No description available.

No description available.

Background: Depression and related phenotypes, such as anxiety and neuroticism are thought to have a common genetic background. The malfunction of the serotonergic system is likely to play an important role in the etiology of these phenotypes, with compelling evidence coming from animal and human studies. However, recent studies indicate that other factors should be investigated, such as environmental stress. Aim: To investigate the role of the serotonergic gene variants (HTR1A-7 and SLC6A4) in depression, anxiety and neuroticism, in interaction with each other and other factors, such as stressful events. Method: Two large independent Caucasian cohorts, haplotype tagging single nucleotide polymorphisms (htSNPs) and existing genome-wide genotype data were used. Phenotypes were assessed by detailed questionnaires about psychiatric phenotypes (depression, anxiety and neuroticism) as well as background information, such as physical health. Environmental stress factors were investigated in one cohort by self-reported life event (recent and childhood) questionnaires. Healthy participants from this cohort took part in a computerised task to measure the effect of a functional polymorphism in the HTR1A gene on threat-related emotional information processing. ResultsMy study confirmed the importance of stressful life events in depression and anxiety modulated via the 5-HT1A and 5-HT1B autoreceptor, but not via the SLC6A4. I found evidence for epistatic interaction between HTR2A and SLC6A4 genes and between different subunits of the HTR3 gene which may contribute towards the depressive phenotype. Finally, certain alleles of SNPs in other serotonergic receptors (5-HT4 and 5-HT6) were also associated with depression, anxiety and neuroticism however, this association was weak. On the other hand, my study did not provide evidence for the interaction between the serotonin transporter 5-HTTLPR polymorphism and stressful life events which is widely reported in the literature. Conclusion: This study provides further support for the serotonergic hypothesis of depression and confirms the role of the environment in the aetiology of depression. The results show evidence of possible epistatic interaction between the SLC6A4 and HTR2A genes. These results highlight the complex interactions between the members of the serotonergic pathway as well as the role of the environment on the individual.

No description available.

Problem gambling is the subclinical form of pathological gambling and both are characterized by difficulties in the limiting of money and time spent on gambling. Genetic and personality factors have been implicated in gambling disorders (PG). As PG is classified as an impulse-control disorder, the serotonin (5-HT) system has been suggested to be involved. We sought to better understand the complex relationship between personality traits, PG, and 5-HT genes. We investigated ten 5-HT candidate genes for association with PG and personality traits. We also examined personality traits for association with PG. We found that MAOA and HTR3A haplotypes were associated with Agreeableness and Conscientiousness personality domains, PG was associated with high Neuroticism and low Conscientiousness scores, and the MAOA gene may play a role in PG. Our findings contribute to the better understanding of how 5-HT genes may be involved in the neurobiological mechanisms underlying PG and personality.

Problem gambling is the subclinical form of pathological gambling and both are characterized by difficulties in the limiting of money and time spent on gambling. Genetic and personality factors have been implicated in gambling disorders (PG). As PG is classified as an impulse-control disorder, the serotonin (5-HT) system has been suggested to be involved. We sought to better understand the complex relationship between personality traits, PG, and 5-HT genes. We investigated ten 5-HT candidate genes for association with PG and personality traits. We also examined personality traits for association with PG. We found that MAOA and HTR3A haplotypes were associated with Agreeableness and Conscientiousness personality domains, PG was associated with high Neuroticism and low Conscientiousness scores, and the MAOA gene may play a role in PG. Our findings contribute to the better understanding of how 5-HT genes may be involved in the neurobiological mechanisms underlying PG and personality.

