Posttraumatic stress disorder (PTSD) is classified as an anxiety disorder and the characteristic symptoms (re-experiencing, avoidance as well as numbing of general responsiveness and hyperarousal) of this disorder develop in response to a traumatic event. The disorder is characterised by hypothalamic-pituitary-adrenal (HPA) axis abnormalities linked with changes in cortisol moreover, the hippocampus and cortex also play a role in the neurobiology. With regard to the neurochemistry of this disorder it is known that gamma amino butyric acid (GABA) is involved however, the precise role of GABA in PTSD and how stress changes GABA concentrations in the brain are still not fully understood. Another aspect regarding PTSD that has not been clearly defined is the treatment of PTSD. Classic anxiolytics such as diazepam is expected to relieve the anxiety linked with PTSD. Studies with this group of drugs have however not produced the concrete evidence needed to establish it as a treatment of choice for PTSD and subsequently other classes of drugs have been investigated as possible treatment options for PTSD. Among these is lamotrigine, which in a clinical study was found to be effective in alleviating symptoms of PTSD. Moreover, a possible pharmacokinetic-pharmacodynamic relationship for each of these drugs has also not been elucidated. In order to elude on some of these uncertainties, an animal model of PTSD, time dependent sensitisation (TDS), was used. GABA levels in the rat hippocampus and frontal cortex were determined at two different time intervals following the TDS procedure (1 day and 7 days post re-stress). High performance liquid chromatography (HPLC) with electrochemical (EC) detection was used to determine gamma amino butyric acid (GABA) concentrations. To investigate the possible anxiolytic effects of diazepam and lamotrigine in this model, as well as a possible pharmacokinetic-pharmacodynamic relationship for each drug, pharmacokinetic profiles for both drugs were established in order to find the times of peak and trough levels of each drug. Blood samples were collected at different time intervals after drug administration either from the tail vein of rats (lamotrigine) or directly from the heart (diazepam). Subsequently, drug concentrations at each time interval were determined by means of HPLC with ultraviolet (UV) detection. The behaviour of rats was analysed using the elevated plus-maze (EPM) at peak or trough concentrations of the drugs and this was performed after either acute administration of the drug, or after a 14 day chronic treatment regime. GABA levels in the hippocampus were not found to change statistically significantly in response to stress at either 1 day or 7 days post re-stress. In the frontal cortex, however, GABA levels increased in response to stress at 1 day post re-stress, with a statistically insignificant, but strong trend towards an increase, at 7 days post re-stress. With regard to the pharmacokinetic profiles, the peak concentration of diazepam was found to occur at 60 minutes, with lamotrigine's peak at 120 minutes. The behavioural studies indicated that acute treatment with diazepam 3 mg/kg resulted in a statistically significant increase in both ratio open arm entries and ratio time spent in the open arms at peak level of the drug. After acute treatment with diazepam 3 mg/kg a statistically significant decrease in ratio time spent in open arms was also found when the ratio time spent in open arms at peak level of the drug and the ratio time spent in open arms at trough level of the drug was compared. In response to chronic treatment with diazepam 3 mg/kg for 14 days, test animals exhibited an increase in the ratio open arm entries at trough level of the drug, with a statistically insignificant yet definite trend towards an increase at peak level. Acute treatment with lamotrigine 10 mg/kg resulted in no statistically significant change in EPM parameters. In response to chronic treatment, however, a statistically significant increase was found in ratio time spent in open arms at peak level of the drug, with a statistically insignificant trend towards an increase at trough level. From the results of this study, we may therefore conclude that GABA-levels in the brain are definitely affected, but in different ways, following TDS-stress. A pharmacokinetic-pharmacodynamic relationship between the drugs' levels and aversive behaviour could also be established. Furthermore it appears that more sustained anxiolytic effects are evident following chronic treatment with both drugs than with acute administration of these drugs. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2006

Posttraumatic stress disorder (PTSD) is an anxiety disorder that may follow exposure to severe emotional trauma and presents with various symptoms of anxiety, hyperarousal and cognitive anomalies. Interestingly, only 10-30% of an exposed population will go on to develop full-blown PTSD. Cholinergic neurotransmission is implicated in anxiety as well as other typical manifestations of PTSD, particularly cognitive changes. The frontal cortex and hippocampus regulate and in turn are affected by stress, and have also been implicated in the underlying neuropathology of PTSD. These areas are densely innervated by cholinergic neurons originating from the basal forebrain. In this study, the time dependent sensitization (TDS) model was used to induce symptoms of PTSD in animals. The study was designed to determine the long-term effects of an intense, prolonged aversive procedure on central muscarinic acetylcholine receptor (mAChR) characteristics and the correlation if any of those findings to cognitive aspects and general arousal as characteristics associated with PTSD. In order to achieve this goal, male Sprague-Dawley rats were exposed to the TDS stress paradigm with behavioral/neuro-receptor assessments performed on day 7 post re-stress (duration of each experiment in whole is 14 days). Acoustic startle reflex (ASR) was used to determine emotional state (hyperarousal), while the conditioned taste aversion (CTA) paradigm was implemented in order to assess