Rumination, or extensive mind wandering defines one of the key cognitive symptoms of major depressive disorder (MDD). Several symptoms included in the psychiatric disorder have been associated with altered connectivity within the large-scaled system default mode network (DMN). Although it’s well-known that antidepressant treatment, such as selective serotonin reuptake inhibitor (SSRI) and serotonin norepinephrine reuptake inhibitor (SNRI) tend to positively affect symptoms and alterations of MDD, results are inconsistent regarding DMN connectivity pre-and-post treatment. This systematic review aims to compile findings from studies investigating DMN connectivity in MDD patients’ pre-and post SSRI and SNRItreatment, and to find possible correlations with symptomatic improvements. Five articles were included for further analysis after the literature search in MEDLINE ESBSCO and Scopus. Main findings are in alignment with previous research and suggest both hypo-and hyper DMN connectivity at baseline in MDD patients, and connectivity patterns significantly similar to healthy controls following antidepressant treatment. Future research might consider placebo controlled trials for more diverse, and quantified results, and also consider further investigation on both first-line treatments and other promising antidepressants.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24088号 / 医博第4864号 / 新制||医||1059(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 林 康紀, 教授 渡邉 大, 教授 髙橋 良輔 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

<p>Individuals with mood disorders are particularly vulnerable to weight gain, due in part to an illness symptom profile that impacts appetite and energy and the iatrogenic weight-gain effects associated with psychotropic medications. The exact physiological mechanisms through which medication causes weight gain have yet to be clearly elucidated. The studies comprising this thesis examine changes in caloric consumption, physical activity and basal metabolic rate (BMR) in depressive disorder (MDD) patients starting on selective serotonin reuptake inhibitors (SSRIs). Since both depression and obesity have been linked to inflammation, we also monitored changes in cytokines and adipokines throughout treatment. In our sample, we observed a mean weight gain from baseline, prior to medication, to 6 months after the initiation of pharmacotherapy. We note that this weight gain is not likely due to increased caloric consumption, but could be related to the proportions of macronutrients being consumed and expended, as well as physical activity level. We also observed changes in adipokines and cytokines that are reflective of pharmacotherapy and not weight gain, even in the absence of clinical improvement. Collectively these studies have begun to shed light on the mechanisms involved in the weight gain experienced by MDD patients being treated with SSRI antidepressants. A better understanding of these mechanisms will lead to better management of the adverse metabolic side effects associated with psychotropic medication, and will improve patient compliance.</p> / Master of Science (MSc)

Approximately 10% of pregnant women take antidepressants. Prenatal exposure to selective serotonin reuptake inhibitors (SSRIs), a class of antidepressants, has been shown to alter serotonergic signaling in the brain. However, the effects of SSRIs on peripheral serotonin (5HT) synthesis and/or signaling have largely been ignored. Serotonin in the gut is critical for intestinal function and dysregulation of this pathway is associated with intestinal disease. Therefore, the goal of this study was to determine the effects of perinatal exposure to the SSRI fluoxetine (Prozac®) on intestinal health in the offspring. Dams were given vehicle or fluoxetine hydrochloride (FLX 10 mg/kg/d; N=15) for 2 weeks prior to mating until weaning. We assessed markers of serotonergic signaling, inflammation, and composition of the gut microbiota in the offspring. Male offspring of fluoxetine-treated dams had significantly elevated serum levels of 5-HT and decreased expression of the 5HT2A receptor and MAO. In female offspring there was no effect of SSRI exposure to alter any components of serotonergic signaling. Although we did not find any evidence of increased inflammation following fluoxetine exposure, there were significant alterations in the composition of the gut microbiota in the exposed offspring. Male offspring of SSRIs-exposed mothers had changes in key components of the gut serotonergic system in association with elevated levels of serum 5-HT and alterations in the gut microbiota in adulthood. The impact of these changes on intestinal health and the reasons for the sex specific effects remain to be determined. / Thesis / Master of Science in Medical Sciences (MSMS)

