A filamina A (FLNA) é uma proteína de citoesqueleto com diversas funções, dentre as quais estão motilidade celular e ancoragem de receptores de membrana. A alteração de sua expressão foi anteriormente descrita em diversos tipos de neoplasia. Em tumores hipofisários, demonstrou-se que sua expressão se correlacionou à expressão de receptores de dopamina tipo 2 (DRD2) em prolactinomas, e com a sinalização intracelular do receptor de somatostatina tipo 2 (SSTR2) após ativação por agonista, em somatotropinomas. Neste estudo, avalariam-se a expressão da FLNA, DRD2, SSTR2 e SSTR5 em diversos tumores hipofisários: prolactinomas, somatotropinomas, corticotropinomas e adenomas clinicamente não funcionantes (ACNF). Avaliou-se também a correlação entre a expressão da FLNA e resposta aos tratamentos medicamentosos, com agonista dopaminérgico (AD) ou com ligantes do receptor de somatostatina (LRS), e entre FLNA e as características de invasividade e/ou agressividade tumorais. Houve correlação entre a expressão de FLNA e a expressão de DRD2 e, entre FLNA e a resposta ao AD, nos ACNFs. Nos corticotropinomas, houve correlação entre a expressão da FLNA e critérios de invasividade tumoral. Portanto, o papel da FLNA nos tumores hipofisários pode depender do tipo celular implicado. Além disso, o envolvimento da FLNA nos mecanismos de resistência aos medicamentos utilizados nos tumores hipofisários, AD ou LRS, não deve estar relacionado apenas à sua ação na ancoragem e reciclagem dos receptores DRD2 e SSTRs, mas também à sua ação na motilidade celular, propiciando caratecterísticas de invasividade / Filamin A (FLNA) is a cytoskeletal protein with a variety of functions, including cell motility and membrane receptor anchorage. Changes in FLNA expression has already been described in several types of neoplasia. In pituitary tumors, its expression has been shown to correlate with the expression of dopamine type 2 receptors (DRD2) in prolactinomas and with intracellular somatostatin type 2 receptor (SSTR2) signaling after agonist activation in somatotropinomas. The expression of FLNA, DRD2, SSTR2 and SSTR5 in different pituitary tumors: prolactinomas, somatotrophinomas, corticotrophinomas and clinically nonfunctioning adenomas (CNFA) were evaluated. We also correlate FLNA expression to sensibility to drug treatments with dopamin agonists (DA) or somatostatin receptor ligands (SRL), and to tumor invasiveness and/or aggressiveness. Positive correlation between FLNA expression and DRD2 expression and between FLNA and DA response were found in CNFA. In corticotrophinomas, there was correlation between FLNA expression and tumor invasiveness. Therefore, the role of FLNA in pituitary tumors seems to depend on the cell type involved. Additionally, FLNA involvement in the mechanisms of drug (DA or SRL) resistance in pituitary tumors could not be related only to its action in the anchoring and recycling of DRD2 and SSTR receptors, but also to its action on cellular motility and invasiveness