aversive memory. Muscarinic receptor binding studies were performed in the frontal cortex and hippocampus. Moreover, both the stress-exposed and control animals were pre-tested in the acoustic startle chamber in order to attempt to separate stress sensitive from stress-resilient animals based on predetermined ASR criteria. The ASR niodel was previously validated in our laboratory, while the CTA model was validated in this project before application. In the CTA model, an i.p. injection with lithium chloride (LiCl) (associated with digestive malaise), was used as unconditioned stimulus (US) and was paired with a saccharinlcyclamate drinking solution as conditioned stimulus (CS) to induce aversion to the novel taste (CS) when presented in the absence of the US. Population data of animals tested in the ASR experiment indicated no statistical significant difference between stressed and control animals. However, when each animal was assessed individually, 22.5 % of the exposed population displayed all increase above the predetermined criteria of 35 % in startle response, indicating a state of heightened arousal. In contrast, only 4.2 O h of control animals (no stress) displayed an increase in arousal based on the above mentioned criteria. Muscarinic receptor densities (Bm,) in the total population of animals exposed to stress showed a statistical significant increase in both the hippocampus and frontal cortex when compared to controls, with no changes in & values observed in either one of the areas. In the CTA experiment, TDS stress was implemented as US paired with a saccharinlcyclamate drinking solution as CS. An acute session of prolonged stress (as used in the TDS model) effectively induced aversion to a novel taste and a subsequent reminder of the stress (restress) paired with the CS sustained the acquire adversive memory. Furthermore, LiCl was reintroduced as US in order to assess the effect of prior exposure to two types of stress (acute and TDS) on subsequently acquired CTA memory. Prior exposure to acute stress had no significant effect on subsequently acquired aversive memory when measured either 3- or 7 days post-conditioning (CS-US). Stress-restress (TDS) exposure, however, indicated a significant decrease in aversive memory from 3- to 7 days post-conditioning (CS-US) as well as a significant decrease in aversive memory between the control- and the TDS group 7 days post-conditioning. The mAChR density (B,,) in the frontal cortex; but not in the hippocampus, was elevated at the same point in time (7 days post CS-US pairing) that CTA memory was impaired following TDS stress (stress-restress). Ultimately, these data support an association between altered cholinergic receptors and hyperarousallanxiety in an animal model of PTSD. The data also support the phenomenon of individual susceptibility to stress in animals that parallels that observed in humans exposed to severe trauma. Impaired aversive memory (CTA) is a consequence of prior exposure to TDS stress, but not acute stress, and is likewise mediated by an altered central cholinergic transmission displayed as an increase in mAChRs in the frontal cortex. The lack of studies regarding the influence of the cholinergic system in PTSD related behavior earns ,this project value as inimitable PTSD research. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2007.

Cette thèse a pour but d’identifier, dans la mise en scène européenne des années 1990-2000, les pratiques de la frontalité et d’en déterminer les enjeux en termes de mise en scène, de jeu et de présence de l’acteur et de réception du spectateur. L’analyse distingue trois modalités d’intervention de la frontalité, chaque fois remises dans leur perspective historique. La première est celle de l’interpellation, dans l’héritage du théâtre de foire ou d’intervention. La frontalité y est le support d’un acte de communication. Deuxièmement, la frontalité prend une dimension cérémonielle et devient le fondement de l’acte théâtral pour élaborer, cette fois, une relation indirecte avec les spectateurs. Dans sa troisième modalité, la frontalité dépasse le face-à-face entre acteurs et spectateurs, soit par le recours à l’image vidéo, créant un face-à-face médiatisé, soit par l’extension de la frontalité à l’ensemble de la scène. Finalement, l’usage de la frontalité témoigne d’une nouvelle économie de la représentation fondée sur un principe de réciprocité entre le geste du metteur en scène, l’engagement de l’acteur, la production scénique et l’individu spectateur. Au-delà du souci de conduire le spectateur à une activité critique ou à une participation fusionnelle, la frontalité invite à interroger sa position de retrait et sa passivité extérieure. / This thesis aims at identifying the practices of frontal acting in the European performances between the 1990’s and the 2000’s in order to define its challenges with regards to the staging, the acting, the actor’s presence on stage as well as in terms of spectator’s perception. Our analysis distinguishes three modes of frontal acting, by replacing each of them in its historical context. The first one is “interpellation” inherited from the Theatre performances at fairs and the Agit-Prop Theatre. In this case, frontal acting is considered as a medium for communication. The second mode, frontal acting takes a ceremonial dimension and becomes the basis of the theatrical moment in order to create, this time, an indirect relationship between actors and spectators. In its third mode, frontal acting exceeds the face-to-face between actors and spectators either thanks to the use of the video – creating media attention around the face-to-face – or thanks to the extension of frontal acting to the full stage. Finally, the use of frontal acting indicates the emergence of a new performance mode based on a reciprocity principle between the gesture of the director, the commitment of the actor, the performance and the spectator as an individual. Beyond the willingness to lead the spectator to a critical thought processor to a fusional participation, frontal acting invites to question his distant position and his external passivity.