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Medicine in the branch of Psychiatry Melbourne, 2005 / Sexual dysfunction is a common side effect of treatment with antidepressants, particularly those with a serotonergic action. The problem has significant implications for a patient’s quality of life and their compliance with medication. Given the often longterm nature of depressive disorders and their treatment this side effect poses a potential management challenge and may have serious prognostic implications. There are currently few evidence-based treatment strategies for the management of antidepressant induced sexual dysfunction. This study was conducted to evaluate the usefulness of granisetron, a serotonin type-3 receptor antagonist, in the treatment of women experiencing sexual dysfunction due to serotonergic antidepressants. Twelve women with antidepressant induced sexual dysfunction were assigned to receive either granisetron (N=5) or placebo (N=7) in a 14-day randomised, double blind, placebo controlled drug trial. Two subjects in the granisetron group did not complete the study. Each subject’s sexual functioning was assessed at baseline, day 7 and day 14 using both the Arizona Sexual Experience Scale and the Feiger Sexual Function and Satisfaction Questionnaire. No statistical differences were measured either at baseline or at endpoint between the granisetron and placebo groups. The study did not produce evidence supporting the usefulness of granisetron as an adjunctive medication in women with antidepressant induced sexual dysfunction. Furthermore, this finding does not suggest a primary role for the serotonin type-3 receptor in the pathogenesis of this side effect.

O decanoato de nandrolona é um esteróide anabólico-androgênico (EAA), derivado da testosterona, utilizado de maneira abusiva por indivíduos procurando ganho de força física ou apenas efeitos estéticos. Doses suprafisiológicas desses compostos têm sido associadas a efeitos psiquiátricos adversos, especialmente episódios de impulsividade e aumento no comportamento agressivo. Considerando o desconhecimento dos mecanismos neurais envolvidos nessa desinibição comportamental, nós investigamos a integridade da transcrição de componentes do sistema serotoninérgico (intimamente relacionados à expressão de comportamentos emocionais) em diversas áreas cerebrais de camundongos sob a administração prolongada de nandrolona. Camundongos machos adultos da linhagem C57Bl/6J receberam uma injeção subcutânea diária de 15 mg/kg de decanoato de nandrolona durante 28 dias. Diferentes grupos de animais foram utilizados para a análise de comportamentos emocionais e para a quantificação da expressão de genes relacionados à serotonina (5-HT), utilizando a transcrição reversa do RNA associada à técnica de PCR em tempo-real. Os camundongos tratados apresentaram um aumento na massa corporal, hiperatividade motora e aumento de comportamentos relacionados à ansiedade em ambientes novos. A imobilidade avaliada no teste de nado forçado apresentou-se reduzida. Os animais que receberam a nandrolona se mostraram mais agressivos e impulsivos para iniciar o ataque aos camundongos oponentes, no modelo de residenteintruso. O EAA induziu uma redução significante na quantidade de transcritos da maioria dos receptores pós-sinápticos de 5-HT investigados na amígdala e no córtex pré-frontal. A expressão do gene do receptor 5-HT1B (reconhecidamente envolvido com as alterações comportamentais observadas) estava também reduzida no hipocampo e hipotálamo. No mesencéfalo, região onde se encontram os corpos neuronais dos neurônios serotoninérgicos que inervam o sistema límbico e demais áreas cerebrais, não se observou nenhuma alteração na expressão dos genes relacionados aos receptores serotoninérgicos pré-sinápticos. Os transcritos do transportador e da enzima de síntese de 5-HT, indicadores da integridade serotoninérgica pré-sináptica, também não se apresentaram alterados. Dessa maneira, concluímos que o efeito de altas doses do EAA decanoato de nandrolona em camundongos confirma os dados encontrados em literatura quanto à desinibição comportamental observada em usuários abusivos humanos. Nosso modelo também foi eficiente em mostrar pela primeira vez alterações moleculares induzidas por este EAA. A redução generalizada na expressão dos genes de receptores de 5-HT na amígdala e córtex pré-frontal sugere essas áreas, pós-sinápticas ao sistema serotoninérgico, como críticas nos efeitos induzidos pelo EAA. Nosso trabalho também sugere um papel importante para o receptor 5-HT1B na desinibição comportamental observada / Nandrolone decanoate is a highly abused anabolic-androgenic steroid (AAS) by individuals looking for gains in physical strength or body appearance. Supraphysiological doses of this testosterone synthetic derivative have been associated with many physical and psychiatric adverse effects, especially reported episodes of impulsiveness and overt aggressive behavior. Since the neural mechanisms underlying AAS-induced behavioral disinhibition are unknown, we investigated the integrity of serotonergic system transcription in several brain areas of mice under prolonged nandrolone administration. Male C57Bl/6J mice received 15 mg/kg of nandrolone decanoate subcutaneously once daily for 28 days, and different sets of animals were used to investigate motor and emotion-related behaviors or 5-HT-related gene expression by qRT-PCR. AAS-injected mice had increased body weight, were hyperactive and displayed more anxious-like behaviors in novel environments. They exhibited reduced immobility in the forced swim test, higher probability of being aggressive and elevated impulsivity to attack the opponent. AAS induced substantial reduction in the transcription of most postsynaptic 5-HT receptors investigated in the amygdala and prefrontal cortex. Interestingly, 5-HT1B mRNA was further reduced in the hippocampus and hypothalamus. At the midbrain level, there was no alteration in 5- HT receptors, transporter or synthetic enzyme gene transcription. In conclusion, high doses of AAS nandrolone in male mice recapitulate the behavioral disinhibition observed in abusers. Furthermore, they are associated with overall decrease in 5-HT receptor gene expression in the amygdala and prefrontal cortex, implicating these areas as critical sites for AASinduced effects and indicating a role for the 5-HT1B receptor in this behavioral disinhibition

