Submitted by Luciana Sebin (lusebin@ufscar.br) on 2016-10-10T13:15:34Z No. of bitstreams: 1 DissGMS.pdf: 1736443 bytes, checksum: 9e6aa510fda128c4e4722add3ed4b7ed (MD5) / Approved for entry into archive by Marina Freitas (marinapf@ufscar.br) on 2016-10-13T20:11:02Z (GMT) No. of bitstreams: 1 DissGMS.pdf: 1736443 bytes, checksum: 9e6aa510fda128c4e4722add3ed4b7ed (MD5) / Approved for entry into archive by Marina Freitas (marinapf@ufscar.br) on 2016-10-13T20:11:13Z (GMT) No. of bitstreams: 1 DissGMS.pdf: 1736443 bytes, checksum: 9e6aa510fda128c4e4722add3ed4b7ed (MD5) / Made available in DSpace on 2016-10-13T20:11:25Z (GMT). No. of bitstreams: 1 DissGMS.pdf: 1736443 bytes, checksum: 9e6aa510fda128c4e4722add3ed4b7ed (MD5) Previous issue date: 2016-02-26 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Ethanol addiction is a serious public health problem that still needs more effective pharmacological treatment. A key factor in the development and maintenance of this disease is the development of neural plasticity that occurs in the mesocorticolimbic brain pathway upon chronic ethanol abuse. These plasticity events are, in general, maladaptive and affect numerous neurotransmitter systems and intracellular molecules. One of these molecules is ΔFosB, a transcriptional factor that is altered after chronic drug use. Behavioral sensitization is a phenomenon resulting from repeated administration of abuse drugs useful for the study of the neural alterations related to addiction. Recent works have shown a role for the imbalance of glutamatergic neurotransmission in the symptoms found in addicted people. In this line, the treatment with N-acetylcysteine, a L-cysteine prodrug that acts restoring extrasynaptic concentrations of glutamate through the activation of cystine-glutamate antiporter, has shown promising results in the treatment of psychostimulant addiction. Thus, we evaluated the effects of N-acetylcysteine treatment in behavioral and molecular alterations induced by chronic ethanol administration. Swiss mice were subject to thirteen days of daily ethanol administration to induce the development of behavioral sensitization. Two hours before each ethanol administration and locomotor activity assessment, animals received N-acetylcysteine injections i.p.. Right after the last test session, their brains were removed for ΔFosB and cystineglutamate antiporter quantification. We found that N-acetylcysteine treatment blocked ethanol-induced behavioral sensitization, the increase of ΔFosB content in the medial prefrontal cortex and its reduction in the nucleus accumbens. Our results suggest a possible use of N-acetylcysteine in the ethanol-related disorders. / A dependência ao etanol é um grave problema de saúde pública que ainda necessita de tratamentos farmacológicos mais efetivos. Um fator chave no desenvolvimento e manutenção dessa doença são as plasticidades neurais que ocorrem na via mesocorticolímbica mediante o abuso crônico de etanol. Estas plasticidades são, em geral, maladaptativas e afetam inúmeros sistemas de neurotransmissores e moléculas intracelulares. Uma dessas moléculas é a ΔFosB, um fator de transcrição que é alterado após o uso crônico de drogas de abuso. A sensibilização comportamental é um fenômeno decorrente da administração repetida de drogas muito útil no estudo das alterações neurais relacionadas à dependência. Trabalhos recentes tem demonstrado um papel do desequilíbrio da neurotransmissão glutamatérgica nos sintomas encontrados em indivíduos dependentes. Neste sentido, o tratamento com a N-acetilcisteína, um pró-fármaco da L-cisteína que atua restaurando as concentrações extrasinápticas do glutamato através da ativação do trocador cistina-glutamato, tem mostrado resultados promissores no tratamento da dependência de psicostimulantes. Assim, avaliamos os efeitos do tratamento com a N-acetilcisteína nas alterações comportamentais e moleculares induzidas pela administração crônica de etanol. Camundongos suíços machos foram submetidos a administrações diárias de etanol por 13 dias a fim de induzir o desenvolvimento da sensibilização comportamental. Duas horas antes de cada administração, os animais receberam uma administração intraperitoneal de Nacetilcisteína. Imediatamente após a última sessão de teste, os cérebros dos animais foram removidos para quantificação de ΔFosB e do trocador cistinaglutamato. Nós encontramos que o tratamento com a N-acetilcisteína bloqueou o desenvolvimento da sensibilização comportamental ao etanol, o aumento de ΔFosB no córtex pré-frontal medial e a sua redução no núcleo acumbens. Nossos resultados sugerem um possível uso da N-acetilcisteína nas desordens relacionadas ao uso de etanol. / FAPESP: 2015/01026-9