Colorectal cancer is the third most common cancer among U.S. women; 63,610 new cases were estimated to have occurred in 2015. Prior studies found a reduced risk of colorectal cancer among antidepressant (AD) users, however, none adjusted for depression, which is itself linked to increased colorectal cancer risk and could confound this relationship. We assessed the relationship between ADs and AD drug classes with risk of colorectal cancer in a prospective cohort of 145,190 women between the ages of 50-79 without a previous history of cancer at enrollment. Current AD use was assessed at baseline. Over an average follow-up of 14 years, there were 5,280 incident cases of colorectal cancer cases. Cox proportional hazard ratios, adjusted for potential confounders including depressive symptoms, were used to estimate hazard ratios. Of all AD users, 51.1% used selective serotonin reuptake inhibitors (SSRIs), 40.7% used tricyclic antidepressants (TCAs), and 15.1% used other ADs. No association was observed between total AD use, SSRI use, and/or other ADs and risk of colorectal cancer. We observed a reduced risk of colorectal cancer among TCA users, which was significant for colon cancer specifically (HR 0.68, 95% CI: 0.48-0.96). Although a reduced risk of colon cancer was observed for TCAs use for less than two years (HR 0.39, 95%: CI 0.19-0.82), no association was observed for TCA use for two or more years (HR 0.85, 95%CI: 0.57-1.26). Our data suggests a protective association between TCA use and risk of colorectal cancer, however more research is needed to verify these findings.

Major depressive disorder (MDD) is considered the current leading cause of disability worldwide (Friedrich, 2017), yet the recovery process in MDD, including neurobiological underpinnings, clinical features and optimal approaches to treatment remains ambiguous. Current definitions of recovery are disputed and involve measures considered subjective in nature, such as thresholds for questionnaires and clinical interviews of symptoms and their duration (De Zwart and Jeronimus, 2019; Fava et al., 2007; Keller, 2003, 2004). Symptom-based measures, although informative of clinical presentation, are not informative of neurobiological underpinnings that may persist even when symptoms are reduced. Indeed, even after treatment, persistent residual symptoms, impairments in quality of life, and vulnerabilities for future return to more severe psychopathology persist (Gotlib and Hammen, 2008; IsHak et al., 2011; Judd et al., 1998a; Kennedy et al., 2004; Kennedy and Foy, 2005; Kennedy and Paykel, 2004). Without assessment of neural mechanisms of recovery in MDD, efforts toward developing novel treatment approaches that are able to address neural processes of illness and to provide sustained remission are slowed. The following collection of studies provide neural and clinical insights into MDD recovery and relate findings to potential treatment approaches that are optimized to individual differences in symptoms and neural functioning and able to address neural vulnerabilities to provide sustained remission. In pursuit of individualized treatment selection in MDD, study one involved a meta-analysis of prior prognostic fMRI studies of response to cognitive behavioral therapy (CBT) or a selective serotonin reuptake inhibitor (SSRI) in MDD. Study one also reported on the application of resulting meta-analytic regions (subgenual and perigenual anterior cingulate cortex) in a confirmatory MDD sample. Although regions showed some predictive potential in the confirmatory sample, when predicting SSRI response, effects were inconsistent with prior studies, suggesting methodological confounds may hinder ready translation. In an assessment of the course of MDD, the second study documented depression symptoms and quality of life across 9-14 years after acute treatment (CBT or SSRI) and found that persistent residual depression symptoms and quality of life deficits were common. In light of the normality of chronic symptoms and impairment, the third study evaluated neural features of treatment (CBT) resistance in MDD within the context of neural mechanisms of change. The third study found a vermis-centered cerebellar