Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Les troubles schizophréniques (SCZ) ont une forte héritabilité, de l’ordre de 80%, mais, une très faible part du risque génétique a été identifiée. La plupart des études ont considéré l’implication de polymorphismes fréquents, chacun ayant un effet relativement faible individuellement, alors que les études de variants du nombre de copies (CNVs) ainsi que les études d’anomalies chromosomiques ont pointé l’implication possible de variants rares et de novo à une forte pénétrance. Dans une première partie, nous présentons une synthèse sur les facteurs génétiques dans la SCZ, puis une revue des arguments en faveur de l’implication d’anomalies du système glutamatergique dans la SCZ, domaine sur lequel s’est centré notre travail. Notre travail s’inscrit dans un projet plus vaste, Synapse to Disease (S2D) ayant pour objectif de séquencer 1000 gènes synaptiques dans des cohortes de patients atteints de schizophrénie ou de troubles du spectre autistique. Nous avons exploré en particulier le système glutamatergique et les récepteurs NMDA. Dans un premier article, nous montrons une association d’une mutation troncante de novo de la kinésine 17, impliquée dans le transport de la sous-unité GRIN2B des récepteurs NMDA. Dans un second article, nous explorons les mutations rares et de novo dans les sous-unités des récepteurs NMDA et montrons l’association de mutation de novo dans GRIN2A et GRIN2B avec des cas de SCZ et d’autisme. Nos résultats renforcent l’idée qu’une part des cas de schizophrénie pourrait être due à l’implication de mutations rare à effet majeur, hypothèse alternative mais non exclusive à l’hypothèse d’interactions entre variants génétiques fréquents à effet mineur. / Schizophrenic disorders (SCZ) have high heritability (around 80%), but only a small part has been characterized. Most studies have focussed on common polymorphisms, each having small individual effect, whereas copy number variant and chromosomal abnormalities studies have pointed to the possible involvement of rare and de novo mutations with high penetrance. In the first part of this manuscript, we will present a synthesis on genetic factors of SCZ and then a review of the arguments supporting an involvement of glutamatergic system abnormalities in SCZ, which is the focus of our research. Our work is part of a global project, Synapse to Disease (S2D), that aimed to sequence 1000 synaptic genes in cohort of patients affected with schizophrenia or autism spectrum disorders. We focussed in particular on the glutamatergic system and NMDA receptors. In a first publication we show an association between SCZ and a de novo truncating mutation of kinesin 17, wich has been implicated in the transport of the GRIN2B subunit of NMDA receptors. In a second publication we explore rare and de novo mutations in NMDA receptor subunits. We show an association between de novo mutations in GRIN2A and GRIN2B with cases of SCZ and autism. Our results strengthen the idea that a portion of schizophrenia cases could be related to rare mutations having a high penetrance, an alternative but not contradictory explanation to the hypothesis for an interaction between common variants having a small effect.

The glutamate system dysfunctions present in schizophrenia raise new questions about possible glutamatergic actions of the atypical antipsychotic clozapine. While clozapine has been shown to partially substitute for the discriminative stimulus of the glutamate agonist N-methyl D-aspartate (NMDA) in rats, NMDA discrimination has not previously been established in mice. The present study was designed to explore the possible role of NMDA activity in clozapine’s discriminative stimulus. Two groups of C57BL/6 mice were trained to discriminate either 2.5 mg/kg CLZ from vehicle or 30 mg/kg NMDA from vehicle in a standard two-lever drug discrimination task. NMDA drug discrimination was successfully established in C57BL/6 mice. While NMDA did not substitute for clozapine, clozapine partially substituted for NMDA at the 0.625 mg/kg dose, demonstrating an asymmetrical relationship between clozapine’s and NMDA’s discriminative stimuli. Dose combination tests further investigated this relationship. It was found that 0.625 mg/kg CLZ + 30 mg/kg NMDA produced partial substitution (61.82% DLR), while 0.625 mg/kg CLZ + 56 mg/kg NDMA full substitution (92.82% DLR) in CLZ-trained mice. In addition, combination testing with 10 mg/kg NMDA + 2.5 mg/kg CLZ and 10 mg/kg NMDA + 5.0 mg/kg CLZ produced full substitution in NMDA-trained mice ((80.04% DLR and 100% DLR, respectively). Finally, it was found that the α1- adrenoreceptor antagonist prazosin fully substituted for both CLZ (3.0 mg/kg = 92.20% DLR) and NMDA (1.0 mg/kg = 98.77% DLR and 3.0 mg/kg = 99.62% DLR). These findings suggest that interactions between clozapine’s and NMDA’s discriminative stimuli may involve antagonism of α1- adrenoreceptors, but further research of other mechanisms including serotonergic, histaminergic, and cholinergic receptor activity or metabolic interactions is needed. Finally, these initial finding suggest that that drugs active at glutamatergic receptors may have potential as therapeutic drugs for treatment of schizophrenia.