O decanoato de nandrolona é um esteróide anabólico-androgênico (EAA), derivado da testosterona, utilizado de maneira abusiva por indivíduos procurando ganho de força física ou apenas efeitos estéticos. Doses suprafisiológicas desses compostos têm sido associadas a efeitos psiquiátricos adversos, especialmente episódios de impulsividade e aumento no comportamento agressivo. Considerando o desconhecimento dos mecanismos neurais envolvidos nessa desinibição comportamental, nós investigamos a integridade da transcrição de componentes do sistema serotoninérgico (intimamente relacionados à expressão de comportamentos emocionais) em diversas áreas cerebrais de camundongos sob a administração prolongada de nandrolona. Camundongos machos adultos da linhagem C57Bl/6J receberam uma injeção subcutânea diária de 15 mg/kg de decanoato de nandrolona durante 28 dias. Diferentes grupos de animais foram utilizados para a análise de comportamentos emocionais e para a quantificação da expressão de genes relacionados à serotonina (5-HT), utilizando a transcrição reversa do RNA associada à técnica de PCR em tempo-real. Os camundongos tratados apresentaram um aumento na massa corporal, hiperatividade motora e aumento de comportamentos relacionados à ansiedade em ambientes novos. A imobilidade avaliada no teste de nado forçado apresentou-se reduzida. Os animais que receberam a nandrolona se mostraram mais agressivos e impulsivos para iniciar o ataque aos camundongos oponentes, no modelo de residenteintruso. O EAA induziu uma redução significante na quantidade de transcritos da maioria dos receptores pós-sinápticos de 5-HT investigados na amígdala e no córtex pré-frontal. A expressão do gene do receptor 5-HT1B (reconhecidamente envolvido com as alterações comportamentais observadas) estava também reduzida no hipocampo e hipotálamo. No mesencéfalo, região onde se encontram os corpos neuronais dos neurônios serotoninérgicos que inervam o sistema límbico e demais áreas cerebrais, não se observou nenhuma alteração na expressão dos genes relacionados aos receptores serotoninérgicos pré-sinápticos. Os transcritos do transportador e da enzima de síntese de 5-HT, indicadores da integridade serotoninérgica pré-sináptica, também não se apresentaram alterados. Dessa maneira, concluímos que o efeito de altas doses do EAA decanoato de nandrolona em camundongos confirma os dados encontrados em literatura quanto à desinibição comportamental observada em usuários abusivos humanos. Nosso modelo também foi eficiente em mostrar pela primeira vez alterações moleculares induzidas por este EAA. A redução generalizada na expressão dos genes de receptores de 5-HT na amígdala e córtex pré-frontal sugere essas áreas, pós-sinápticas ao sistema serotoninérgico, como críticas nos efeitos induzidos pelo EAA. Nosso trabalho também sugere um papel importante para o receptor 5-HT1B na desinibição comportamental observada / Nandrolone decanoate is a highly abused anabolic-androgenic steroid (AAS) by individuals looking for gains in physical strength or body appearance. Supraphysiological doses of this testosterone synthetic derivative have been associated with many physical and psychiatric adverse effects, especially reported episodes of impulsiveness and overt aggressive behavior. Since the neural mechanisms underlying AAS-induced behavioral disinhibition are unknown, we investigated the integrity of serotonergic system transcription in several brain areas of mice under prolonged nandrolone administration. Male C57Bl/6J mice received 15 mg/kg of nandrolone decanoate subcutaneously once daily for 28 days, and different sets of animals were used to investigate motor and emotion-related behaviors or 5-HT-related gene expression by qRT-PCR. AAS-injected mice had increased body weight, were hyperactive and displayed more anxious-like behaviors in novel environments. They exhibited reduced immobility in the forced swim test, higher probability of being aggressive and elevated impulsivity to attack the opponent. AAS induced substantial reduction in the transcription of most postsynaptic 5-HT receptors investigated in the amygdala and prefrontal cortex. Interestingly, 5-HT1B mRNA was further reduced in the hippocampus and hypothalamus. At the midbrain level, there was no alteration in 5- HT receptors, transporter or synthetic enzyme gene transcription. In conclusion, high doses of AAS nandrolone in male mice recapitulate the behavioral disinhibition observed in abusers. Furthermore, they are associated with overall decrease in 5-HT receptor gene expression in the amygdala and prefrontal cortex, implicating these areas as critical sites for AASinduced effects and indicating a role for the 5-HT1B receptor in this behavioral disinhibition

