When a human or animal is threatened or confronted with a stimuli signalling danger, internal defence mechanisms are activated that evoke feelings of fear and anxiety. These emotional responses promote the behaviour patterns necessary for an organism's survival. Animal research seeks to understand how these emotions affect behaviour both physiologically and neurologically in order to develop effective treatment for those suffering from severe anxiety disorders. The aim of this thesis was to examine the role of the amygdala, and dorsal and ventral hippocampus in relation to immediate fear arousal brought on by footshock. This was assessed by examining whether muscimol would interfere with the acoustic startle response before or after footshock presentation, and then comparing these reactions to a control group that received saline infusions. The results of this research are extremely important because they identify various brain structures involved in the fear-arousing effects of footshock as measured by the shock sensitization of acoustic startle. Laboratory rats received muscimol (0.1ug and 0.01ug) infusions into the basolateral amygdala, dorsal and ventral hippocampus. These three brain regions have been identified as playing a prominent role in fear neurocircuitry. The results demonstrated that the GABA A receptor agonist muscimol in doses of 0.1ug and 0.01ug reliably blocked shock sensitization of the acoustic startle response. The muscimol doses did not alter the shock reactivity amplitudes therefore indicating a normal perception of the fear arousing properties of footshock. Therefore, the present study's results suggest that a decrease of GABA activity in the amygdala, dorsal and ventral hippocampus may be essential for the neuronal basis of fear acquisition and expression of unconditioned and conditioned stimuli.

Made available in DSpace on 2014-06-11T19:23:33Z (GMT). No. of bitstreams: 0 Previous issue date: 2012-06-22Bitstream added on 2014-06-13T20:11:01Z : No. of bitstreams: 1 silva_tm_me_araca.pdf: 1258731 bytes, checksum: 9d2da0efd667a88f8de0c4364d2a3ab8 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Injeções no núcleo parabraquial lateral (NPBL) de muscimol, agonista de receptores GABAA, promove aumento de pressão arterial e induz ingestão de NaCl 0.3 M e água em ratos normovolêmicos, saciados e depletados de sódio. A doença periodontal é uma condição inflamatória que promove a liberação de citocinas próinflamatórias, tais como IL-6 e TNF-α e a destruição das estruturas de suporte do dente. As citocinas pró-inflamatórias podem modular a neurotransmissão GABAérgica e ativar neurônios do NPBL. Neste estudo, investigamos o efeito da ativação GABAérgica no NPBL com muscimol na ingestão de NaCl hipertônico e água e parâmetros cardiovasculares em ratos normovolêmicos, saciados e depletados pelo modelo FURO+CAP com doença periodontal. Foram utilizados ratos Wistar divididos em dois grupos: com doença periodontal induzida por ligadura (DP) e sem doença periodontal (grupo controle). Quinze (15) dias após a indução da doença periodontal em ambos os grupos foram implantadas cânulas bilaterais no NPBL. Ratos saciados controles que receberam injeções bilaterais no NPBL de muscimol tiveram aumento na ingestão... / GABAA receptor activation with muscimol in the lateral parabrachial nucleus (LPBN) induces water and hypertonic sodium chloride (NaCl) intake in rats. The purpose of this study was to investigate whether local inflammatory event, such as periodontal disease, is able to alter the effects of injections of muscimol (GABAA receptor agonist) into the LPBN on water and 0.3 M NaCl intake in fluid replete rats and in rats treated with diuretic furosemide (FURO) combined with a low dose of the angiotensin-converting enzyme inhibitor captopril (CAP) injected subcutaneously. Male Wistar rats were divided into two groups: with experimental ligature-induced periodontal disease (PD) and those without PD (control conditions). Fifteen days after application of the ligature, both groups had cannulas implanted bilaterally into the LPBN, and were given simultaneous access to water and 0.3 M NaCl intake. In fluid replete rats without PD, injections of muscimol (0.5 nmol/0.2 μl) into the LPBN induced 0.3 M NaCl intake (15.8 ± 2.4 vs. saline: 0.2 ± 0.05 ml/210 min), water intake (14.2 ± 1.2 vs. saline: 0.6 ± 0.3 ml/210 min) and pressor response (15 ± 3.3 mmHg, vs. saline: 0.6 ± 1.3 mmHg). In fluid replete rats (PD group), a decrease was observed in water intake (6.0 ± 1.4 ml/210 min), pressor response (7.5 ± 3.1 mmHg), but not in 0.3 M NaCl intake induced by muscimol. In rats with FURO + CAP-treatment (control group), injections of muscimol into the LPBN increased 0.3 M NaCl (25.9 ± 5.8 vs. saline: 5.7  1.0 ml/210 min) and water intake (19.9  1.2 vs. saline: 11.2  1.0 ml/210 min). In rats with FURO + CAP-treatment (PD group), a decrease was observed in 0.3 M NaCl intake (10.9 ± 2.9 ml/210 min) and water intake (13.4  2.3 ml/210 min) after... (Complete abstract click electronic access below)