Alterações no sistema glutamatérgico e mudanças no funcionamento do córtex pré-frontal medial (CPFm) têm sido associadas a diversos distúrbios psiquiátricos, dentre os quais a ansiedade. Também é reconhecido que alterações nas concentrações circulantes de glicocorticóides podem induzir alterações nas sinapses e circuitos glutamatérgicos e, consequentemente, modificar a reatividade emocional dos animais. Embora se saiba que os glicocorticóides influenciam a liberação de glutamato no CPFm, a interação entre os efeitos mediados pelos receptores mineralocorticóides (MR) ou glicocorticóides (GR) e o sistema glutamatérgico, na expressão da resposta condicionada de medo, ainda não está elucidada. Nesse sentido, os objetivos do presente estudo foram investigar (i) a influência dos glicocorticóides na expressão do medo condicionado contextual e seus efeitos sobre a atividade do CPFm em ratos, (ii) o papel dos receptores MR e GR localizados no córtex prelímbico (PrL) na expressão da resposta condicionada de congelamento e (iii) a interação entre os mecanismos mediados pelos glicocorticoides e o sistema glutamatérgico, via receptores do tipo NMDA, na expressão dessa resposta. Ratos Wistar machos foram tratados com veículo ou metirapona, um bloqueador de síntese de corticosterona, e expostos a um contexto previamente pareado com choque nas patas. Foram avaliados o tempo de medo contextual (comportamento de congelamento) e a expressão de proteína Fos em diferentes regiões do CPFm. Os resultados mostraram que a exposição ao contexto aversivo levou a um aumento significativo da expressão de congelamento e de proteína Fos no PrL, nas áreas do córtex cingulado anterior 1 e 2 (Cg1 e Cg2), mas não no córtex infralímbico. A administração de metirapona levou a uma diminuição da expressão de congelamento e de proteína Fos no PrL, Cg1 e Cg2. A administração bilateral de espironolactona, um antagonista de receptores MR, no PrL antes do teste diminuiu as respostas de medo e o pré-tratamento com RU38486, um antagonista de receptores GR, aboliu este efeito. Os resultados também mostraram que a diminuição da resposta de congelamento induzida por injeções intra-PrL de corticosterona foi abolida pela administração prévia de RU38486, mas não por espironolactona, indicando que a corticosterona recruta preferencialmente os receptores GR para produzir esses efeitos. A administração prévia do antagonista de receptor NMDA também preveniu os efeitos induzidos pelo tratamento com corticosterona sugerindo que, no PrL, parte dos efeitos rápidos do glicocorticóides sobre a expressão do medo condicionado se dá por uma interação com o sistema glutamatérgico. A administração de NMDA no PrL, antes do teste, induziu efeitos similares ao tratamento com corticosterona nessa região. De modo geral, os resultados sugerem que a liberação de corticosterona durante a apresentação de um estímulo condicionado aversivo influencia a atividade do CPFm de maneira que, uma mudança no equilíbrio das atividades mediadas por MR e GR, por meio de um aumento da atividade de GR, interage com o sistema glutamatérgico via aumento da atividade dos receptores NMDA influenciando a expressão da resposta de medo condicionado contextual. Sugere-se que a redução na expressão do medo condicionado observada após a administração local de corticosterona no PrL também seja decorrente de mudanças no equilíbrio entre MR e GR em direção a um aumento de suas ações mediadas por GR, assim como um aumento na liberação de glutamato e maior atividade de receptores NMDA nessa região. / Changes in the glutamatergic system and in the functioning of the