English Abstract Glutamate carboxypeptidase II (GCPII) is a membrane metallopeptidase expressed in many human tissues, predominantly in prostate, brain and small intestine. In brain it cleaves the most abundant peptide neurotransmitter N-acetyl-L-aspartyl-α-L-glutamate into N-acetyl-L-aspartate and free L-glutamate. Thus, GCPII participates in glutamate excitotoxicity through the release of free glutamate into the synaptic cleft. Inhibition of this activity has been shown to be neuroprotective in rats. In the human jejunal brush border, GCPII cleaves off terminal glutamate moieties from poly-γ-glutamylated folates, which can be then transported across the intestinal mucosa. The function of GCPII in human prostate is unknown but it is overexpressed in prostate cancer. Therefore, GCPII is an important marker of prostate cancer and its progression.Moreover, it could become a perspective target for treatment of prostate cancer as well as neuronal disorders associated with glutamate excitotoxicity. For the development and testing of novel drugs and therapeutics it is necessary to have an appropriate animal model. Mouse (Mus musculus) is such a model and it is widely used by many experimentators. However, no detailed comparison of mouse and human GCPII orthologs regarding their enzymatic activity, inhibition...

The main mammalian circadian pacemaker stored in suprachiasmatic nuclei of the hypothalamus (SCN) is adapted to changes in the external environement by synchronization of its endogenous period with periodic changes of light and dark during day and night. The information about light travels via glutamatergic retinohypothalamic tract to the ventrolateral part of the SCN. Activation of ionotropic glutamate receptors in this area provably mediates the transfer of information about light on the transcriptional mechanism of light-sensitive cells. The role of the NMDA type of ionotropic glutamate receptors is well studied in this field and it is known that some NMDA receptor subunits show a circadian rhythm and an increased expression after a light pulse. Signalization via AMPA type receptors is much less elucidated. The aim of this thesis was to determine which AMPA receptor subunits are expressed in the SCN of the rat and if these subunits show a daily rhythm of expression and a reactivity to light pulse, as well as to outline the possible roles of distinct AMPA receptor subunits in the SCN. Keywords: circadian rhythms, suprachiasmatic nuclei, glutamate receptors, AMPA

Les noyaux supraoptiques (NSO) de l’hypothalamus sont composés de neurones magnocellulaires (NMCs) synthétisant et sécrétant l’ocytocine (OT) ou la vasopressine (VP). L’OT est impliquée dans des fonctions de reproduction comme la parturition et la lactation, la VP quant à elle participe à l’homéostasie hydrominérale et vasculaire. La libération de VP et d’OT dans la neurohypophyse est contrôlée par l’activité électrique des NMCs, elle-même régulée par les principales afférences glutamatergiques et GABAergiques qu’ils reçoivent. Les récepteurs kaïnate (rKA) pré-synaptiques exercent une action modulatrice sur la libération de neurotransmetteur dans le système nerveux central (SNC). Cet effet peut basculer de facilitateur à inhibiteur en augmentant la concentration d’agonistes des rKA. Ils peuvent également être présents sur le compartiment post-synaptique et participer à la réponse synaptique. Nous avons démontré, pour la première fois que des rKA fonctionnels sont présents dans le NSO, à la fois sur les afférences GABAergiques et glutamatergiques mais également sur les NMCs eux-mêmes. Les rKA contenant la sous-unité GluR5 régulent différemment la transmission glutamatergique sur les neurones à OT et à VP. En effet, l’application d’agonistes exogènes pour ces récepteurs induit un effet diamétralement opposé sur ces neurones, un effet facilitateur sur les neurones à OT et inhibiteur sur les neurones à VP, dû à la présence de GluR5 uniquement sur ces derniers. En effet, l’activation de ce récepteur post-synaptique induit la libération d’un messager rétrograde, vraisemblablement la dynorphine, responsable de l’inhibition de la transmission glutamatergique. En ce qui concerne la régulation de la transmission GABAergique, nous avons pu démontrer que l’augmentation de glutamate ambiant générée par la rétraction des processus gliaux se produisant dans le NSO de rate allaitante était suffisante pour inverser l’effet des rKA de facilitateur à inhibiteur sur la libération de GABA. Cette inversion de l’effet des rKA est causée par une modification du mode d’action de ces récepteurs du type ionotropique au type métabotropique. Les résultats obtenus au cours de mes travaux de thèse montrent donc que les récepteurs kaïnate