Chapter 1 provides a general introduction on the role of bioisosterism of fluorine aiming to improve the pharmacokinetics properties of lead compounds. GABAA receptors specifically, synaptic GABAA receptors, extrasynaptic GABAA receptors and GABAA rho receptors are then presented. Compounds that exhibit agonist and partial agonist effects at these receptors are also discussed. The applications of some compounds as GABAA receptor PET radiotracers are also described. Chapter 2 details the synthesis of two fluorinated analogues of muscimol, fluoromuscimol and trifluoromethylmuscimol. Fluoromuscimol was obtained from the lithiation of a Boc-protected isoxazole followed by in-situ fluorination using NFSI, whereas trilfuoromethylmuscimol was obtained from the coupling of a heteroaryl iodide with trifluoromethylcopper species, which was generated in-situ from MFSDA in the presence of CuI. Fluoromuscimol and trifluoromethylmuscimol were assessed on human synaptic, (α₁β₂γ₂), extrasynaptic, (α₄β₂δ) and ρ₁ subunits of the GABAA receptor. The biological results show that fluoromuscimol exhibits greater maximum response in comparison to GABA at the extrasynaptic GABAA receptors (α₄β₂δ), but lower overall potency, whereas trifluoromethylmuscimol was inactive at all the tested GABAA receptors. Chapter 3 discusses the synthesis and late stage fluorination of diaryliodonium salts as precursors to fluoromuscimol. Application of iodonium salts as precursors for nucleophilic fluorination in PET studies are also highlighted. The last part of this chapter focuses on the synthesis of iodomuscimol as a potential alternative SPECT radiotracer to fluoromuscimols in probing GABA binding sites on GABAA receptors.

Orientador: João Carlos Callera / Banca: José Vanderlei Menani / Banca: Juliana Irani Fratucci De Gobbi / Resumo: Injeções no núcleo parabraquial lateral (NPBL) de muscimol, agonista de receptores GABAA, promove aumento de pressão arterial e induz ingestão de NaCl 0.3 M e água em ratos normovolêmicos, saciados e depletados de sódio. A doença periodontal é uma condição inflamatória que promove a liberação de citocinas próinflamatórias, tais como IL-6 e TNF-α e a destruição das estruturas de suporte do dente. As citocinas pró-inflamatórias podem modular a neurotransmissão GABAérgica e ativar neurônios do NPBL. Neste estudo, investigamos o efeito da ativação GABAérgica no NPBL com muscimol na ingestão de NaCl hipertônico e água e parâmetros cardiovasculares em ratos normovolêmicos, saciados e depletados pelo modelo FURO+CAP com doença periodontal. Foram utilizados ratos Wistar divididos em dois grupos: com doença periodontal induzida por ligadura (DP) e sem doença periodontal (grupo controle). Quinze (15) dias após a indução da doença periodontal em ambos os grupos foram implantadas cânulas bilaterais no NPBL. Ratos saciados controles que receberam injeções bilaterais no NPBL de muscimol tiveram aumento na ingestão... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: GABAA receptor activation with muscimol in the lateral parabrachial nucleus (LPBN) induces water and hypertonic sodium chloride (NaCl) intake in rats. The purpose of this study was to investigate whether local inflammatory event, such as periodontal disease, is able to alter the effects of injections of muscimol (GABAA receptor agonist) into the LPBN on water and 0.3 M NaCl intake in fluid replete rats and in rats treated with diuretic furosemide (FURO) combined with a low dose of the angiotensin-converting enzyme inhibitor captopril (CAP) injected subcutaneously. Male Wistar rats were divided into two groups: with experimental ligature-induced periodontal disease (PD) and those without PD (control conditions). Fifteen days after application of the ligature, both groups had cannulas implanted bilaterally into the LPBN, and were given simultaneous access to water and 0.3 M NaCl intake. In fluid replete rats without PD, injections of muscimol (0.5 nmol/0.2 μl) into the LPBN induced 0.3 M NaCl intake (15.8 ± 2.4 vs. saline: 0.2 ± 0.05 ml/210 