Estudos clínicos nos pacientes com epilepsia mostram a importância da neurotransmissão modulada pela dopamina na epilepsia. Múltiplos fatores genéticos predispõem à epilepsia e há evidências de uma relação direta entre a epilepsia e as variações nos genes que codificam proteínas envolvidas na neurotransmissão dopaminérgica. O objetivo do nosso estudo foi investigar se os polimorfismos da via dopaminérgica e o Val66Met do BDNF estavam associados à ocorrência de epilepsia do lobo temporal causada por esclerose hipocampal. Para este fim, avaliamos 119 pacientes com epilepsia do lobo temporal causada por esclerose hipocampal e 113 voluntários saudáveis. Os participantes foram genotipados para os polimorfismos do gene DAT (3\'UTR e Intron 8), receptores dopaminérgicos (DRD2 e DRD4), COMT, MAO e BDNF (Val66Met). Não houve diferença entre pacientes e controles para os polimorfismos relacionados ao DAT, Íntron 8 VNTR (p 0,395) e 3\'UTR VNTR (p 0,614) e para a análise dos haplótipos (3\'UTR e Intron 8) (p 0.205). Não houve diferença entre pacientes e controles para os polimorfismos dos receptores dopaminérgicos DRD2 rs1800497 (p 0.440), DRD4 rs1800955 (p 0.548) e DRD4 VNTR (p 0.318). Não observamos diferença entre pacientes e controles quanto aos polimorfismos COMT rs4680 (p 0.482) e MAOA_uVNTR (p 0.753), metabolizadores de DA. Não observamos diferença na distribuição genotípica do polimorfismo Val66Met (rs6265) do BDNF (p 0,636) e a distribuição alélica (p 0.471) no grupo de pacientes com epilepsia do lobo temporal causada por esclerose do hipocampo. Nossos achados demonstraram que os polimorfismos da via dopaminérgica e BDNF Val66Met analisados neste estudo não parecem estar associados à epilepsia de lobo temporal causada por esclerose de hipocampo / Clinical studies in patients with epilepsy showed the role of neurotransmission modulated by dopamine in epilepsy. Multiple genetic factors predispose to epilepsy; there is evidence for a direct relationship between epilepsy and variations in genes encoding proteins involved in dopaminergic neurotransmission. The aim of our study was to investigate if the polymorphism related to the dopaminergic pathway and BDNF polymorphism Val66Met were associated with the occurrence of temporal lobe epilepsy caused by hippocampal sclerosis. We assessed 119 patients with unequivocal temporal lobe epilepsy caused by hippocampal sclerosis and 113 healthy volunteers. Individuals were genotyped for DAT gene polymorphisms (3\'UTR and Intron 8), dopaminergic receptors (DRD2 and DRD4), COMT, MAO and BDNF. There was no difference between patients and controls considering the polymorphisms related to DAT, Intron 8 VNTR (p 0,395) and 3\'UTR VNTR (p 0.614) and for the analysis of haplotypes (3\'UTR and Intron 8) (p 0.205). There was no difference between patients and controls considering the dopaminergic receptor polymorphisms DRD2 rs1800497 (p 0.440), DRD4 rs1800955 (p 0.548) and DRD4 VNTR (p 0.318). We observed no difference between patients and controls regarding COMT polymorphisms rs4680 (p 0.482) and MAOA_uVNTR (p 0.753), of dopaminergic metabolizers. We did not observe difference in the genotypic distribution of BDNF Val66Met polymorphism (rs6265) (p 0.636) and in the allelic distribution (p 0.4711) in the group with temporal lobe epilepsy caused by hippocampal sclerosis. Our findings suggest that the polymorphisms of the dopaminergic pathway evaluated in this study and BDNF Val66Me do not appear to be associated with temporal lobe epilepsy caused by hippocampal sclerosis

Attention deficit hyperactivity disorder (ADHD) affects up to 10% of school-aged children and half as many adults. The core features of impulsivity, hyperactivity, and inattentiveness commonly give rise to academic underachievement, poor social relationships, and increased risk for mood and anxiety disorders. Although the relevant neurobiological mechanisms remain poorly understood, altered mesocorticolimbic dopamine (DA) transmission has been proposed. The aim of the present study was to compare striatal DA function in treatment-naive adults with ADHD vs. age- and IQ-matched controls. Two PET/[11C]raclopride scans, one with placebo and one with d-amphetamine (d-AMP; 0.3 mg/kg, p.o.), were administered to five men with ADHD and five healthy male volunteers. The ADHD group differed from controls in demonstrating significant d-AMP-induced reductions in posterior caudate (p<0.05). These results may support a proposed model of reduced DA tone leading to increased phasic signaling in ADHD.