Lo scopo della presenta ricerca è analizzare il ruolo del sistema di ricompensa in relazione al costrutto BIS/BAS (Behavioural Inhibition System/ Behavioural Activation System) in un contesto sano e di dipendenza da sostanza. Il lavoro ha inoltre esplorato l'asimmetria cerebrale frontale nelle scelte decisionali che implicano stimoli di ricompensa e condizioni punizione. I risultati hanno confermato l'ipotesi di un anomalia del sistema di ricompensa in individui con alto BAS e in pazienti con dipendenza da sostanza, che sovrastimavano la ricompensa immediata a scapito di quella a lungo termine durante l’Iowa Gambling Task. Un’altra componente cruciale emersa da questo progetto è una iper-attivazione del lobo frontale di sinistra rispetto a quello di destra in risposta alle opzioni più rischiose. Questo "effetto di sbilanciamento inter-emisferico” potrebbe essere considerato come un indicatore critico del comportamento decisionale disfunzionale nella dipendenza o come fattore di vulnerabilità allo sviluppo di dipendenze. Infine, questo "modello di squilibrio corticale" è stato applicato ad altre forme di dipendenza comportamentale, misurate con l’Internet Addiction Test (IAT). In effetti, un aumento dell'attività frontale di sinistra è stata osservata per gli individui ad alto IAT in risposta a stimoli premianti. In particolare, i risultati ottenuti sottolineano l'importanza di un modello integrato di dipendenza che tiene conto del sistema motivazionale (BIS/BAS) correlato alla lateralizzazione dell'attività corticale. / The aim of this PhD research was intended to analyze the role of the reward system by the BIS/BAS (Behavioural Inhibition System/ Behavioural Activation System) construct in healthy and addiction context. It explored the frontal brain asymmetry in decisional choices implying reward stimuli and punishment conditions. Results confirmed the hypothesis of a “reward bias” induced by high-BAS individuals and patients suffering from Substance Use Disorder (SUD) to overestimate the immediate reward to the detriment of the delayed reward during the Iowa Gambling Task. Another critical component is the frontal left-hyper activation of the brain in response to more risky options. This "inter-hemisphere" unbalancing effect can be considered as a critical indicator of the dysfunctional decision behavior in dependence or as a vulnerability factor to the development of addiction. Finally, this “cortical imbalance model” was applied to other forms of behavioural addiction, measured by the Internet Addiction Test (IAT). Indeed, an increased left frontal activity was observed for high-IAT individuals in response to rewarding stimuli. In particular, the results underlined the importance of an integrated model of addiction that takes into account the motivational system (BIS / BAS) related to the lateralization of cortical activity.

O objetivo do estudo foi avaliar parâmetros da cinemática palpebral durante o piscar espontâneo e movimentos sacádicos palpebrais em pacientes com ptose congênita submetidos à correção cirúrgica pela técnica de suspensão frontal com fáscia muscular. Com um sistema de câmeras de captação infravermelha para análise tridimensional de movimentos foi feito registro simultâneo de movimentos de supercílio e de pálpebra. Para análise do piscar espontâneo foram avaliados 17 pacientes com ptose congênita que realizaram correção cirúrgica pela técnica de suspensão frontal com utilização de fáscia muscular autógena (n=14), e fáscia lata preservada (n=3), e para o estudo do movimento sacádico palpebral, a avaliação foi dos 14 pacientes que utilizaram apenas fáscia autógena. Um grupo controle com 17 indivíduos normais também foi medido. Para análise do piscar espontâneo um programa foi utilizado para medidas de amplitude e velocidade máxima de movimento durante a observação de um filme comercial por 5 minutos. Para análise do movimento sacádico palpebral foram realizadas medidas em 10, 20, 30, 40 e 50 graus do olhar para baixo. A avaliação da superfície ocular em lâmpada de fenda com utilização de fluoresceína foi realizada nos pacientes que apresentavam ou não lagoftalmo. O número de piscadelas foi significativamente diminuído nos pacientes. A distribuição do intervalo entre as piscadelas foi similar nos dois grupos. A média de amplitude da fase descendente do piscar dos pacientes foi apenas 38% da média do grupo controle. A inclinação da reta da \"main sequence\" para o piscar espontâneo para os pacientes foi mais baixa. Nos controles o movimento do supercilio foi muito pequeno e insignificante durante o piscar espontâneo. Nos pacientes, a média de amplitude do movimento do supercílio foi cinco vezes maior que nos controles chegando a 45% da amplitude do piscar. Os movimentos sacádicos palpebrais mostraram uma importante restrição e não aumentou além de 30 graus do olhar para baixo. A velocidade máxima da pequena amplitude dos movimentos sacádicos palpebral foi muito baixa. Enquanto a movimentação do supercilio no grupo controle ficou entre 3,3 e 9,3% do movimento sacadico palpebral, nos pacientes a movimentação do supercílio foi responsável por 43,5 a 57,4% do