sont présents sur l’ensemble des sites de la synapse dans le NSO de l’hypothalamus de rats adultes. De plus, ces rKA régulent différemment les neurones à OT et les neurones à VP, ce qui suggère qu’ils pourraient jouer des rôles importants dans la régulation de leur activité et des processus physiologiques les impliquant. / Magnocellular neuroendocrine cells (MNCs) from the supraoptic nucleus (SON) of the hypothalamus synthesize and release the hormones oxytocin (OT) and vasopressin (VP). OT is involved principally in reproductive functions such as parturition and lactation, whereas VP plays a key role in body fluid and cardiovascular homeostasis. The release of OT and VP from the neurohypophysis is controlled by the electrical activity of hypothalamic MNCs, which is itself regulated by GABAergic and glutamatergic synaptic inputs. Presynaptic kainate receptors (KARs) exert a modulatory action on transmitter release in different structures of the central nervous system. This effect can be switched from facilitation to inhibition by an increased concentration of KAR agonists. KAR can also be present postsynaptically where they were shown to participate to the synaptic response in some brain regions. We have demonstrated for the first time that functional KARs were present on GABAergic and glutamatergic inputs as well as on SON neurons. GluR5-containing KARs differentially regulate glutamatergic transmission on OT and VP neurons. Indeed, applications of exogenous agonists of GluR5 induced opposite effects, a facilitatory effect on OT neurons and an inhibitory effect on VP neurons, the latter resulting from an indirect action mediated by postsynaptic GluR5-containing KARs on VP neurons. Thus, activation of these receptors induced the release of a retrograde messenger, probably dynorphin, which in turn act presynaptically to inhibit glutamate release. Regarding the modulation of GABAergic transmission in the SON, we here showed that the increased levels of ambient glutamate associated with the physiological withdrawal of astrocytic processes occuring during lactation could modify the activity of presynaptic KARs. We demonstrated for the first time that a physiological astrocytic plasticity modifies the mode of action of presynaptic KARs from ionotropic to metabotropic, thereby inversing their coupling with GABA release from facilitation into inhibition. The results obtained during my PhD have thus showed that KARs are present both pre-and post-synaptically on adult MNCs. Moreover, KARs differentially regulate OT and VP neurons, which suggest that KARs could play key roles in the regulation of their activity and in physiological processes in which MNCs are involved

Os neurônios do grupamento catecolaminérgico C1, localizados na porção ventrolateral do bulbo, são classicamente conhecidos por seu envolvimento no controle cardiovascular. O modelo atual propõe que os neurônios C1 são recrutados em situações que ofereçam risco de vida aos indivíduos, desencadeando respostas generalizadas e estereotipadas em defesa da homeostase. Tais respostas envolvem ajustes cardiovasculares, imunológicos, neuroendócrinos, metabólicos, termorregulatórios e respiratórios. Ferramentas anatômicas e funcionais foram utilizadas para investigar se os neurônios C1 contribuem para os ajustes respiratórios induzidos pela hipóxia e pela hipercpania. Os resultados mostram que os neurônios C1 contribuem para a aumento da ventilação induzido pela hipóxia, mas não pela hiperpania, via aumento da frequência da respiratória. Além disso, demonstramos que o aumento da frequência respiratória promovido pela ativação do grupamento C1 depende da ativação de receptores glutamatérgicos, mas não adrenérgicos, localizados na região do complexo pré-Bötzinger. / The catecholaminergic C1 neurons, located in the rostral ventrolateral portion of the medulla, are classically known by their involvement in the cardiovascular control. Recent models suggest that C1 neurons are recruited in situations of life risk, triggering generalized and stereotyped responses to homeostasis. Such responses involve cardiovascular, immunologic, neuroendocrine, metabolic, thermoregulatory and respiratory adjustments. Thus, anatomic and functional tools were used to assess the contribution of C1 neurons to the respiratory adjustments induced by hypoxia and hypercapnia. The results show that these neurons contribute to the increase of ventilation induced by hypoxia, but not by hypercapnia, via an increase of the breathing frequency. Moreover, we demonstrated that increase of breathing frequency promoted by the activation of C1 neurons depend on the activation of glutamatergic receptors, but not adrenergic, located in the pre-Bötzinge complex.