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No. of bitstreams: 2 Dissertação - Oscar Romero Lopes Rodrigues - 2015.pdf: 1210572 bytes, checksum: 9080ec829a41c8754d39489573c4cd56 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2015-03-13 / Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq / The Laboratório de Química Farmaceutica Medicinal designed and synthesized a new piperazine derivative tert-butyl 4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazine-1-carboxylate (LQFM104) based on molecular framework of clozapine. This study aimed the pharmacological evaluation in the central nervous system of the LQFM104. Treatment with LQFM104 at doses of 25 , 50 or 100 μmol/kg (p.o.) in the open-field test did not alter in animals the number of grooming behavior, the number of fecal boluses, the total number of crossings, immobility time, number of rears, the percentage of crossings in the central area and the time spent in the center. None of groups of doses tested with LQFM104 was able to change the time spent in the chimney test. In pentobarbital-induced sleep test, the treatment with LQFM104 25, 50 or 100 μmol/kg (p.o.) did not affect sleep latency, while the sleep duration has increased by 65%, 64.4% and 78.6% respectively compared to the control group treated orally with vehicle 10 ml/kg (28.8 ± 2.9 minutes). In the standardization of apomorphine-induced climbing test, the treatment with haloperidol at dose of 2.6 μmol/kg was able to reduce the climbing behavior in 97.8%, whereas clozapine at dose of 45 μol/kg, has reduced this behavior in 78 % when compared to control (16.87 ± 2.8). The LQFM104 50 or 200 μmol/kg (p.o.) was not able to reduce the climbing behavior. In the forced swimming test just LQFM104 50 μmol/kg (p.o.) was able to reduce the immobility time in 19.8% compared to the control group ( 263.2 ± 6.7 seconds) and increased the latency to immobility in 43%, compared with the control ( 70.6 ± 6.5 seconds). Similarly, in the tail suspension test, only the LQFM104 50 μmol/kg (p.o.) increased immobility time (32.1%) compared to the control (216.1 ± 13.2 seconds). The LQFM104 50 μmol/kg (p.o.) had their antidepressant-like effects completely reversed by blocking treatment with PCPA and NAN-190. And the quantification of brain-derived neurotrophic factor the LQFM104 50 μmol/kg (p.o.) did not change these levels. The results with LQFM104 in the open-field test indicated no changes in spontaneous locomotor activity and showed no anxiogenic activity. The chimney test did not reveal impairment in motor coordination. The pentobarbital-induced sleep test increased sleep duration without reducing the latency, thus suggesting a sedative action. The forced swimming test and the tail suspension test confirmed for LQFM104 50 μmol/kg (p.o.) an antidepressant activity in mice. The blockade with NAN-190 