min), water intake (14.2 ± 1.2 vs. saline: 0.6 ± 0.3 ml/210 min) and pressor response (15 ± 3.3 mmHg, vs. saline: 0.6 ± 1.3 mmHg). In fluid replete rats (PD group), a decrease was observed in water intake (6.0 ± 1.4 ml/210 min), pressor response (7.5 ± 3.1 mmHg), but not in 0.3 M NaCl intake induced by muscimol. In rats with FURO + CAP-treatment (control group), injections of muscimol into the LPBN increased 0.3 M NaCl (25.9 ± 5.8 vs. saline: 5.7  1.0 ml/210 min) and water intake (19.9  1.2 vs. saline: 11.2  1.0 ml/210 min). In rats with FURO + CAP-treatment (PD group), a decrease was observed in 0.3 M NaCl intake (10.9 ± 2.9 ml/210 min) and water intake (13.4  2.3 ml/210 min) after... (Complete abstract click electronic access below) / Mestre

Lors d'une tâche cognitive telle que la navigation spatiale dans un environnement connu, l'individu peut utiliser des stratégies différentes pour atteindre un but. Il peut baser sa navigation sur une représentation mentale de l'espace (globale) ou utiliser une stratégie mettant en jeu des informations égocentriques ou associatives (indices physiques internes ou externes associatifs). Deux grands systèmes cérébraux sont impliqués dans l’apprentissage spatial : la formation hippocampique et les ganglions de la base. Ces deux systèmes utilisent des modalités différentes : l'hippocampe est plus spécifiquement lié à l'apprentissage par rapport à un référentiel externe (apprentissage allocentrique) alors que les ganglions de la base sont plutôt liés à l'apprentissage par rapport à un référentiel interne (apprentissage égocentrique). L’apprentissage parallèle entre les deux systèmes partage à la fois des aspects compétitifs et coopératifs. L’hippocampe étant peu atteint dans les stades précoces de la maladie de Parkinson, ceci fournit l'opportunité de développer des méthodes de rééducation basées sur le renforcement de l'apprentissage allocentrique. Dans cette optique, il faut tout d'abord bien comprendre le fonctionnement de ces mécanismes d'apprentissage dans le cerveau sain. Nous proposons ici un test qui vise à analyser les processus d'apprentissage des deux systèmes, pendant une tâche de navigation dans un labyrinthe. Nous voulons développer une variante de cette tâche qui permet de différencier le rôle respectif de l'hippocampe et des ganglions de la base dans ces processus d'apprentissage. L’objectif de cette étude est d'étudier les différentes modalités d'apprentissage spatial (allocentrique et egocentrique) afin de définir leurs cinétiques d'apprentissage et les interactions entre ces deux systèmes. Ces connaissances seront utilisées par la suite afin de pallier au déficit spécifique d'apprentissage égocentrique dans la maladie de parkinson. Ce projet a pour but de mettre au point une tâche de navigation spatiale permettant de mieux connaitre les modalités des différentes stratégies utilisées lors de la navigation spatiale chez le primate dans un premier temps. Ces données pourront éventuellement servir à l'ajustement d'un protocole pour des sujets humains sains ou souffrant de déficits cognitifs pouvant être compensés par l'adaptation stratégique. / In spatial navigation task, we can use several strategies to reach a goal. We can build a mental representation (global) of the environment, use egocentric (body-based) information or use available cues (internal or external). Two structures known to have roles in spatial information are the hippocampus and the striatum. It is now generally held that allocentric (external reference frame) learning is related to the hippocampus. On the other hand, the striatum is believed to be involved in egocentric representation. There is a parallel processing between those two system which sharing both competitive and cooperative interactions. The hippocampus is less damaged in the early stages of Parkinson disease, this aspect allows the possibility to develop rehabilitation protocols based on the use of allocentered learning when the egocentered one is biased. We have first to better understand how these two systems functionally operate in the normal brain. Here we present a task which permits the study of the spatial learning processes in a maze. Our global aim is to differentiate the respective functions of the hippocampus and basal ganglia in the spatial learning modalities (allocentered or egocentered) and define their kinetics and interactions. The resultant knowledge will may serve to develop cognitive rehabilitation tasks for people with cognitive disorders can be compensated by strategic adaptation.