O desenvolvimento humano pode ser influenciado pelo ambiente. Estímulos recebidos ao longo da vida determinam seu progresso e sucesso. Estímulos positivos levam ao desenvolvimento de habilidades, melhorando funções cognitivas e da memória, enquanto estímulos negativos podem predispor a patologias como o estresse. Eventos estressantes durante a infância aumentam a predisposição para o desenvolvimento de transtornos psiquiátricos ao longo da vida. A separação materna, modelo animal de estresse pós-natal, promove diversas alterações comportamentais e encefálicas. Animais submetidos à separação materna apresentam comportamentos que mimetizam doenças psiquiátricas humanas. Por outro lado, diversos trabalhos sugerem que o enriquecimento ambiental pode ter efeito benéfico na reversão ou atenuação de modificações comportamentais e encefálicas promovidas por modelos animais de depressão, esquizofrenia, ansiedade e hiperatividade. Esses aspectos motivaram-nos a estudar se as alterações causadas por estresse podem ser revertidas ou atenuadas pelo enriquecimento do ambiente. Há evidências que sugerem um importante envolvimento de células gliais e de transportadores de glutamato presentes nessas células em modelos animais de transtornos psiquiátricos. Sendo assim, investigamos a expressão de mRNA e proteínas de dois transportadores de glutamato gliais e um neuronal, do receptor de glutamato AMPA, de marcadores gliais GFAP, S100?, glutamina sintase (GS) e do marcador de neurônios maduros NeuN na camada molecular e granular do giro denteado do hipocampo de ratos de 60 dias. Observamos que a separação materna diminui a expressão das proteínas GLAST, GLT-1, GS e NeuN, reduz a expressão dos genes Gria1 (AMPA) e S100?, e aumenta a expressão da proteína EAAC1 no giro denteado. Nossos dados sugerem uma reversão das alterações causadas pela separação materna em relação ao gene Gria1/AMPA e às proteínas GLAST, GLT-1 e EAAC1 após o enriquecimento ambiental. Portanto, o enriquecimento ambiental pode reverter as modificações causadas pela separação materna nas vias glutamatérgicas. Esses efeitos benéficos podem ser investigados para auxiliar no tratamento de transtornos psiquiátricos relacionados à separação materna. / Human development can be influenced by the environment. Stimuli received throughout life determine its progress and success. Positive stimuli lead to development of skills, improving cognitive and memory functions, while negative stimuli may predispose to pathologies such as stress. Stressful events during childhood increase the predisposition to psychiatric disorders throughout life. Maternal separation, an animal model of postnatal stress, promotes several behavioral and encephalic changes. Animals submitted to maternal separation stage behaviors associated with psychiatric diseases in humans. On the other hand, some researches have suggested that environmental enrichment may have some beneficial effects on the reversal or attenuation of behavioral and encephalic modifications promoted by animal models of depression, schizophrenia, anxiety and hyperactivity, which motivates us to study if these changes, stirred by this kind of stress, can be reversed or mitigated by environmental enrichment. There are evidences suggesting the involvement of glial cells and glutamate transporters existent in these cells in psychiatric disorders and animal models of these disorders. Therefore, we investigated mRNA and protein expression of two glial and one neuronal glutamate transporters, AMPA glutamate receptor, glial markers GFAP, S100?, glutamine synthase (GS), and the NeuN neuronal marker in the molecular and granular layer of the hippocampal gyrus in sixty-days-old rats. We observed that maternal separation decreases expression of GLAST, GLT-1, GS and NeuN proteins, reduces Gria1 (AMPA) and S100? gene expression, and increases EAAC1 protein expression in the dentate gyrus. After environmental enrichment, our data suggests a reversal of the maternal separation changes in the Gria1/AMPA gene and the GLAST, GLT-1 and EAAC1 proteins. Therefore, environmental enrichment may reverse the maternal separation changes in the glutamatergic pathways. These beneficial effects may be investigated to aid in the treatment of psychiatric disorders related to maternal separation.