movimento palpebral. Lagoftalmo foi encontrado em 13 (76,5%) dos pacientes. Apenas 3 (23%) mostraram sinais de ceratopatia superficial inferior, apesar da presença do fenômeno de Bell. A amplitude e velocidade do piscar espontâneo está severamente diminuída em pacientes com suspensão frontal com fáscia muscular. Esse tipo de material causa um efeito restritivo permanente nas propriedades elásticas das pálpebras. Após a cirurgia a amplitude do piscar é dependente da amplitude do movimento do supercílio. O lagoftalmo é uma consequência natural da suspensão frontal com fáscia muscular. / The purpose of the present investigation was to measure lid kinematics parameters in spontaneous blink metrics and downward eyelid saccadic movements in patients with congenital ptosis operated with frontalis slings with muscles fascia. A optoeletronic system was employed with infrared 3-dimensional video motion analyzer to simultaneously measure brow motion and spontaneous blinks in 17 patients with congenital ptosis who underwent frontalis sling with autogeneous muscle fascia (n=14) and banked fascia lata (n=3). Downward eyelid saccadic movements were analyzed only in the 14 patients with autogeneous muscle fascia. A control group of equal number of healthy subjects was also measured. For analyses of spontaneous blinks, a customized software identified and quantified the amplitude and maximum velocity during 5 minutes observation of a commercial movie. For downward eyelid saccadic movements, 10, 20, 30, 40 and 50 degrees of downgaze were measure. The corneal status of the patients with and without lagophthalmos was evaluated with slit lamp biomicroscopy with fluorescein staining. Blink rate was significantly diminished in the patients. The distribution of interblink time was similar in both groups. The mean amplitude of the down phase of the patients\' blinks was only 38% of the controls. The main sequence slope of the patients´ blinks was abnormally low. In controls brow motion was a minute and random event no related to blinks. In the patients, the means brow amplitude was 5 times higher than in controls reaching 45% of the blink amplitude. The lid saccades of the patients were severely restricted and did not increase beyond 30 degrees of downgaze. The maximum velocity of the small amplitude lid saccades was also abnormally low. While in controls brow motion accounted for about 3,3 to 9,3% of the lid saccades, in the patients brow motion was responsible for more than 43,5% to 57,4% lid movements. Lagophthalmos was detected on 13 (76,5%) patients. Out of these 3 (23%) showed signs of inferior superficial keratopathy despite the presence of normal. Spontaneous blink amplitude and velocity are severely impaired in patients with fascia slings. This material has a permanent restrictive effect on the elastic properties of the lids. After surgery blinking amplitude is linearly related to the amplitude of brow motion. Postoperative lagophthalmos is a natural consequence of the slings with muscle fascia.

Os receptores canabinoides do tipo 1 (CB1) e vaniloides de potencial transitório 1 (TRPV1) presentes no córtex pré-frontal medial ventral (CPFMv) modulam de maneira oposta a resposta emocional condicionada (REC) no modelo do medo condicionado contextual (MCC). Enquanto a ativação de receptores CB1 reduz as respostas comportamental e cardiovascular da REC, a ativação de TRPV1 aumenta tais parâmetros. Além destes receptores, receptores de glutamato do tipo NMDA e o sistema nitrérgico no CPFMv estão envolvidos na modulação da REC. Possivelmente, tanto a resposta modulada pelo receptor CB1 quanto pelo TRPV1 estão ligadas à modulação da liberação de glutamato e produção de óxido nítrico (NO). Outro neurotransmissor que também possui papel importante na REC é a acetilcolina (ACh) e que provavelmente atua via NO e eCBs. O favorecimento desta neurotransmissão no CPFMv aumenta a REC por meio da ativação de receptores muscarínicos M3. É descrito que a ativação de receptores muscarínicos induz a produção de NO, o qual pode aumentar a liberação de glutamato e, assim, aumentar a REC. Além disso, a ativação de receptores muscarínicos também podem induzir a produção de endocanabinoiodes (eCBs), como a anandamida (AEA), neuromoduladores que podem influenciar a liberação de glutamato, via CB1 ou TRPV1 e, consequentemente, podem afetar a REC. Portanto, o objetivo do trabalho foi avaliar se um antagonista CB1 (NIDA41020) e um agonista TRPV1 (capsaicina) atuam através da via NMDA/NO e se o aumento dos níveis de ACh modula a neurotransmissão gluatamatérgicapor meio de eCBs e NO. Ratos wistars com cânulas direcionadas para o CPFMv foram submetidos ao protocolo de medo condicionado ao contexto. No dia seguinte, cateter de polietileno foi implantado na artéria femoral para posterior registro cardiovascular. 