medial prefrontal cortex (mPFC) have been associated with different psychiatric disorders, including anxiety. It is also recognized that changes in circulating levels of glucocorticoids can induce changes in glutamatergic synapses and circuits and therefore alter the emotional reactivity of animals. Although is known that glucocorticoids can influence the release of glutamate in the mPFC, the interaction between mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) activation and the glutamatergic activity on the expression of conditioned fear response is not yet elucidated. The aims of the present study were to investigate (i) the influence of glucocorticoids on the expression of contextual conditioned fear and its effects in the activity of the mPFC in rats, (ii) the role of MR and GR in the prelimbic cortex (PrL) on expression of conditioned freezing response and (iii) a possible interaction between the effects mediated by the glucocorticoids and the glutamatergic system, via NMDA receptors on the expression of this response. Male Wistar rats were treated with vehicle or metyrapone, a corticosterone synthesis blocker, and exposed to a context previously paired with footshock. The time of contextual fear (freezing behavior) and Fos protein expression in different regions of mPFC were evaluated. The results showed that exposure to the aversive context induced a significant increase in freezing and Fos protein expression in the PrL, in the anterior cingulate cortex, areas 1 and 2 (Cg1 and Cg2), but not in the infralimbic cortex. The administration of metyrapone induced a decrease on the expression of freezing and Fos in PrL, Cg1 and Cg2. Bilateral administration of spironolactone (a MR antagonist) in PrL before the test, decreased conditioned fear response and the pretreatment with RU38486 (a GR antagonist) abolished this effect. The results also showed that the decrease of freezing response induced by intra-PrL corticosterone injections was abolished by prior administration of RU38486, but not by spironolactone, indicating that corticosterone recruits preferentially GR to produce the observed effects. Prior administration of the NMDA receptor antagonist also prevented the effects induced by corticosterone treatment in the PrL, suggesting that part of rapid effects of glucocorticoids on the expression of conditioned fear occurs by an interaction with the glutamatergic system. Additionally, NMDA administration in the PrL prior to the test induced similar effects to corticosterone treatment in this region. Overall, the results suggest that the release of corticosterone during the presentation of a conditioned aversive stimulus influences the mPFC activity so that a change in the balance of the activities mediated by MR and GR through an increase in GR activity interacts with the glutamatergic system by increasing the activity of NMDA receptors influencing the expression of contextual fear conditioning response. It is suggested that the reduction in the expression of conditioned fear observed after local administration of corticosterone in the PrL is also due to changes in the balance between MR and GR towards an increase in the actions mediated by GR, as well as an increase in the release of glutamate and a greater NMDA receptor activity in this region.

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.

Le cortex préfrontal médian (mPFC) est nécessaire pour la formation desreprésentations contextuelles et l’expression de la mémoire suite au conditionnementde peur. Des études récentes ont montré des changements dépendants del’apprentissage dans l’excitabilité intrinsèque des neurones du mPFC. Il n’estcependant pas établit, si ces changements se font à l’échelle régionale ou s’ils sontspécifiques du type neuronal. La connectivité spécifique et les propriétés intrinsèquesde différents types neuronaux pourraient entrainer certaines populations neuronales àêtre préférentiellement impliquées dans le traitement de l’information au cours d’unetâche d’apprentissage. Dans ce projet, nous avons étudié cette hypothèse par l’étudede la plasticité de l’excitabilité intrinsèque dans la partie prélimbique (PL) du mPFCdans