O estresse sido relacionado às causas de diferentes transtornos psiquiátricos, como os transtornos de humor. Dentre os modelos utilizados no estudo da neurobiologia da depressão e que empregam a exposição a agentes estressores, o desamparo aprendido tem sido bastante empregado. Nesse sentido, a adaptação ao estresse parece envolver um fortalecimento da neurotransmissão serotoninérgica do Hipocampo Dorsal (HD) ou do Núcleo Mediano da Rafe (NMnR), estruturas essas anatômica e funcionalmente vinculadas. O HD recebe projeções serotoninérgicas oriundas do NMnR, onde também estão localizados receptores de glutamato de tipo NMDA (NMDAr), os quais controlam a liberação de serotonina no HD e também no próprio NMnR. Entretanto, ainda não se sabe qual o papel dos NMDA na adaptação ao estresse. Assim, o objetivo desse trabalho é investigar se as ativações dos NMDAr do NMnR são capazes de prevenir ou atenuar os efeitos da exposição a choques elétricos inescapáveis. Para tanto, foram utilizados ratos Wistar com cânula guia direcionada ao NMnR e submetidos ao desamparo aprendido. Os animais foram divididos de acordo com o tratamento farmacológico (injeções intracerebrais - i.c.) com salina, AP7 e/ou NMDA, combinadas de forma compor os seguintes grupos: salina + salina, AP7 + salina, salina + NMDA e AP7 + NMDA. O tratamento intracerebral foi realizado imediatamente antes (inj + CI CE; Estudo 1) ou depois (CI + inj CE; Estudo 2) da exposição a choques inescapáveis nas patas (CI). Após 24h os animais foram submetidos a choques escapáveis sinalizados (CEs) por uma luz. O grupo controle do estudo (inj CE; Estudo 3) recebeu os diferentes tratamentos i.c. e foi testado 24h depois. As respostas de esquiva, fuga, falha bem como as latências de respostas e cruzamentos foram registradas e agrupadas em blocos de cinco respostas consecutivas (BT). Os dados dos animais que tiveram sítio de injeção confirmado, após análise histológica, foram analisados estatisticamente utilizando-se MANOVA de medidas repetidas com post hoc de Bonferroni. Foi considerado como significativo o valor de p<0,05. O tratamento antes da pré-exposição com AP7 + NMDA aumentou o número de esquivas, diminuindo a latência para essas respostas. Quando o tratamento com AP7 e/ou NMDA foi realizado imediatamente após a pré-exposição, não foram observadas diferenças em relação ao grupo controle (salina + salina). Não foram observadas diferenças entre os grupos na condição controle. Os dados mostram que o bloqueio da neurotransmissão mediada por NMDA no NMnR previne os efeitos da exposição prévia a um estressor, sugerindo que a ativação destes receptores é importante para a aquisição das memórias relacionadas ao episódio estressante. / Exposure to stressful situations has been related to different psychiatric diseases, such as mood disorders. Learned helplessness has been widely used to investigate the neurobiology of depression among the animal models that involve exposure to uncontrollable aversive stimuli, learned. In this sense, it seems adaptation to the stressful conditions involves an increase in serotoninergic neurotransmission within the dorsal Hippocampus (dH) or Median Raphe Nucleus (MnRN), which are interrelated. The dH receives serotoninergic projections from the MnRN which, in turn, also has NMDA-type glutamate receptors (NMDAr). These NMDAr regulate serotonin release in the dH and also within the MnRN itself. However, the role of MnRN NMDAr it is not known in the development of tolerance to stress. Therefore, the aim of this work was to investigate if MnRN NMDAr activation can prevent and/or attenuate the behavioural effects of exposure to inescapable electric footshocks. Male wistar rats with guided cannulas aimed to the MnRN were submitted to the learned helplessness model. Animals were divided into groups according to the pharmacological treatment (intracerebral injections) they received of Saline, AP7 (NMDAr antagonist) and/or NMDA (NMDAr agonist) as follows: saline + saline, AP7 + saline, saline + NMDA or AP7 + NMDA. Intracerebral treatment was performed immediately before (inj + Ifs SEFs) or after (Ifs + inj SEFs) exposure to inescapable footshocks (IFs). Twenty-four hours later rats were tested and received light-signalized escapable footshocks (SEFs). In an additional control condition, rats received the intracerebral treatment 24 h before test, but were not pre-exposed to IFs (inj SEFs). Avoidance, fight, failure and latency to these responses were registered and presented in blocks of five consecutive trials. Data of animals with confirmed brain site injections were analyzed by repeated measures MANOVA followed by Bonferroni post hoc test. Significance was considered for p<0,05. Pre-exposure treatment with AP7 + NMDA increased number of avoidance responses, decreasing latency to response. When treated with AP7 and/or NMDA immediately after exposure to IFs, no differences were observed when compared to control rats. Also, no differences between groups were detected in control condition, when rats were treated 24 h before test with SEFs. Our data shows that blockade of NMDAr prevents development of behavioral consequences of stress, suggesting that activation of these receptors are important for the acquisition of stressful memories.