24h após, as drogas foram administradas no CPFMv e o tempo de congelamento e a resposta autonômica foram avaliados durante a reexposição ao contexto. Tanto o NIDA quanto a capsaicina aumentaram a expressão da REC, independentemente de a administração ser na porção PL ou IL. A resposta do antagonismo de CB1 parece depender da ativação de TRPV1 e a resposta do antagonismo TRPV1 depende da ativação de CB1. O aumento da REC induzida por antagonista CB1 ou agonista TRPV1 foi prevenida com a administração prévia de antagonista NMDA ou inibidor da enzima nNOS. A administração de um sequestrador de NO ou de um inibidor da enzima guanilato ciclase solúvel (GCs) preveniu apenas a resposta do antagonismo CB1. O aumento da REC evocado pelo agonista TRPV1 foi prevenido com a microinjeção de antioxidante/sequestrador de radicais livres. Desta maneira, os resultados demonstram que no CPFMv o receptor CB1 modula a expressão da REC através da via NMDA/NO/GCs e o receptor TRPV1 através da via NMDA/NO/Estresse nitrosativo. Além disso, a administração de um inibidor da enzima acetilcolinesterase (AChE) aumentou a REC, sendo este efeito prevenido com a administração prévia de antagonista NMDA, inibidor da nNOS, sequestrador de NO, inibidor da GCs e antagonista de receptores TRPV1. O aumento da REC evocado pelo antagonista CB1 e agonista TRPV1 não foi prevenido pela administração local prévia de antagonista de receptores M3. Este resultado indica que a resposta promovida pela ACh modula a neurotransmissão glutamatérgica possivelmente através da produção de NO e ativação de TRPV1pela AEA e que os eCBs não modulam a transmissão colinérgica no CPFMv. Portanto, podemos sugerir que a re-exposição ao contexto aversivo aumenta os níveis de ACh no CPFMv e, assim, ativa receptores M3 que, por sua vez, induzem a produção de eCBs, possivelmente AEA, e NO. O NO atuaria pré- sinapticamente aumentando a liberação de glutamato, e a AEA ativaria receptores TRPV1 pós-sinápticos que ativaria mecanismos de estresse nitrosativo decorrentes da produção do NO. / CB1 and TRPV1 receptors present in the ventromedial prefrontal cortex (vmPFC) have been related in the modulation of defensive behavior, as fear conditioning response. In contextual fear conditioning, CB1 and TRPV1 antagonism increase and decrease, respectively, the behavior and autonomic response during the reexposure to aversive context. CB1 and TRPV1 activation lead to decrease and increase of glutamate release, respectively. Glutamate is an important neurotransmitter in vmPFC involve in cardiovascular and behavioral response. NMDA activation can promote nitric oxide (NO) production, and this mediator could regulate the pre-synaptic and post-synaptic signaling. Another important neurotransmission related to REC and eCBs/NO is Acetylcholine (ACh). AChE inhibitor in vmPFC increase conditioned response expression through M3 receptor activation. Muscarinic activation leads to NO production and this event can increase the glutamate release. Moreover, muscarinic activation also can induce endocannabinoid (eCBs) production and modulation of glutamatergic neurotransmission by CB1 and TRPV1 receptors. Thus, NO and eCBs production by muscarinic activation probably affect conditioned response through glutamate release. Our aim in this study was to investigate if CB1 antagonism and TRPV1 agonism promote an increase in conditioned response by NMDA/NO pathway. In addition, AChE inhibitor inject in vmPFC modulate glutamatergic neurotransmission by NO and eCBs. Male wistars rats with guide cannulas invmPFC were submitted to contextual fear conditioning. 1 day after conditioning, a polyethylene catheter was implanted in the femoral artery for cardiovascular recording. Following 24h, drugs were administrated in vmPFC and freezing behavior and autonomic response was recorded during context reexposure. CB1 antagonism and TRPV1 agonism increased the expression of conditioned emotional response and the response was not different when injected in PL or IL subareas. The response of CB1 antagonism depends on TRPV1 activation and response of TRPV1 antagonism depends on CB1 activation, demonstrating the relation of these receptors. The effect induced by CB1 antagonism and TRPV1 agonism were prevented by an NMDA antagonism and preferential neuronal NO synthase inhibitor. In case of CB1 antagonism, NO scavenger and a soluble guanylate cyclase inhibitor (sGC) also prevented this response, but not response induced by TRPV1 agonism. Effect of TRPV1 agonism was prevented by administration of antioxidant/free radical scavenger. In addition, inhibition of AChE in vmPFC increased the conditioned response and this effect was prevented by NMDA antagonist, nNOS inhibitor, NO scavenger, sGC inhibitor and TRPV1 antagonist. CB1 antagonist and TRPV1 agonist increased conditioned response and M3 antagonist was not able to prevent this effect. Our results demonstrated that the response promoted by ACh modulate glutamatergic neurotransmission through NO and TRPV1 activation (by AEA). Moreover, endocannabinoid system did not affect cholinergic neurotransmission. Therefore, we suggest that reexposure to aversive context increase ACh concentration in vmPFC and thus induce activation of the M3 receptor. M3 receptor promote NO and eCBs production. NO act in pre-synaptic terminalenhancing glutamate release and AEA activate the TRPV1 receptor in the postsynaptic terminal that act by nitrosative stress in NO pathway.