Submitted by Viviane Lima da Cunha (viviane@biblioteca.ufpb.br) on 2016-08-19T14:12:14Z No. of bitstreams: 1 arquivototal.pdf: 1783924 bytes, checksum: cd370846eb175ca5a7541394c0b1e78d (MD5) / Made available in DSpace on 2016-08-19T14:12:14Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 1783924 bytes, checksum: cd370846eb175ca5a7541394c0b1e78d (MD5) Previous issue date: 2016-03-31 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Episodic memory is a declarative type of memory rich in temporal and spatial contexts. This type of memory has been atributed only to humans, but animals have been demonstrating an episodic-like memory, based on behavioural criteria and, considered as a memory for a particular event (“what”) that happened in a particular place (“where”) and in a particular time (“when”). To be considered as an episodic-like memory, these behavioural aspects must be evoked in an integrative and associative way, excluding any possibility of being evoked separately. For a long time it has been demonstrated that the medial temporal lobe (MTL) is important for processes involving episodic-like memory characteristics and, the hippocampus and other areas, such as the perirhinal, postrhinal, entorhinal and medial prefrontal cortices seem to be involved in one or more of episodic-like memory behavioural aspects. In this work we sought to investigate the role of the hippocampal subfield CA1 with bilateral infusions of the GABAA agonist muscimol, in an integrative episodic-like memory task. 24 naïve male wistar rats, ranging from 3 to 4 months, weighing 270-360g and kept in controlled coditions, were used as subjects. This task is done in an open-field and it depends on the tendency of rats to explore novelty. There were three trials: sample 1, sample 2 and test. Each one had a duration of five minutes and the intertrial interval was of 1 hour. In sample 1, rats were allowed to explore four novel objects (A) in specific locations. In sample 2, four new objects (B) were disposed in the open-field, where two of them were placed in locations previously occupied by objects “A”, and two of them were placed in new positions. In the test trial, animals were exposed to four copies of previously seen objects, where two of them were stationary to its initial position (A1 and B1) and another two were displaced (A2 and B2). The pattern of exploration expected to this task is of A1>B1 (temporal pattern), B2>B1 (spatial pattern) and A1>A2 (integrative pattern). Animals of the control group did evoked an episodic-like memory in the test trial, while the animals in the experimental group didn’t. This was not influenced by a lack of exploration in the muscimol group. Histology showed that the cannulae and niddle tips were placed in the right positions. Altogether, our data provides evidence that CA1 plays an essential role in the recollection of the episodic-like memory components, although it’s not clear if it does by having a role in the recognition of objects alone, or on the association of temporal and spatial aspects of episodic-like memory. / A memória episódica é uma memória declarativa rica em contexto espacial e temporal. Este tipo de memória tem sido atribuído apenas a humanos, mas alguns animais têm demonstrado uma memória similar à episódica, baseada em critérios que podem ser mostrados através do comportamento e, tida como a memória para eventos (“o quê”) que ocorreram em um devido local (“onde”) e num determinado espaço de tempo (“quando”). Para ser considerada uma memória similar à episódica, estes aspectos comportamentais devem ser evocados de forma integrada e associativa, não havendo a possibilidade de se recordar cada aspecto separado. Há algum tempo tem sido demonstrado que o lobo temporal medial (LTM) é importante para processos que envolvem características da memória similar à episódica e, o hipocampo e áreas como os córtices perirrinal, pósrrinal, entorrinal e pré-frontal medial parecem estar envolvidas em um ou mais dos aspectos comportamentais deste tipo de memória. Neste trabalho nós procuramos avaliar o papel da área hipocampal CA1 em uma tarefa de memória similar à episódica integrativa dos três aspectos comportamentais através da inativação bilateral com o agonista GABAA muscimol. Para tal, utilizamos 24 ratos wistar machos de 3 a 4 meses de idade, pesando entre 270-360g e mantidos em condições controladas. Esta tarefa é realizada em uma arena circular e é baseada no paradigma da novidade, que aponta que em estado saudável, ratos sempre vão preferir explorar algo novo. Foram realizadas três sessões na