cluster that was unresponsive to CBT, whereas prefrontal and parietal cortical regions were responsive, providing support of prior theories that CBT directly affects cognitive control and cortical regulatory processes in contrast to salience-driven subcortical functioning (Clark and Beck, 2010; DeRubeis et al., 2008; Frewen et al., 2008; Mayberg, 2003). In consideration of findings, clinical recommendations that pertain to treating residual symptoms and associated neural features toward asymptomatic remission are provided. Future research directions are also provided regarding neuroscience informed precision medicine, current therapy and medication practices, and the larger picture of MDD chronicity broadly. / Doctor of Philosophy / Major depressive disorder (MDD) is considered the leading cause of disability worldwide (Friedrich, 2017), yet there are many aspects of MDD recovery that are unclear such as neural and clinical features and optimal treatment approaches. Current definitions of recovery involve questionnaires and interviews, which may not accurately represent all aspects of recovery (De Zwart and Jeronimus, 2019; Fava et al., 2007; Keller, 2003, 2004). For example, they do not assess neural or biological features of recovery that may continue even if symptoms improve. Indeed, even after treatment, often some minimal depression symptoms, impairments in quality of life, and risks for future more severe symptoms continue (Gotlib and Hammen, 2008; IsHak et al., 2011; Judd et al., 1998a; Kennedy et al., 2004; Kennedy and Foy, 2005; Kennedy and Paykel, 2004). Without assessing neural features of MDD and recovery, developing treatments that can address illness- related neural features and provide sustained recovery are slowed. The following studies report on neural and clinical features of MDD recovery to approach treatment and sustained recovery with consideration of individual differences in symptoms and neural functioning. Pursuing neuroimaging measures of individual differences to inform treatment selection, study one involved a statistical review of prior neuroimaging prediction studies of MDD treatment. Study one also reported on whether the regions suggested by the statistical review to inform treatment selection would be useful when applied to a prior MDD treatment study. Findings suggested functioning of the identified brain regions can help inform treatment selection, but method differences among studies included in the review hinder application of resulting regions. In an assessment of the course of MDD, the second study documented depression symptoms and quality of life across 9-14 years after treatment and found at least minimal depression symptoms as well as impairments in quality life commonly continued after treatment. In light of persistent symptoms and impairment, the third study aimed to identify neural features of MDD that did not respond to treatment, as well as neural features that were responsive to treatment. The third study found that therapy directly affects cognitive control processes, but may not affect brain regions associated more with emotion-driven processes. Clinical recommendations pertain to treating depression symptoms that continue after treatment toward asymptomatic recovery. Future research directions pertain to neuroscience informed treatment selection, current therapy and medication practices, and the larger picture of persistent depression symptoms broadly.

Serotonin receptors play a variety of functional roles in the body. Some indications and treatment claims for one of the classes of serotonin receptors, the 5-HT3 receptor family, include: anxiety, depression, chemotherapy- and radiation-induced emesis, constipation, irritable bowel syndrome, pain, drug addiction, and satiety control. A 5-HT3 receptor partial agonist, MD-354, served as a lead compound in the development of new 5-HT3 receptor ligands. Using halogenated analogs the study investigated their effect on binding to the 5-HT3 receptor. Conformationally-constrained analogs (quinazolines) were shown to be a novel class of 5-HT3 receptor antagonists. The log P values were determined for several analogs, and indicated that these ligands should be able to penetrate the blood-brain barrier. A homology model of the 5-HT3 receptor was built and the docking modes were assessed for these two series. Quinazolines were investigated for antidepressant properties using the mouse tail suspension test, and were shown to possess antidepressant-like activity.