O objetivo do presente estudo foi avaliar se ratos tratados com chá de ayahuasca apresentam i) alterações comportamentais no campo aberto e labirinto em cruz elevado (LCE); ii) alterações na expressão do transportador de glutamato (EAAC1) no córtex pré-frontal (CPF) e no hilus do giro denteado do hipocampo (HDG). Doze grupos de ratos Wistar machos (250g, n=10/cada) foram usados. Eles receberam 2 or 4ml/Kg de chá de ayahuasca ou água: dose única (agudo), 3 vezes/dia por 3 dias alternados (subcrônico) e 1 vez/dia por 15 dias (crônico). Trinta minutos após a última ingestão os animais foram submetidos aos testes comportamentais. Vinte e quatro horas após eles foram anestesiados, perfundidos e seus encéfalos seccionados (40-m) no hipocampo e CPF para os experimentos de imunoistoquimica para EAAC1. Comparações estatísticas entre cada grupo tratado com ayahuasca e seu respectivo controle foram feitas utilizando o teste t de Student e consideradas significantes quando p0,05. Apenas a ingestão subcrônica de ayahuasca induziu redução significante na atividade locomotora (27%) no campo aberto. No LCE nenhum dos tratamentos com ayahuasca induziu alterações significantes em ambos numero de entradas e tempo de permanência nos braços abertos. A ingestão subcrônica ou crônica de chá de ayahuasca induziu aumento significante na expressão de EAAC1 no HGD (20-67%). Em contraste, no CPF a expressão de EAAC1 foi significantemente reduzida em ratos tratados com 2 ou 4ml/Kg subcronicamente ou 4ml/Kg cronicamente (17-25%). A ingestão aguda de 2ml/Kg induziu discreto aumento na expressão de EAAC1 (16%). Estes resultados sugerem que i) Ayahuasca induz alterações nas atividades locomotora e exploratória de forma dependente da dose e frequência de ingestão; ii) Ayahuasca não tem efeito no nível de ansiedade; iii) A ingestão aguda, subcrônica e subcrônica de ayahuasca disparam distintos mecanismos no hipocampo e CPF envolvendo a modulação da neurotransmissão glutamatérgica. / This work aimed at investigating whether rats treated with Ayahuasca beverage show i) behavioral alterations in the open field and elevated plus maze (EPM); ii) alterations in the expression of glutamate transporter (EAAC1) in the prefrontal cortex (PFC) and in the hilus of dentate gyrus of the hippocampus (HDG). Twelve groups of male Wistar rats (250g, n=10/each) were used. They received 2ml/Kg or 4ml/Kg of ayauhasca beverage or water: only once (acute), 3 times/day for 3 days (sub-chronic) or once/day for 15 days (chronic). Thirty minutes after the last ingestion the animals were submitted to behavioural tests. After 24 hours they were anaesthetized, perfused and their brains sectioned (40-m) in the hippocampus and PFC for immunohistochemistry (IH) detection of EAAC1. Comparisons between ayahuasca and control groups used Student t test. Significance was set at p0.05. Only sub-chronic ingestion of Ayahuasca induced a decrease in locomotor (27%) activit in the open field. On the EPM all treatments with Ayahuasca induced no significant increase in both number of entries and time spent in the open arms. The sub-chronic and chronic treatments with Ayahuasca induced a significant increase in EAAC1 expression in the HDG (20-67%). In contrast, in the PFC the expression of EAAC1 was significantly decreased in rats treated with 2 or 4ml/Kg sub-chronically or 4ml/Kg chronically (17-25%). Acute ingestion of 2ml/Kg induced a smaller increase in EAAC1-IC (16%). These results suggest that i) Ayahuasca changes the locomotor and exploratory activities in a way depending the dose and frequency of ingestion; ii) Ayahuasca does not have effect on the level of anxiety; iii) Acute, sub-chronic or chronic ingestion of Ayahuasca beverage trigger distinct mechanisms in the PFC and hippocampus involving the modulation of glutamate neurotransmission.