tarefa: a sessão de amostra 1, amostra 2 e teste. Cada sessão teve duração de cinco minutos e o intervalo entre sessões foi de uma hora. Na sessão de amostra 1 foi permitido que o animal explorasse quatro objetos novos (A) em disposições específicas. Na sessão de amostra 2 quatro novos objetos (B) foram expostos, sendo dois alocados em posições ocupadas pelos objetos “A” e dois em novas posições. Na sessão de teste os animais entraram em contato dois objetos da primeira sessão e, dois objetos da segunda sessão, onde um objeto de cada sessão era estacionário em relação à sua posição inicial (A1 e B1) e outro objeto era deslocado (A2 e B2). O padrão de exploração esperado para esta tarefa é de A1>B1 (padrão temporal), B2>B1 (padrão espacial) e A1>A2 (padrão integrativo). Os animais do grupo controle conseguiram evocar o episódio na sessão de teste da tarefa, enquanto que os animais do grupo experimental não conseguiram e, isto não foi influenciado por uma falta de motivação em explorar por parte do grupo experimental. Um exame histológico verificou a posição correta das cânulas e agulhas de infusão para a área CA1. Concluímos que CA1 é importante para a resolução da tarefa, mas não fica claro se o é por influenciar no reconhecimento de objetos, ou porque influenciou diretamente no processamento dos aspectos espacial e temporal.

L’anxiété est un symptôme prédominant au cours des périodes initiales de sevrage à la cocaïne et est considérécomme un facteur important de rechute. Le but de cette étude était de caractériser les dysfonctionnementscérébraux qui pourraient contribuer à l’expression de cet état pathologique chez le rat.Les rats sont traités avec de la cocaïne en chronique et le comportement anxieux est évalué au cours du sevragedans différents paradigmes expérimentaux (tests du labyrinthe en croix surélevé, du confinement dans un brasouvert surélevé et de l’enfouissement défensif). Nos résultats ont montré que le sevrage à la cocaïne induit unétat anxieux élevé qui persiste pendant au moins 28 jours de sevrage. Nous avons ensuite utilisél’immunohistochimie de Fos pour comparer les patterns d’activation cérébrale chez les rats sevrés et témoinsaprès exposition au test de l’OA. Nos données ont montré que l’anxiété élevée des rats sevrés était accompagnéed’une altération de la réactivité des neurones glutamatergiques de la partie dorsale du cortex préfrontal médian(dCPFm) et de certaines régions sous-corticale (aires hypothalamiques latérale et antérieure et le noyauparaventriculaire du thalamus). Nous avons ensuite montré que l’inactivation pharmacologique du dCPFm avecdu muscimol atténuait les comportements anxieux des rats sevrés suggérant ainsi une hyperréactivité de cetterégion corticale durant le traitement des informations de type anxieux. Notre étude amène des données nouvellesquant aux substrats neuronaux sous-tendant l’anxiété pathologique observée au cours du sevrage à la cocaïne etsouligne l’importance du CPFm dans la régulation de cet état d’anxiété pathologique. / Anxiety is one of the prevailing symptoms observed during the initial period of abstinence in cocaine abusersand is considered as an important factor of relapse. The aim of this study was to provide further insight into thecerebral dysregulations that might contribute to this pathological state in rats.Rats were treated chronically with cocaine and anxiety-behaviors were assessed in different paradigms duringwithdrawal (elevated plus maze, open arm and shock probe burying tests). Our results demonstrated that cocainewithdrawal induced persistent heightened levels of anxiety that last for at least 28 days. We then used Fosimmunohistochemistry to map neuronal activation patterns in withdrawn rats confined to one open arm (OA) ofan elevated plus maze. Our data showed that the exacerbated anxiety observed in cocaine treated rats exposed toan OA was accompanied by an altered reactivity of the dorsal part of the medial prefrontal cortex (dmPFC)glutamatergic neurons and some sub-cortical regions (anterior and lateral hypothalamic areas and theparaventricular nucleus of the thalamus). Finally, we showed that pharmacological inactivation of the dmPFCwith muscimol considerably attenuated anxiety-related behaviors in cocaine withdrawn rats suggesting anexaggerated response of this cortical area during the processing of anxiogenic stimuli. The present studyprovides new data on the neural substrate underlying pathological anxiety observed during cocaine withdrawaland highlights the importance of the dmPFC in the regulation of this pathological anxiety state.