and PCPA suggests the involvement of serotonergic system and 5-HT1A receptor. / O laboratório de Química Farmacêutica Medicinal projetou e sintetizou um novo derivado piperazínico o tert-butil 4-((1-fenil-1H-pirazol-4-il)metil)piperazina-1-carboxilato (LQFM104) baseado no arcabouço molecular da clozapina . O objetivo deste estudo foi a avaliação farmacológica no sistema nervoso central do LQFM104. O tratamento com LQFM104 nas doses de 25, 50 ou 100 μmol/kg (v.o.), no teste de campo aberto não alterou nos animais o número de comportamento de auto-limpeza, o número de bolos fecais, o número total de cruzamentos, o tempo de imobilidade, número de levantadas, a porcentagem de cruzamentos na área central e o tempo despendido no centro. Nenhum dos grupos de doses testadas com LQFM104 tiveram alterações no tempo gasto pelo teste da chaminé. No teste do sono induzido por pentobarbital, o tratamento com LQFM104 25, 50 ou 100 μmol/kg (v.o.) não afetou a latência ao sono, enquanto que a duração do sono aumentou em 65%, 64,4% e 78,6% respectivamente, em comparação com o grupo controle tratado oralmente com veículo 10 ml/kg (28,8 ± 2,9 minutos). Na padronização do teste de escalada induzido por apomorfina, o tratamento com haloperidol na dose de 2,6 μmol/kg foi capaz de reduzir o comportamento de escalada em 97,8%, e a clozapina, na dose de 45 μmol/kg, causou este comportamento reduzido em 78% quando comparado com o controle (16,87 ± 2,8). O LQFM104 nas doses de 50 ou 200 μmol/kg (v.o.) não foi capaze de reduzir o comportamento de escalada. No teste do nado forçado, apenas a dose de 50 μmol/kg (v.o.) foi capaz de reduzir o tempo de imobilidade, em 19,8% em comparação com o grupo controle (263,2 ± 6,7 segundos) e aumentou a latência para a imobilidade em 43%, em comparação com o controle (70,6 ± 6,5 segundos). De modo semelhante, no teste de suspensão pela cauda, apenas o LQFM104 50 μmol/kg (v.o.), aumentou o tempo de imobilidade (32,1%) em comparação com o controle (216,1 ± 13,2 segundos). O LQFM104 50 μmol/kg (v.o.) teve seu efeito tipo antidepressivo completamente revertido pelo bloqueio com o tratamento com PCPA e NAN-190. Na quantificação do fator neurotrófico derivado do cérebro o LQFM104 50 μmol/kg (v.o.) não alterou esses níveis. Os resultados com LQFM104 no teste de campo aberto não indicaram nenhuma alteração na atividade locomotora espontânea e não mostraram nenhuma atividade ansiogênica. O teste da chaminé não mostrou diminuição na coordenação motora. O teste de sono induzido por pentobarbital aumentou a duração do sono, sem reduzir a latência, o que sugere uma ação sedativa. O teste do nado forçado e o teste de suspensão pela cauda confirmou para LQFM104 50 μmol/kg (v.o.) uma atividade tipo antidepressiva em camundongos. O bloqueio com PCPA e NAN-190 sugerem o envolvimento de sistema serotonérgico e do receptor 5-HT1A.