Recentemente suspeitas de que mecanismos epigenéticos poderiam estar relacionados à fisiopatologia da depressão foram levantadas. Estudos recentes indicam que as alterações na transcrição gênica, induzidas por estresse ou por drogas antidepressivas, parecem envolver mecanismos epigenéticos. Nesse sentido, resultados preliminares de nosso grupo de pesquisa indicaram pioneiramente inibição global da metilação de DNA através da administração sistêmica do agente inibidor da DNA metiltransferase (DNMTs), 5-aza-2-deoxicitidina (5-azaD), induz efeito tipo-antidepressivo, dose-dependente, no modelo animal do nado forçado em ratos(Sales et al., 2011). O córtex pré-frontal medial ventral (CPFMv) é uma estrutura límbica intimamente relacionada com a neurobiologia da depressão. Evidências recentes indicam que o efeito tipo-antidepressivo aparece associado a aumento dos níveis da neurotrofina BDNF (brain derived neurotrophic factor) e de seu receptor TrkB no CPFMv, sendo a sinalização intracelular mediada pela ativação da proteína m-TOR. Contudo, não há evidências de que esses mecanismos moleculares estariam envolvidos nos efeitos induzidos pelos inibidores da metilação do DNA. Sabe-se, no entanto, que tanto o BDNF quanto TrkB têm sua expressão regulada por metilação do DNA. Diante disso, o objetivo presente trabalho será investigar a participação da via BDNF-TrkB-mTOR do CPFMv no efeito antidepressivo induzido por inibidores da metilação de DNA. Para tanto, ratos tratados com inibidores da metilação de DNA (5-azaD ou RG-108), em dois momentos diferentes (imediatamente após o PT e 23horas após o PT) foram submetidos ao teste do nado forçado (FST). Outro grupo de animais recebeu uma injeção intra-CPMv de k252a ou Rapamicina, 40 minutos antes do teste e uma injeção de BDNF intra-CPFMv, 30 minutos antes do teste. Em outro experimento, grupos independentes de animais submetidos ao nado forçado foram tratados sistemicamente com RG-108 e receberam injeção intra-CPFMv de K252a (antagonista de Trk) ou de rapamicina (inibidor da m-Tor), a fim de investigar se o efeito dessas drogas depende da via BDNF-TrkB-mTOR no CPFMv. Um grupo independente foi tratado com RG108 e CPFM desses animais foi dissecado para posterior análise da expressão de BDNF, TrkB e m-TOR, bem como da metilação de DNA. O tratamento com RG108 e 5azaD sistêmico reduziu o tempo de imobilidade dos animais submetidos ao nado forçado nos dois tempo de administração. A administração intra-CPFMv de BDNF promoveu efeito antidepressivo no FST, e esse efeito foi bloqueado pela administração de k252a ou Rapamicina no CPFMv. No mesmo sentido, o efeito antidepressivo do RG108 sistêmico foi bloqueado pela administração intra-CPFMv de k252a ou Rapamicina. Entretanto, a medida dos níveis de metilação global no CPFMv não apresentou alteração como tratamento com RG108, e também não mostrou alteração nos níveis de BDNF presente no CPF. O tratamento com RG108 não alterou a expressão, bem como a ativação de TRkB e mTOR. Concluímos que os inibidores da metilação do DNA apresentam agudamente efeito tipo antidepressivo rápido, que necessita da funcionalidade integral da via BDNF-TRkB-mTOR. Entretanto, esse efeito parece não alterar a síntese e expressão das proteínas envolvidas nessa via no que diz respeito ao CPFmv. / Recent studies indicate that changes in gene transcription induced by stress or antidepressant drugs appear to involve epigenetic mechanisms. Accordingly, results of our research group pioneered indicated global inhibition of DNA methylation through systemic administration of an inhibitor of DNA methyltransferase (DNMTs), 5-aza-2-deoxycytidine (5-AzaD), induces antidepressant-like effect dose-dependent in the animal model