deux groupes neuronaux bien définis : ceux projetant vers l’amygdaleipsilatérale et ceux projetant vers le mPFC controlatéral. Nous avons utilisé à la fois leconditionnement à la peur contextuelle, un traçage rétrograde, et des enregistrementsélectrophysiologiques en cellule entière des neurones pyramidaux marqués chez lessouris mâles C57bl/6J adultes âgées de 2 à 3 mois. Nous montrons que l’excitabilitédes neurones projetant vers l’amygdale présentent des changements dépendants del’apprentissage, suite au conditionnement de peur contextuelle. En revanche,l’excitabilité des neurones projetant vers le mPFC controlatéral ne présente pas dedifférence entre les animaux entrainés et témoins. Ensemble, ces résultats indiquentque les changements induits par l’apprentissage dans l’excitabilité intrinsèque ne sontpas généralisés à tous les neurones du PL mais sont par contre définis par les ciblesdes neurones qui projettent sur de longues distances. / The medial prefrontal cortex (mPFC) is necessary for the formation of contextualrepresentations and memory expression following fear conditioning. Recent studieshave shown learning-dependent changes in the intrinsic excitability of mPFC neurons.It is not clear, however, whether these changes are region-wide or neuron-typespecific. The specific connectivity and intrinsic properties of different neuronal typescould cause certain neuronal populations to be preferentially involved in informationprocessing in a learning paradigm. In this project, we investigated this hypothesis bystudying the plasticity of intrinsic excitability in the prelimbic (PL) part of the mPFCin two defined neuronal groups: those projecting to the ipsilateral amygdala and thoseprojecting to the contralateral mPFC. We used contextual fear conditioning togetherwith retrograde tracing and whole-cell electrophysiological recordings of labelledpyramidal neurons in adult 2-3 month old male C56BL/6J mice. We show thatneurons projecting to the amygdala display learning-dependent changes in neuronalexcitability following contextual fear conditioning. In contrast, the excitability ofneurons projecting to the contralateral mPFC does not differ between trained andcontrol animals. Together, these results indicate that learning-induced changes inintrinsic excitability are not generalised across all PL neurons but instead are definedby the neurons’ long-range projection targets.

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Zunehmend mehr Beweise aus der sozialen Neurowissenschaft deuten darauf hin, dass der mediale präfrontale Cortex (mPFC) eine entscheidende neurale Komponente in der Verarbeitung von sozialem Ereigniswissen ist. Die vorliegende Arbeit stellt eine integrative Theorie der kognitiven und neuronalen Grundlagen von sozialem Ereigniswissen vor. Die „Structural and Temporal Representation Binding“ (STRing) Theorie postuliert, dass der mPFC abstrakte dynamische summarische Repräsentationen in Form von Ereignissimulatoren speichert, die Wissen über soziale Abläufe mittles Einbinding von Regionen im posterioren Cortex und limbischen System generieren. Neurowissenschaftliche Befunde für die Differenzierung von Simulatorenfunktionen entlang der dorso-ventralen Achse des mPFC werden diskutiert und die Spezifität der Simuatoren für die Entwicklung von Ereignis-, Personen, und Selbst-Schemata dargestellt. / Accumulating evidence from social neuroscience research demonstrates that the medial prefrontal cortex (mPFC) is a crucial neural component in the processing of social event knowledge. This work proposes an integrative theory of the cognitive and neural bases of social event knowledge. The structural and temporal representation binding (STRing) theory assumes that the mPFC represents abstract dynamic summary representations in the form of event simulators, which give rise to social event knowledge via binding with regions in the posterior cerebral cortex and limbic system. Neuroscience findings for the segregation of simulator functions along the dorso-ventral mPFC axis will be discussed and the specificity of simulators for the development of event, person, and self schemata will be demonstrated.

