relevância da hiperstimulação de NMDAr na manifestação do comportamento agressivo. / Nandrolone decanoate (ND), an anabolic androgenic steroid (AAS), induces an aggressive phenotype by mechanisms involving glutamate-induced N-methyl-d-aspartate receptor (NMDAr) hyperexcitability. The astrocytic glutamate transporters remove excessive glutamate surrounding the synapse. However, the impact of supraphysiological doses of ND on glutamate transporters activity remains elusive. We investigated whether ND-induced aggressive behavior is correlated with GLT-1 activity, glutamate levels and abnormal NMDAr responses. Two-month-old untreated male mice (CF1, n=20) were tested for baseline aggressive behavior in the resident-intruder test. Another group of mice (n=188) was injected with ND (15mg/kg) or vehicle for 4, 11 and 19 days (short-, mid- and long-term endpoints, respectively) and was evaluated in the resident-intruder test. Each endpoint was assessed for GLT-1 expression and glutamate uptake activity in the frontoparietal cortex and hippocampal tissues. Only the long-term ND endpoint significantly decreased the latency to first attack and increased the number of attacks, which was associated with decreased GLT-1 expression and glutamate uptake activity in both brain areas. These alterations may affect extracellular glutamate levels and receptor excitability. Resident males were assessed for hippocampal glutamate levels via microdialysis both prior to, and following, the introduction of intruders. Long-term ND mice displayed significant increases in the microdialysate glutamate levels only after exposure to intruders. A single intraperitoneal dose of NMDAr antagonists, memantine or MK-801, shortly before the intruder test, decreased aggressive behavior. In summary, long-term ND-induced aggressive behavior is associated with decreased extracellular glutamate clearance and NMDAr hyperexcitability, emphasizing the role of this receptor in mediating aggression mechanisms.