Indivíduos com fissura labiopalatina apresentam características craniofaciais que os diferenciam da população em geral. A proposta desta pesquisa foi, por meio de radiografias cefalométricas póstero-anteriores, estudar as dimensões transversais totais da face e as assimetrias esqueléticas faciais horizontais em indivíduos portadores de fissura labiopalatina unilateral completa. Utilizou-se neste estudo 34 radiografias cefalométricas póstero-anteriores, de indivíduos com fissura labiopalatina unilateral completa, já submetidos às cirurgias primárias e sem tratamento ortodôntico prévio. A amostra foi composta de 14 do gênero feminino e 20 do masculino, divididos igualmente pela lateralidade da fissura, com média de idade de 9 anos e 8 meses. As mensurações transversais totais e as hemifaciais foram realizadas por meio da demarcação de 5 pares de pontos bilaterais, correspondendo às mensurações em largura facial superior (Lo-Lo’), bizigomática (ZZ’), nasal (Cn-Cn’), maxilar (J-J’) e mandibular (Ag-Ag’). Para a análise das dimensões transversais totais da face suas mensurações foram comparadas aos valores normativos existentes na literatura especializada. A assimetria facial foi verificada tomando-se o lado sem fissura como controle e comparado-o com o lado fissurado. Ambas as análises consideraram a lateralidade da fissura e o gênero, Pode-se concluir que , as dimensões transversais totais da face destes indivíduos apresentaram-se maiores em relação às normas clínicas correspondentes, independente da lateralidade da fissura. Não existiram diferenças significantes nas mensurações entre os grupos com fissura à direita e à esquerda. O gênero masculino apresentou, em média, mensurações maiores que o feminino. Houve tendência do lado fissurado ser maior que o não fissurado, particularmente quanto à largura nasal. O gênero masculino apresentou menor tendência de assimetria, independente da lateralidade da fissura. O melhor entendimento das alterações do padrão de crescimento facial e das suas particularidades torna-se imprescindível para que o indivíduo com fissura labiopalatina alcance os melhores resultados estéticos, funcionais e psíquicos. / Individuals with cleft lip and palate present craniofacial characteristics that differentiate them from the general population. The aim of this research was to study, through frontal cephalometric radiographies, total facial transverse dimensions and the skeletal horizontal asymmetries in complete cleft lip and palate individuals. Thirty four frontal cephalometric radiographies obtained from complete cleft lip and palate individuals were used in this study and individuals were previously submitted toprimary surgery but not submitted to previous orthodontic treatment. The sample was constituted by 14 female and 20 male individuals, equally divided according to the cleft laterality, mean age of 9 years-old and 8 months. Total transverse and hemifacial measures were accomplished demarcating five pairs of bilateral points, corresponding to superior facial width (Lo-Lo'), bizygomatic (Z-Z'), nasal (Cn-Cn'), maxillary (J-J') and mandibular (Ag-Ag') measures. Total transverse dimensions were analyzed by comparison to existent normative values in the specialized literature. The facial asymmetry was verified by comparison with the non-cleft side used as control side. Both analyses considered cleft laterality and gender. In conclusion, the total transverse facial dimensions of these individuals were larger in relation to the corresponding clinical norms, independent of the cleft laterality. There were no significant statistical differences in the measurements between groups with right or left cleft. Measurements in male individuals were larger than the ones verified in females. There was tendency cleft side larger than control side, in particular for the nasal width. Male individuals presented smaller asymmetry tendency, independent on cleft laterality. A better understanding of the alterations in facial growth pattern and about their particularities it becomes indispensable to better aesthetic, functional and psychic results in cleft lip and palate individuals.

A exposição prolongada a estressores socio-ambientais induz alterações duradouras nos níveis afetivo, cognitivo e fisiológico característicos de transtornos de ansiedade e depressão. No paradigma de estresse crônico variado (ECV) é possível modelar essas alterações com base na exposição aleatória, intermitente e incerta dos roedores a vários estressores. Porém, alguns indivíduos também demostram uma capacidade notável de adaptação ativa e persistem diante de eventos imprevisíveis e incontroláveis. Sabe-se também que o sistema neural histaminérgico (SNH) é um indicador sensível do estresse e regula as reações defensivas relacionadas. Contudo, pouco se sabe sobre o papel da histamina no modelo de ECV. Considerando ainda que o perfil comportamental dos camundongos estressados pelo ECV seja contraditório, o presente estudo investigou se (1) duas linhagens de camundongos seriam susceptíveis a respostas relacionadas ao estresse; (2) a neurotransmissão histaminérgica estaria envolvida na ansiedade induzida pelo estresse; (3) o tratamento crônico com L-histidina (LH) combinado ou não ao ECV modificaria a expressão de Fos em áreas cerebrais límbicas. Para testar o impacto do protocolo ECV sobre respostas do tipo depressivas, os comportamentos de camundongos Suíços não estressados (NST) e estressados (ST) foram analisados na tarefa de esquiva ativa de duas vias e no teste de suspensão da cauda. Não foi detectado aumento significativo da imobilidade passiva, mas o grupo ST apresentou hiperreatividade na tarefa de esquiva. Como etapa seguinte, os efeitos do ECV no comportamento ansioso dos animais NST e ST foi verificado no labirinto em cruz elevado (LCE). Notavelmente, camundongos C57Bl/6 estressados desenvolveram respostas ansiogênicas, enquanto a linhagem de Suíço exibiu um perfil comportamental heterogêneo no LCE. Estes resultados indicam que o regime de ECV induz um efeito ansiogênico de modo consistente em animais C57Bl/6 adultos, enquanto os camundongos Suíço são resilientes ao protocolo. Além disso, a ansiedade induzida pelo ECV não foi revertida ou potencializada pela administração crônica de LH, enquanto que a estimulação farmacológica prolongada do SNH poderia representar um potencial estresse isoladamente. Adicionalmente, uma hipo-ativação