Avec l'avènement de la téléphonie et des réseaux mobiles, l'impact des radiofréquences (RF) sur la santé humaine est plus que jamais un sujet d'actualité. Les résultats des recherches Homme et animal restent controversés et ne permettent pas de conclusion définitive sur l’existence ou non d’effets des RF, notamment sur le cerveau. Ainsi, nos résultats montrent que chez le rat, jeune, adulte et âgé, une exposition de 3 mois à un signal LTE 4G (900 MHz, 61V/m, DAS = 0,33 W/kg) n’a aucun effet sur l’apprentissage et la mémoire spatiale récente et ancienne, ni sur l’anxiété ou la locomotion. L’expression des gènes a été étudiée par séquençage haut débit des ARNm, en conditions "Basal" et "Apprentissage" dans l’hippocampe dorsal et le cortex préfrontal médian. Nos résultats montrent que des gènes appartenant à des regroupements fonctionnels spécifiques sont modulés en réponse à l’exposition aux RF dans l'hippocampe dorsal en condition "Basal" et dans le cortex préfrontal médian, pendant et suite à un apprentissage spatial. Cependant, il est important de noter que ces modulations génétiques n'impactent pas le rappel d'un souvenir récent ou ancien. En perspective, il sera important de connaître les possibles répercussions que ces régulations peuvent avoir à plus long terme sur le fonctionnement cérébral. / The increasing development of mobile phone technology and networks raises the question of the impact of electromagnetic fields in the radiofrequency range (RF) on human health and well-being. However, data from humans and animal scientific research remain controversial and do not allow to conclude about potential harmful effects of RF, particularly on the brain. Thus, our results showed that, in young, adult and aged rats, a chronic exposure (3 months) to a 4G LTE signal (900 MHz, SAR = 0.33 W/kg, 61V/m) had no impact on spatial learning and long-term memory, nor on anxiety and locomotion. Gene expression was studied using high throughput RNA sequencing in the dorsal hippocampus and medial prefrontal cortex, both in "Basal" and "Learning" conditions. Our results show that some genes belonging to specific functional groups were modulated by RF in the dorsal hippocampus in "Basal" condition and, in the median prefrontal cortex during and after spatial learning. However, it is to note that these gene expression modulations have no impact on recent or remote memory. In perspective, it will be important to explore the potential effects of such changes in brain functioning.

Les systèmes cholinergique et dopaminergique jouent un rôle prépondérant dans les fonctions cognitives. Ce rôle est exercé principalement grâce à leur action modulatrice de l’activité des neurones pyramidaux du cortex préfrontal. L’interaction pharmacologique entre ces systèmes est bien documentée mais les études de leurs interactions neuroanatomiques sont rares, étant donné qu’ils sont impliqués dans une transmission diffuse plutôt que synaptique. Ce travail de thèse visait à développer une expertise pour analyser ce type de transmission diffuse en microscopie confocale. Nous avons étudié les relations de microproximité entre ces différents systèmes dans le cortex préfrontal médian (mPFC) de rats et souris. En particulier, la densité des varicosités axonales en passant a été quantifiée dans les segments des fibres cholinergiques et dopaminergiques à une distance mutuelle de moins de 3 µm ou à moins de 3 µm des somas de cellules pyramidales. Cette microproximité était considérée comme une zone d’interaction probable entre les éléments neuronaux. La quantification était effectuée après triple-marquage par immunofluorescence et acquisition des images de 1 µm par microscopie confocale. Afin d’étudier la plasticité de ces relations de microproximité, cette analyse a été effectuée dans des conditions témoins, après une activation du mPFC et dans un modèle de schizophrénie par déplétion des neurones cholinergiques du noyau accumbens. Les résultats démontrent que 1. Les fibres cholinergiques interagissent avec des fibres dopaminergiques et ce sur les mêmes neurones pyramidaux de la couche V du mPFC. Ce résultat suggère différents apports des systèmes cholinergique et dopaminergique dans l’intégration effectuée par une même cellule pyramidale. 2. La densité des varicosités en passant cholinergiques et dopaminergiques sur des segments de fibre en microproximité réciproque est plus élevée comparé aux segments plus distants les uns des autres. Ce résultat suggère un enrichissement du nombre de varicosités axonales dans les zones d’interaction. 