of forced swimming in rats (Sales et al., 2011). The ventral medial prefrontal (vmPFC) cortex is a limbic structure closely related to the neurobiology of depression. Recent evidence indicates that the antidepressant-like effect appears associated with increased levels BDNF (Brain derived neurotrophic factor) and its receptor TrkB in vmPFC, and intracellular signaling mediated by activation of protein mTOR. However, there is no evidence that these molecular mechanisms are involved in the effects induced by inhibitors of DNA methylation. It is known, however, both as BDNF and TrkB expression is regulated by DNA methylation. Thus, the goal of this work is to investigate the role of BDNF-TRkB pathway mTOR-vmPFC in the antidepressant effect induced by inhibitors of DNA methylation. To this end, rats treated with inhibitors of DNA methylation (5-Azad or RG-108), at two different times (immediately after 23hours after the PT and PT) were subjected to the forced swim test (FST). Another group received an intra-vmPFC injection of K252a or Rapamycin 40 minutes before the test, and an injection intra-vmPFC of BDNF 30 minutes before the test. In another experiment, separate groups undergoing the forced swim were treated systemically with RG-108 and received intra-vmPFC of K252a (Trk antagonist) or injection of rapamycin (m-Tor inhibitors) in order to investigate the effect these drugs depends on BDNF-TrkB-mTOR pathway in vmPFC. A separate group was treated with RG108 and mPFC these animals were dissected for analysis of the expression of BDNF and TrkB m-TOR, as well as DNA methylation. The systemic treatment whit 5azaD and RG108 reduced the immobility time of rats subjected to FST administration in both time. The intra-vmPFC BDNF administration promoted antidepressant effect in the FST, and this effect was blocked by the administration of K252a or Rapamycin in vmPFC. Similarly, the antidepressant effect of systemic RG108 was blocked by intra-vmPFC of K252a or Rapamycin administration. However, the measurement of the levels of global methylation in CPFMv did not change as treatment with RG108, and also showed no change in the levels of BDNF present in the CPF. Treatment with RG108 did not alter the expression and activation of TrkB and mTOR. We conclude that inhibitors of DNA methylation present acutely antidepressant-like effect, it needs the full functionality of the BDNF-TrkB-mTOR pathway. However, this effect seems not to alter the synthesis and expression of proteins involved in this pathway at vmPFC.

Introdução: Mecanismos epigenéticos, como a metilação de DNA, desempenham um papel importante na neurobiologia da depressão. Enquanto o estresse aumenta a metilação de DNA e reduz a expressão de genes envolvidos na plasticidade neuronial, inibidores de DNA metiltransferases (DNMTi), enzimas que catalisam a metilação de DNA, aumentam rapidamente a expressão gênica e induzem efeitos tipo-antidepressivos em modelos animais. Considerando, ainda, que antidepressivos convencionais podem interferir com mecanismos epigenéticos, este trabalho testou a hipótese de que drogas DNMTi induzem efeito tipo-antidepressivo agudo e sustentado em modelos animais. Além disso, avaliamos se o efeito de antidepressivos convencionais e de DNMTis sobre os níveis de mRNA e de metilação de DNA em diferentes genes associados a depressão e regulados por mecanismos epigenéticos (BDNF, TrkB, 5-HT1A, NMDA e AMPA) em estruturas encefálicas (hipocampo dorsal, ventral e córtex pré-frontal) de animais submetidos a modelo animal de depressão. Métodos: Para tanto, ratos Wistar foram submetidos ao modelo do desamparo aprenddo [learned helplessness, LH, pré-teste (PT), 40 choques inescapáveis nas patas]. Os