A substância cinzenta periaquedutal dorsal (SCPd) e o colículo inferior (CI) são duas estruturas do teto mesencefálico que, juntamente com a amígdala, o hipotálamo dorsomedial e o colículo superior, estão envolvidas na modulação da expressão comportamental dos estados de medo. A estimulação química ou elétrica destas estruturas produz uma série de respostas comportamentais defensivas. Além disso, dados comportamentais com modelos animais de ansiedade têm fornecido evidências da existência de uma regulação inibitória tônica GABAérgica na SCPd e CI. Neste estudo investigamos o envolvimento da neurotransmissão GABAérgica na expressão do medo condicionado e do medo incondicionado. Para isso, os efeitos da administração de muscimol (agonista GABA-A) e semicarbazida (inibidor da descarboxilase do ácido glutâmico) na SCPd e CI foram analisados no teste do sobressalto potencializado pelo medo, na resposta de congelamento condicionada, nos limiares de congelamento e fuga determinados por estimulação elétrica dessas estruturas e no congelamento pós-estimulação. No modelo de medo incondicionado, microinjeções de muscimol intra-SCPd reduziram a aversividade da estimulação elétrica, mas não o congelamento pós-estimulação, ao passo que a semicarbazida produziu efeitos pró-aversivos em ambas as condições. O muscimol também causou redução significativa no sobressalto potencializado pelo medo e congelamento condicionado, enquanto que a semicarbazida não alterou essas respostas. Já a microinjeção de ambas as drogas no CI não produziu efeitos no modelo condicionado, mas no teste incondicionado, o muscimol reduziu a aversividade da estimulação elétrica. Esses dados mostram uma participação diferencial de mecanismos GABAérgicos no medo condicionado e incondicionado. Estes mecanismos na SCPd parecem estar envolvidos tanto no medo condicionado quanto no incondicionado, enquanto que no CI eles parecem participar somente do medo incondicionado. / The dorsal periqueductal gray (dPAG) and inferior colliculus (IC) are two structures of the midbrain tectum that, together with amygdala, dorsomedial hypothalamus and superior colliculus, are involved in the modulation of the expression of fear-related behaviors. The chemical or electrical stimulation of these structures produces a series of behavioral defensive responses. Moreover, behavioral data from animal models of anxiety have provided evidences of tonic inhibitory GABAergic regulation in dPAG and IC. This study investigated the involvement of GABAergic neurotransmission in the expression of unconditioned and conditioned fear. To this aim, the effects of intra-dPAG and IC administration of muscimol (GABA-A agonist) and semicarbazide (glutamic acid decarboxylase inhibitor) were examined in the fear potentiated startle test, in conditioned freezing, in the thresholds for freezing and escape determined by electrical stimulation of these structures, and in the post-stimulation freezing. In the unconditioned model, intra-dPAG injections of muscimol reduced the aversiveness of the electrical stimulation but had no effects on the post-stimulation freezing, while semicarbazide produced aversive-like effects in both conditions. Muscimol also caused significant reduction in fear potentiated startle and conditioned freezing, while semicarbazide had no effect in these responses. In contrast, intra-IC injections of both drugs were ineffective in the conditioned model. In the unconditioned model, however, muscimol reduced the aversiveness of the electrical stimulation. These data show a differential participation of GABAergic mechanisms on conditioned and unconditioned fear. These mechanisms in the dPAG seem to be involved in both conditioned and unconditioned fear, while in IC they seem to participate in unconditioned fear only.