Myopia is a refractive defect of the eye in which collimated light produces images focused in front of the retina. Myopia can be artificially induced in animal models by form deprivation (form deprivation myopia, FDM) or by application of negative lenses (lens induced myopia, LIM). In this study myopia was induced using diffusers. The project had two main aims: 1. To determine if there is an interaction between the GABAergic system and dopaminergic system in the retina in terms of myopia? 2. To determine if there is an interaction between the GABAergic system and cholinergic system in the retina in terms of myopia? Firstly, an experiment focusing on the interaction between dopaminergic receptors antagonists and GABAC receptor antagonist was developed. Comparison of the different drug treated eye with the control was found and the effects of combination injections were compared to individual drug injections. Use of different blockers for various subtype of receptors simplified the understandings the underlying pharmacological interventions for GABAC receptor antagonist TPMPA. The D1 subtype of receptors was found to be involved in transmission of signals from GABAC receptors. Our results showed that D1 receptor antagonist SCH-23390 antagonizes the actions of TPMPA. In addition to this it was also found that possibly 5HT receptor may also play an important role in modulation of signaling from GABA receptor to dopaminergic receptors in the retina. These results were consistent with the drug combination effects for agonists. GABA A/C receptor agonist muscimol negativate the efficacy of D1 receptor agonist SKF-38393 but the activity of D2/4 receptor agonist quinpirole was not affected by muscimol. Although dopaminergic receptors are found to interact with GABAergic signaling, but an alternative interaction with anticholinergic (most widely studied antimyopic agents) could not be ruled out. This problem led to a follow-up experiment, in which GABA receptors intervention in anticholinergic agents was studied. The GABAergic receptor agonist muscimol when injected with anticholinergics (atropine and pirenzepine) showed a moderate interaction. As muscimol interacted with atropine to a lesser extent a more specific M1/5 receptor antagonist pirenzepine (earlier found to inhibit myopia) was used under these circumstances. The second aim to study the interaction between muscimol and pirenzepine showed more interaction with GABAA/C receptor agonist. There were data suggesting that there is a muscarinic and GABAergic interaction in retina, such that each modulation of each receptor had an effect on FDM. However, a drug combination treatment helped in understanding the underlying mechanism. Several previous studies have indicated that there exist a strong interaction between excitatory neurotransmitter acetylcholine and inhibitory transmitter GABA in retina. The results of this study indicate a similar finding. Thus results of this study may be summarized as: 1. D1 antagonists and not D2 antagonists blocks the antimyopic effects of GABAC antagonist TPMPA 2. GABA A/C agonist muscimol partially blocks the antimyopic activity of anticholinergics (e.g. atropine and pirenzepine).

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

A filamina A (FLNA) é uma proteína de citoesqueleto com diversas funções, dentre as quais estão motilidade celular e ancoragem de receptores de membrana. A alteração de sua expressão foi anteriormente descrita em diversos tipos de neoplasia. Em tumores hipofisários, demonstrou-se que sua expressão se correlacionou à expressão de receptores de dopamina tipo 2 (DRD2) em prolactinomas, e com a sinalização intracelular do receptor de somatostatina tipo 2 (SSTR2) após ativação por agonista, em somatotropinomas. Neste estudo, avalariam-se a expressão da FLNA, DRD2, SSTR2 e SSTR5 em diversos tumores hipofisários: prolactinomas, somatotropinomas, corticotropinomas e adenomas clinicamente não funcionantes (ACNF). Avaliou-se também a correlação entre a expressão da FLNA e resposta aos tratamentos medicamentosos, com agonista dopaminérgico (AD) ou com ligantes do receptor de somatostatina (LRS), e entre FLNA e as características de invasividade e/ou agressividade tumorais. Houve correlação entre a expressão de FLNA e a expressão de DRD2 e, entre FLNA e a resposta ao AD, nos ACNFs. Nos corticotropinomas, houve correlação entre a expressão da FLNA e critérios de invasividade tumoral. Portanto, o papel da FLNA nos tumores hipofisários pode depender do tipo celular implicado. Além disso, o envolvimento da FLNA nos mecanismos de resistência aos medicamentos utilizados nos tumores hipofisários, AD ou LRS, não deve estar relacionado apenas à sua ação na ancoragem e reciclagem dos receptores DRD2 e SSTRs, mas também à sua ação na motilidade celular, propiciando caratecterísticas de invasividade / Filamin A (FLNA) is a cytoskeletal protein with a variety of functions, including cell motility and membrane receptor anchorage. Changes in FLNA expression has already been described in several types of neoplasia. In pituitary tumors, its expression has been shown to correlate with the expression of dopamine type 2 receptors (DRD2) in prolactinomas and with intracellular somatostatin type 2 receptor (SSTR2) signaling after agonist activation in somatotropinomas. The expression of FLNA, DRD2, SSTR2 and SSTR5 in different pituitary tumors: prolactinomas, somatotrophinomas, corticotrophinomas and clinically nonfunctioning adenomas (CNFA) were evaluated. We also correlate FLNA expression to sensibility to drug treatments with dopamin agonists (DA) or somatostatin receptor ligands (SRL), and to tumor invasiveness and/or aggressiveness. Positive correlation between FLNA expression and DRD2 expression and between FLNA and DA response were found in CNFA. In corticotrophinomas, there was correlation between FLNA expression and tumor invasiveness. Therefore, the role of FLNA in pituitary tumors seems to depend on the cell type involved. Additionally, FLNA involvement in the mechanisms of drug (DA or SRL) resistance in pituitary tumors could not be related only to its action in the anchoring and recycling of DRD2 and SSTR receptors, but also to its action on cellular motility and invasiveness

No description available.