animais receberam injeções sistêmicas de DNMTi (5-AzaD ou RG108), antidepressivos (imipramina ou fluoxetina), ou veículo, por 1 ou 7 dias, e foram submetidos a sessão teste do desamparo aprendido (T, 30 choques escapáveis) no último dia. Adicionalmente, um grupo independente foi submetido ao mesmo protocolo experimental e sacrificados 1 h após a última injeção. As estruturas encefálicas foram dissecadas para posterior análise molecular [imunoprecipitação de DNA metilado (meDIP) e quantificação de RNAm por qRT-PCR). Resultados: O estresse dos choques nas patas aumentou o número de falhas no teste. O tratamento com DNMTi agudamente, assim como com antidepressivos (tratamento repetido), foi capaz de atenuar essas alterações comportamentais, efeito considerado tipo-antidepressivo nesse modelo. Ainda, o estresse aumentou a metilação de DNA e reduziu os níveis de RNAm para BDNF e TrkB, enquanto que o tratamento com RG108 atenuou essas alterações moleculares no córtex pré-frontal de ratos. Conclusão: Os presentes resultados indicam que DNMTi, diferente de antidepressivos convencionais, são capazes de induzir rápido e sustentado efeito tipo-antidepressivo. Além disso, BDNF e TrkB parecem ser importantes para a resposta comportamental induzida pela inibição de DNMTs no córtex pré-frontal de ratos submetidos ao LH. / Introduction: Epigenetic mechanisms, such as DNA methylation, are thought to play an important role in the neurobiology of depression. While stress increases DNA methylation and decreases the expression of genes involved in neuronal plasticity, DNA methyltransferases inhibitors (DNMTi) increases gene expression and induces antidepressant-like effects in animal models. Considering that conventional antidepressants could interfere with epigenetic mechanisms, this work tested the hypothesis that acute treatment with DNMTi would induce acute and long-lasting antidepressant-like effects. Furthermore, we evaluated whether the stress could induce changes in the mRNA and DNA methylation levels in different genes involved with depression and regulated by epigenetic mechanisms (BDNF, TrkB, 5-HT1A, NMDA and AMPA) in different brain structures [dorsal hippocampus, ventral hippocampus and prefrontal cortex (PFC)] and whether such changes would be attenuated by systemic treatment with DNMTi (acutely) and antidepressants (chronically). Methods: Male Wistar rats were submitted to the learned helplessness model (LH; pretest session, 40 inescapable foot shocks). The animals received systemic injection the DNMTi (5-AzaD or RG108), antidepressants (imipramine or fluoxetine) or vehicle for one or seven days and were submitted to the LH test (30 escapable foot shocks) in the last day. Additionally, one independent group were submitted to the same experimental protocol and sacrificed one hour after last injection for collection of brain samples to further molecular analyses (methylated DNA immunopreciptation and mRNA levels by qRT-PCR). Results: Exposure to inescapable footshocks increased the number of escape failures in the test. Treatment with DNMTi (acute), as well as with antidepressants (repeated treatment), attenuated stress-induced behavioral responses, an antidepressant-like effect in this model. Moroever, stress increased DNA methylation and decreased RNAm levels of BDNF and TrkB, while treatment with RG108 attenuated molecular changes induced by stress in rat PFC. Conclusion: The present results indicate that DNMTi, different from conventional antidepressants, are able to induce rapid and sustained antidepressant-like effects. In addition, BDNF and TrkB appear to be important for behavioral response induced by inhibition of DNMTs in the rat PFC submitted to the LH.