3. La densité des varicosités en passant sur des segments de fibre cholinergique en microproximité de cellules pyramidales, immunoúactives pour c-Fos après une stimulation visuelle et une stimulation électrique des noyaux cholinergiques projetant au mPFC est plus élevée que la densité des varicosités de segments en microproximité de cellules pyramidales non-activées. Ce résultat suggère un enrichissement des varicosités axonales dépendant de l’activité neuronale locale au niveau de la zone d'interaction avec d'autres éléments neuronaux. 4. La densité des varicosités en passant des fibres dopaminergiques a été significativement diminuée dans le mPFC de rats ayant subi une déplétion cholinergique dans le noyau accumbens, comparée aux témoins. Ces résultats supportent des interrelations entre la plasticité structurelle des varicosités dopaminergiques et le fonctionnement cortical. L’ensemble des donneès démontre une plasticité de la densité locale des varicosités axonales en fonction de l’activité neuronale locale. Cet enrichissement activité-dépendant contribue vraisemblablement au maintien d’une interaction neurochimique entre deux éléments neuronaux. / The cognitive functions of the rat medial prefrontal cortex (mPFC) are modulated by ascending modulatory systems such as the cholinergic and dopaminergic afferent systems. However, despite the well-documented pharmacological interactions between the cholinergic and dopaminergic afferents and pyramidal cells in the PFC, there is only scarce neuroanatomical data on the reciprocal interrelationships between these neuronal elements in the mPFC. This might be due to the diffuse rather than synaptic transmission mode of intercellular communication of the cholinergic system in the mPFC. For these reasons, the neuroanatomical relationships between the cholinergic and dopaminergic systems and pyramidal cells in the mPFC are examined, with an emphasis on the local density of the cholinergic and dopaminergic axon varicosities. To analyze the plasticity of these interrelationships, the two systems were examined in condition of increased neuronal activity in the mPFC, or of decrease dopaminergic activity in a model of schizophrenia. The microproximity relationships between cholinergic and dopaminergic fibers as well as with pyramidal cells were studied in the mPFC of rats and mice. In particular, the number of axon varicosities in cholinergic and dopaminergic fiber segments within 3 µm from each other or from pyramidal cells were quantified. This microproximity was considered as a possible interaction zone between two neuronal elements. Quantification was performed using triple immunofluorescence labeling and acquisition of 1 µm optic sections using confocal microscopy. To assess the plasticity of these relationships, the analysis has been performed in control condition as well as after a cortical activation or a decreased dopaminergic input in a schizophrenia model. Our results demonstrate a neuroanatomical convergence of cholinergic and dopaminergic fibers on the same pyramidal cell from layer V (output) of mPFC, suggestinggests the integration of different types of inputs by the same pyramidal cell, which may be transmitted to subcortical areas to execute prefrontal cognitive control. Close apposition between cholinergic and dopaminergic fibers could also be seen in the mPFC. There was an increase of the density of cholinergic and dopaminergic en passant varicosities on those fiber segments within microproximity of each other, compared to those outside the reciprocal microproximity, supporting functional importance of the close apposition between those two ascending neuromodulatory systems into the mPFC. There was enrichment of cholinergic en passant varicosities on the fiber segments within microproximity of c-Fos activated pyramidal cells in the mPFC of visually and HDB electrically stimulated rats, indicating association between axonal varicosity density and the local neuronal activity. There was decrease of dopaminergic en passant varicosities in the mPFC of rats with ChAT depletion in the N.Acc., compared to controls. This evidence supports the association between dopaminergic axonal varicosities and relevant neuronal activity in a complex neuronal network. This thesis shows that the density of cholinergic and dopaminergic axonal varicosity density in the mPFC is influenced by and contributes to the relevant local neuronal activity from the interactions of different transmitter systems. Such interactions of different systems in a complex and intricate prefrontal neuronal network endeavour to maintain the delicate balance for cognitive processes.