das áreas corticais pré-limbicas e infralímbicas foi relacionada à condição de estresse crônico, sem efeitos resultantes do tratamento farmacológico. A expressão de Fos+ induzida pela exposição ao LCE foi detectada nos subnúcleos lateral, basolateral e central, porém não houve ativação diferencial destes subnúcleos amígdaloides influenciados pelo ECV e/ou tratamento. Assim, os resultados apresentadas corroboram evidências de que respostas ao estresse são genética e experiência-dependentes, resultando em resiliência ou má adaptação de indivíduos e linhagens. Além disso, o ECV foi capaz de causar uma resposta ansiogênica acompanhada de hipo-ativação de subáreas específicas do córtex pré-frontal medial, região cerebral importante na regulação dos comportamentos defensivos e nas respostas psicofisiológicas do estresse. Finalmente, o tratamento crônico com LH não alterou os parâmetros comportamentais e neuroanatômico-funcionais influenciados pelo estresse. / Chronic exposure to socio-environmental stressors leads to a myriad of long-term alterations in affective, cognitive and physiological levels, which typifies prevalent neuropsychiatric disorders. Importantly, chronic variable stress (CVS) is an experimental model for anxiety- and depressive-like disorders based on the random, intermittent, and uncertain exposure to various stressors. Some individuals also show a remarkable ability to adapt and actively cope and persist in the face of such unpredictable and uncontrollable events. Histamine is a sensitive indicator of stressful experiences and modulates the activation of neuroendocrine stress response to influence defensive reactions. However, little is known about the role of histamine on CVS model. While the behavioral profile of CUS-stressed mice is also contradictory, we investigated whether (1) two widely used mouse strains were susceptible to stress-related responses; (2) histaminergic neurotransmission is involved on stress-induced anxiety; (3) L-histidine (LH) chronic treatment combined to CVS changes Fos expression in limbic areas. To test the impact of the CVS protocol on depressive-like responses, the performance of non-stressed (NST) and stressed (ST) Swiss animals was analyzed in the two-way avoidance task and in the tail suspension test. No increased passive immobility was detected, but the ST group did display hyperreactivity in the avoidance task. Next, the effects of CVS on anxiety were examined in the elevated plus maze (EPM). Remarkably, stressed C57Bl/6 developed anxiogenic responses, while Swiss mice displayed a heterogeneous behavioral profile in the EPM. These results indicate that 2-week-long CVS regimen consistently induces anxiogenic-like response in adult C57Bl/6 mice, while Swiss animals seem to be resilient. Additionally, CVS-induced anxiety is not reversed or potentialized by the chronic administration of LH, but the histamine precursor appears to be a potential stressor per se. Importantly, a hypoactivation of the prelimbic and infralimbic cortical areas was related to the chronic stress condition, with no main effects of the pharmacological treatment. EPM induced Fos+ expression was detected in the lateral, basolateral and central subnuclei, without differential activation of these amygdaloid subnuclei provoked by CVS and/or histaminergic stimulation. The present evidences corroborate the concept that stress responses can be genetic- and experience-dependent, resulting in resilience or maladaptation of a particular strain. Also, stress-induced anxiety could be related to a hypoactivation of the medial prefrontal cortex, important brain region in regulating the defensive behaviors and HPA stress response.

Dentre as manifestações clínicas observadas em pacientes sépticos, as disfunções neurológicas são, provavelmente, as de fisiopatologia mais obscura e pobremente explorada, o que consequentemente as torna de difícil entendimento e tratamento médico. Adicionalmente, estudos epidemiológicos indicam que a síndrome séptica é mais frequente e mais letal em pacientes idosos. Nesse contexto, este trabalho objetivou comparar os efeitos da sepse, induzida pelo modelo de ligadura e perfuração cecal, no encéfalo de ratos jovens e idosos por meio da análise da expressão gênica de larga escala (transcriptoma), a fim de averiguar como as alterações no padrão de expressão podem estar relacionadas a disfunções neurológicas. Os resultados deste estudo indicaram a diminuição da expressão dos genes Bcl-3, S100A8 e uridina fosforilase 1, bem como o aumento da expressão de Stefin A3, sendo tais efeitos característicos das manifestações comuns da sepse no sistema nervoso central, independentemente da idade dos animais; por outro lado, a diminuição da expressão do gene da haptoglobina foi observada apenas nos animais idosos com sepse. De forma geral, na comparação entre animais idosos e jovens, os resultados desta pesquisa apontaram que animais idosos apresentam uma quantidade menor de genes modificados pela sepse, o que sugere menor capacidade de ativar mecanismos neuroprotetores / Among the clinical manifestations observed in septic patients, the neurological dysfunctions are probably the most obscure and poorly explored pathophysiology, which consequently makes them difficult to understand and to treat. Additionally, epidemiological studies indicate that septic syndrome is more frequent and more lethal in elderly patients. In this context, this article is aimed at comparing the effects of sepsis, induced by the ligature model and cecal perforation, on the brain of young and elderly rats by means of the analysis of the large scale gene expression (transcriptome), in order to investigate how the changes in this expression may be related to neurological dysfunctions. The results of this study indicated decreased expression of the Bcl-3, S100A8 and uridine phosphorylase 1 genes, as well as increased expression of Stefin A3, these effects being characteristic of the common manifestations of central nervous system sepsis regardless of the age of the animals; on the other hand, decreased haptoglobin gene expression was observed only in the elderly animals with sepsis. In general, in the comparison between old and young animals, the results of this research indicated that elderly animals present a smaller amount of genes modified by sepsis, which suggests a smaller capacity to activate neuroprotective mechanisms