Introdução: Mecanismos epigenéticos, como a metilação de DNA, desempenham um papel importante na neurobiologia da depressão. Enquanto o estresse aumenta a metilação de DNA e reduz a expressão de genes envolvidos na plasticidade neuronial, inibidores de DNA metiltransferases (DNMTi), enzimas que catalisam a metilação de DNA, aumentam rapidamente a expressão gênica e induzem efeitos tipo-antidepressivos em modelos animais. Considerando, ainda, que antidepressivos convencionais podem interferir com mecanismos epigenéticos, este trabalho testou a hipótese de que drogas DNMTi induzem efeito tipo-antidepressivo agudo e sustentado em modelos animais. Além disso, avaliamos se o efeito de antidepressivos convencionais e de DNMTis sobre os níveis de mRNA e de metilação de DNA em diferentes genes associados a depressão e regulados por mecanismos epigenéticos (BDNF, TrkB, 5-HT1A, NMDA e AMPA) em estruturas encefálicas (hipocampo dorsal, ventral e córtex pré-frontal) de animais submetidos a modelo animal de depressão. Métodos: Para tanto, ratos Wistar foram submetidos ao modelo do desamparo aprenddo [learned helplessness, LH, pré-teste (PT), 40 choques inescapáveis nas patas]. Os animais receberam injeções sistêmicas de DNMTi (5-AzaD ou RG108), antidepressivos (imipramina ou fluoxetina), ou veículo, por 1 ou 7 dias, e foram submetidos a sessão teste do desamparo aprendido (T, 30 choques escapáveis) no último dia. Adicionalmente, um grupo independente foi submetido ao mesmo protocolo experimental e sacrificados 1 h após a última injeção. As estruturas encefálicas foram dissecadas para posterior análise molecular [imunoprecipitação de DNA metilado (meDIP) e quantificação de RNAm por qRT-PCR). Resultados: O estresse dos choques nas patas aumentou o número de falhas no teste. O tratamento com DNMTi agudamente, assim como com antidepressivos (tratamento repetido), foi capaz de atenuar essas alterações comportamentais, efeito considerado tipo-antidepressivo nesse modelo. Ainda, o estresse aumentou a metilação de DNA e reduziu os níveis de RNAm para BDNF e TrkB, enquanto que o tratamento com RG108 atenuou essas alterações moleculares no córtex pré-frontal de ratos. Conclusão: Os presentes resultados indicam que DNMTi, diferente de antidepressivos convencionais, são capazes de induzir rápido e sustentado efeito tipo-antidepressivo. Além disso, BDNF e TrkB parecem ser importantes para a resposta comportamental induzida pela inibição de DNMTs no córtex pré-frontal de ratos submetidos ao LH. / Introduction: Epigenetic mechanisms, such as DNA methylation, are thought to play an important role in the neurobiology of depression. While stress increases DNA methylation and decreases the expression of genes involved in neuronal plasticity, DNA methyltransferases inhibitors (DNMTi) increases gene expression and induces antidepressant-like effects in animal models. Considering that conventional antidepressants could interfere with epigenetic mechanisms, this work tested the hypothesis that acute treatment with DNMTi would induce acute and long-lasting antidepressant-like effects. Furthermore, we evaluated whether the stress could induce changes in the mRNA and DNA methylation levels in different genes involved with depression and regulated by epigenetic mechanisms (BDNF, TrkB, 5-HT1A, NMDA and AMPA) in different brain structures [dorsal hippocampus, ventral hippocampus and prefrontal cortex (PFC)] and whether such changes would be attenuated by systemic treatment with DNMTi (acutely) and antidepressants (chronically). Methods: Male Wistar rats were submitted to the learned helplessness model (LH; pretest session, 40 inescapable foot shocks). The animals received systemic injection the DNMTi (5-AzaD or RG108), antidepressants (imipramine or fluoxetine) or vehicle for one or seven days and were submitted to the LH test (30 escapable foot shocks) in the last day. Additionally, one independent group were submitted to the same experimental protocol and sacrificed one hour after last injection for collection of brain samples to further molecular analyses (methylated DNA immunopreciptation and mRNA levels by qRT-PCR). Results: Exposure to inescapable footshocks increased the number of escape failures in the test. Treatment with DNMTi (acute), as well as with antidepressants (repeated treatment), attenuated stress-induced behavioral responses, an antidepressant-like effect in this model. Moroever, stress increased DNA methylation and decreased RNAm levels of BDNF and TrkB, while treatment with RG108 attenuated molecular changes induced by stress in rat PFC. Conclusion: The present results indicate that DNMTi, different from conventional antidepressants, are able to induce rapid and sustained antidepressant-like effects. In addition, BDNF and TrkB appear to be important for behavioral response induced by inhibition of DNMTs in the rat PFC submitted to the LH.