甲基安非他命是一種被廣泛濫用的非法神經興奮劑，而且使用之後常伴隨著精神疾病的發生，動物研究也顯示，施打甲基安非他命所引起的神經毒性不僅會造成多巴胺神經元及血清素神經元的損傷，也引起認知功能和社交行為的缺失，同時對於產生迷幻作用的5-HT2A受體作用劑的行為反應增強。N,N,N-trimethylglycine (TMG)和N,N-dimethylglycine (DMG)是甘胺酸的甲基化衍生物，由於這兩種藥物具有治療神經系統疾病的潛力，因此本研究的目的為評估TMG及DMG是否可以預防或改善小鼠在甲基安非他命的暴露下所導致的行為缺失包括新位置辨識測試，新物體辨識測試，社交行為互動測試以及使用5-HT2A受體作用劑DOI 誘導小鼠頭部抽搐(head twitch )的行為。實驗方式為腹腔注射給予雄性ICR小鼠甲基安非他命，一天注射四劑（4 × 5mg/kg），每劑間隔兩小時。實驗一，小鼠在暴露甲基安非他命，先確認行為改變後，給予腹腔注射TMG及DMG (10或30 mg/kg)連續七天，評估TMG及DMG的治療效果。實驗二在施打每劑甲基安非他命30分鐘前給予TMG及DMG (100 mg/kg)，七天後進行行為評估，實驗三，評估TMG及DMG個別及混合劑量的治療效果，小鼠給予甲基安非他命之後，先確認行為改變，再給予腹腔注射TMG及DMG (20、5+5或是10+10 mg/kg) 連續七天，七天後進行行為測試。實驗四，檢測TMG及DMG的治療效果是否藉由活化NMDA受體glycine binding site，小鼠給予甲基安非他命七天之後，腹腔注射TMG及DMG (20 mg/kg)並在給予TMG及DMG前30分鐘給予glycine binding site 拮抗劑7-chlorokynurenic acid (7-CK) (1 mg/kg)，連續給藥七天，七天後進行行為評估。實驗結果發現連續給予七天TMG及DMG在個別劑量及混合劑量中都能夠恢復甲基安非他命所造成的認知功能缺損，社交退縮和降低由DOI 誘導小鼠頭部抽搐行為表現，以及在紋狀體中酪氨酸羥化酶的蛋白質表達減少情況。而前給予7-CK則阻斷TMG及DMG對甲基安非他命所造成的認知功能缺損，社交退縮的改善作用，但是對TMG及DMG對DOI 誘導小鼠頭部抽搐的行為的改善作用影響較小，顯示TMG及DMG可能都是經由活化NMDA 受體的glycine binding site改善甲基安非他命所造成的認知功能缺損，社交退縮，這些發現表示，TMG及DMG具有治療甲基安非他命成癮者所造成的精神分裂等異常症狀的潛力。 / Methamphetamine (METH) is a widely abused illicit psychostimulant. METH use is commonly associated with psychosis. A neurotoxic regimen of METH, which damages the dopaminergic and serotonergic neurons, causes cognitive dysfunction, social interaction deficits, and supersensitivity to hallucinogen in mice. N,N,N-trimethylglycine (TMG) and N,N-dimethylglycine (DMG) are methyl derivatives of amino acid glycine and naturally occur as intermediate metabolites in choline-to-glycine metabolism. Growing evidence shows that both compounds have potential to treat some neurological disorders. The aim of this study was to examine the protective and therapeutic effects of TMG and DMG on METH-induced behavioral aberrations. The novel location recognition test (NLRT), the novel objective recognition test (NORT), the social interaction and the hallucinogenic 2, 5-dimethoxy-4-iodoamphetamine (DOI)-induced head twitch response were evaluated. Male ICR mice received one day drug treatment with four injections of METH (4 × 5 mg/kg, i.p.) or saline at 2h interval. First, TMG or DMG (10 or 30 mg/kg, i.p.) were separately administered once daily for seven consecutive days after the behavioral impairment was confirmed in METH-treated mice. Seven days after final injection of TMG and DMG, the behavioral tests were monitored. Secondly, the preveting effects of TMG and DMG were examined by TMG and DMG (100 mg/kg, i.p.) pretreatment, 30 min prior to each dose of METH. Third, the lower dose (20 mg/kg) and combined effects of TMG and DMG (5+5 or 10+10 mg/kg i.p.) were evaluated. Fourth, in order to determine if the improving effects of TMG and DMG are mediated by NMDA receptor glycine binding site, the glycine binding site antagonist 7-CK (1 mg/kg, i.p.) was administered 30 min prior to each dose of TMG and DMG (20 mg/kg, i.p.), TMG and DMG dose-dependently improved, but not prevented the METH-induced cognition deficits, social withdrawal and hypersensitivity to hallucinogen with additional effect. Pretreatment of 7-CK, reversed the improving effects of TMG and DMG on behavioral deficits after METH exposure, yet had minor effect on hypersensitivity to hallucinogen. These results demonstrate that TMG and DMG might activate the glycine binding site of NMDA receptor to improve METH-induced cognition deficits and social withdrawal. TMG and DMG may be the novel therapeutic agents for psychiatric disorders related to METH abuse.