A substância cinzenta periaquedutal dorsal (SCPd) e o colículo inferior (CI) são duas estruturas do teto mesencefálico que, juntamente com a amígdala, o hipotálamo dorsomedial e o colículo superior, estão envolvidas na modulação da expressão comportamental dos estados de medo. A estimulação química ou elétrica destas estruturas produz uma série de respostas comportamentais defensivas. Além disso, dados comportamentais com modelos animais de ansiedade têm fornecido evidências da existência de uma regulação inibitória tônica GABAérgica na SCPd e CI. Neste estudo investigamos o envolvimento da neurotransmissão GABAérgica na expressão do medo condicionado e do medo incondicionado. Para isso, os efeitos da administração de muscimol (agonista GABA-A) e semicarbazida (inibidor da descarboxilase do ácido glutâmico) na SCPd e CI foram analisados no teste do sobressalto potencializado pelo medo, na resposta de congelamento condicionada, nos limiares de congelamento e fuga determinados por estimulação elétrica dessas estruturas e no congelamento pós-estimulação. No modelo de medo incondicionado, microinjeções de muscimol intra-SCPd reduziram a aversividade da estimulação elétrica, mas não o congelamento pós-estimulação, ao passo que a semicarbazida produziu efeitos pró-aversivos em ambas as condições. O muscimol também causou redução significativa no sobressalto potencializado pelo medo e congelamento condicionado, enquanto que a semicarbazida não alterou essas respostas. Já a microinjeção de ambas as drogas no CI não produziu efeitos no modelo condicionado, mas no teste incondicionado, o muscimol reduziu a aversividade da estimulação elétrica. Esses dados mostram uma participação diferencial de mecanismos GABAérgicos no medo condicionado e incondicionado. Estes mecanismos na SCPd parecem estar envolvidos tanto no medo condicionado quanto no incondicionado, enquanto que no CI eles parecem participar somente do medo incondicionado. / The dorsal periqueductal gray (dPAG) and inferior colliculus (IC) are two structures of the midbrain tectum that, together with amygdala, dorsomedial hypothalamus and superior colliculus, are involved in the modulation of the expression of fear-related behaviors. The chemical or electrical stimulation of these structures produces a series of behavioral defensive responses. Moreover, behavioral data from animal models of anxiety have provided evidences of tonic inhibitory GABAergic regulation in dPAG and IC. This study investigated the involvement of GABAergic neurotransmission in the expression of unconditioned and conditioned fear. To this aim, the effects of intra-dPAG and IC administration of muscimol (GABA-A agonist) and semicarbazide (glutamic acid decarboxylase inhibitor) were examined in the fear potentiated startle test, in conditioned freezing, in the thresholds for freezing and escape determined by electrical stimulation of these structures, and in the post-stimulation freezing. In the unconditioned model, intra-dPAG injections of muscimol reduced the aversiveness of the electrical stimulation but had no effects on the post-stimulation freezing, while semicarbazide produced aversive-like effects in both conditions. Muscimol also caused significant reduction in fear potentiated startle and conditioned freezing, while semicarbazide had no effect in these responses. In contrast, intra-IC injections of both drugs were ineffective in the conditioned model. In the unconditioned model, however, muscimol reduced the aversiveness of the electrical stimulation. These data show a differential participation of GABAergic mechanisms on conditioned and unconditioned fear. These mechanisms in the dPAG seem to be involved in both conditioned and unconditioned fear, while in IC they seem to participate in unconditioned fear only.

Ce travail de thèse avait pour objectif d’étudier le rôle de l’habénula latérale (HbL) dans les processus mnésiques chez le Rat en utilisant une approche par inactivation réversible grâce à l’administration de muscimol ou de CNQX. Nous avons ainsi montré l’implication de l’HbL dans : i) les processus d’encodage et de rappel d’une mémoire spatiale en piscine de Morris ; ii) la mémoire de travail, comme relais potentiel d’informations en provenance du cortex préfrontal médian, dans un paradigme de non-appariement différé à la position en boites de conditionnement opérant; iii) la réponse émotionnelle, aux niveaux comportemental et physiologique, à une situation stressante. L’ensemble de ces résultats suggèrent que l’HbL est impliquée dans les processus « online » de gestion des informations sensorielles, et qu’elle participe à la prise en compte de l’aspect émotionnel d’une situation. Ces particularités en font un lien important potentiel entre gestion des émotions et cognition. / The main objective of this thesis was to investigate the role of the lateral habenula (LHb) in mnemonic processes in rats using reversible inactivations with muscimol or CNQX. We have shown the involvement of the LHb in : i) encoding and retrieval of spatial reference memory in the Morris water maze ; ii) working memory, as a potential relay of top-down information coming from the medial prefrontal cortex, in a delayed non-matching to position paradigm using operant chambers ; iii) the behavioral and physiological responses to stressful situations. Altogether, those results suggest that the LHb is involved in the « online » process of sensory information. They also suggest that it is involved in coping with particularly stressful situations, and further position the LHb as an interface between emotions and cognition.