No description available.

Evidências de estudos genético-epidemiológicos têm demonstrado a existência de um fator de risco genético para o desenvolvimento da esquizofrenia. Na presente Tese, um total de 245 pacientes com esquizofrenia e 834 controles foi selecionado com o objetivo de investigar a diferença na distribuição de alelos e genótipos de seis polimorfismos de quatro diferentes genes do sistema dopaminérgico nesses dois grupos: 1. TaqI A1/A2 do DRD2 - rs1800497; 2. -141C (Ins/Del) do DRD2 - rs1799732; 3. Ser-9-Gly do DRD3 - rs6280; 4. VNTR da região 3´ não-codificadora do SLC6A3; 5. A1343G do SLC6A3 - rs6347; 6. A/G da região 3´ não-codificadora do COMT - rs165599. Os resultados mostraram associação dos polimorfismos -141C (Ins/Del) do DRD2 (rs1799732) e A1343G do SLC6A3 (rs6347) com esquizofrenia na amostra investigada. / Evidences from genetic epidemiological studies have demonstrated the existence of a genetic risk factor for schizophrenia. In the present work a total of 245 schizophrenic patients and 834 controls were selected to investigate differences in the allelic and genotypic distribution of six polymorphisms from four different genes of the dopaminergic system between the groups: 1. TaqI A1/A2 of the DRD2 - rs1800497; 2. -141C (Ins/Del) of the DRD2 - rs1799732; 3. Ser-9-Gly of the DRD3 - rs6280; 4. VNTR in the 3\'-untranslated region of the SLC6A3; 5. A1343G of the SLC6A3 - rs6347; 6. A/G in the 3\'-untranslated region of the COMT - rs165599. The results have found an association of the polymorphisms -141C (Ins/Del) of the DRD2 (rs1799732) and A1343G of the SLC6A3 (rs6347) with schizophrenia in the investigated sample.

Evidências de estudos genético-epidemiológicos têm demonstrado a existência de um fator de risco genético para o desenvolvimento da esquizofrenia. Na presente Tese, um total de 245 pacientes com esquizofrenia e 834 controles foi selecionado com o objetivo de investigar a diferença na distribuição de alelos e genótipos de seis polimorfismos de quatro diferentes genes do sistema dopaminérgico nesses dois grupos: 1. TaqI A1/A2 do DRD2 - rs1800497; 2. -141C (Ins/Del) do DRD2 - rs1799732; 3. Ser-9-Gly do DRD3 - rs6280; 4. VNTR da região 3´ não-codificadora do SLC6A3; 5. A1343G do SLC6A3 - rs6347; 6. A/G da região 3´ não-codificadora do COMT - rs165599. Os resultados mostraram associação dos polimorfismos -141C (Ins/Del) do DRD2 (rs1799732) e A1343G do SLC6A3 (rs6347) com esquizofrenia na amostra investigada. / Evidences from genetic epidemiological studies have demonstrated the existence of a genetic risk factor for schizophrenia. In the present work a total of 245 schizophrenic patients and 834 controls were selected to investigate differences in the allelic and genotypic distribution of six polymorphisms from four different genes of the dopaminergic system between the groups: 1. TaqI A1/A2 of the DRD2 - rs1800497; 2. -141C (Ins/Del) of the DRD2 - rs1799732; 3. Ser-9-Gly of the DRD3 - rs6280; 4. VNTR in the 3\'-untranslated region of the SLC6A3; 5. A1343G of the SLC6A3 - rs6347; 6. A/G in the 3\'-untranslated region of the COMT - rs165599. The results have found an association of the polymorphisms -141C (Ins/Del) of the DRD2 (rs1799732) and A1343G of the SLC6A3 (rs6347) with schizophrenia in the investigated sample.