A expressão de respostas de medo condicionadas e incondicionadas geradas por estímulos auditivos de natureza aversiva envolve a transmissão neural do colículo inferior (CI) para o núcleo geniculado medial do tálamo, principalmente através do seu núcleo central (CIc). Como outras drogas de abuso, o álcool atua em múltiplos alvos no cérebro produzindo uma variedade de efeitos, incluindo tanto efeitos recompensadores quanto aversivos. A ingestão crônica e a síndrome de abstinência ao álcool promovem alterações severas na regulação homeostática entre GABA e glutamato: os principais neurotransmissores inibitório e excitatório respectivamente, do sistema nervoso central, particularmente do CI. Esse estudo tem o objetivo de investigar os efeitos da interrupção crônica de álcool no processamento da informação acústica no CIc de ratos dependentes de álcool pelo uso da técnica dos potenciais evocados auditivos (PEA). Como uma medida adicional, os PEAs também foram registrados em ratos sob os efeitos do álcool. A influência da neurotransmissão de GABA e de glutamato na modulação das modificações induzidas pela abstinência ao álcool foi analisada por microinjeções locais no CI do agonista GABAA muscimol e do antagonista NMDA AP7. Nossos resultados mostraram que a ingestão crônica de álcool promove o seu bem conhecido efeito ansiolítico no processamento da informação auditiva no CIc, reduzindo a amplitude do PEA. Por outro lado, a abstinência ao álcool causa um aumento da sensibilidade dos neurônios do CIc a estímulos auditivos. Este efeito apareceu somente após 96 horas da retirada do álcool. Os resultados obtidos com a manipulação farmacológica mostraram que o muscimol e o AP7 promoveram efeitos bastante distintos com cursos de tempo diferentes. De fato, o muscimol foi eficaz na redução dos PEAs em ratos com 48 horas de abstinência. O antagonismo de receptores glutamatérgicos NMDA ocorreu somente após 96 horas da retirada do álcool. Esses resultados mostraram que as modificações induzidas pela abstinência ao álcool em neurônios do CIc de ratos dependentes de álcool são diferentemente modulados por mecanismos GABA e NMDA. / The expression of conditioned and unconditioned fear responses generated by auditory stimuli of aversive nature, involves neural transmission from the inferior colliculus (IC) to the medial geniculate nucleus of the thalamus and thence to the integrates acoustic information of aversive nature, mainly by its central nucleus (cIC). Like other drugs of abuse, alcohol acts on multiple targets in the brain to produce a complex array of effects, including both rewarding and aversive ones. Alcohol administration and alcohol withdrawal syndrome promote severe changes in the normal homeostatic regulation between GABA and glutamate; the major inhibitory and excitatory neurotransmitters in the IC, respectively. This study was aimed at investigating the alcohol chronic withdrawal effects on the processing of acoustic information in the cIC of alcohol-dependent rats through the use of the auditory evoked potentials (AEPs) technique. As an additional measure AEPs were also recorded in rats under alcohol effects. The influence of GABA and glutamate neurotransmission on the modulation of changes induced by alcohol withdrawal was analyzed by local IC microinjections of the GABAA agonist muscimol and the NMDA antagonist AP7. Our results showed that the chronic intake of alcohol promotes its well-known anxiolytic-like effects on the processing of auditory information in the cIC, reducing the amplitude of the AEPs. On the other hand, alcohol withdrawal causes increased sensitivity of the cIC neurons to auditory stimuli. This effect appeared only after 96 hours of alcohol withdrawal. The results obtained with the pharmacological manipulation showed that muscimol and AP7 promoted quite distinct effects with different time courses. In fact, muscimol was effective in reducing AEPs in 48 hours withdrawal-rats. The antagonism of glutamate NMDA receptors occurred only at 96 hours of alcohol withdrawal. These results showed that the changes induced by alcohol withdrawal on cIC neurons of alcohol-dependent rats are differently modulated by GABA and NMDA mechanisms.