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CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / O Transtorno Afetivo Bipolar (TAB) à uma doenÃa crÃnica, altamente incapacitante e associada a custo excessivo aos sistemas de saÃde. Atualmente, reconhece-se o papel importante da Angiotensina II em transtornos de ansiedade e humor. A desregulaÃÃo do Sistema renina-angiotensina (SRA) cerebral pela ativaÃÃo de receptores da angiotensina II subtipo 1 (AT1Rs) està associada à formaÃÃo de espÃcies reativas de oxigÃnio, ativaÃÃo de vias prÃ-inflamatÃrias, reduÃÃo da neuroplasticidade e disfunÃÃo mitocondrial, estando esses eventos relacionados com a fisiopatologia do TAB. Assim, objetivou-se avaliar a aÃÃo da candesartana (CDS) em um modelo animal de mania induzido por d-anfetamina (AMPH). Utilizou-se camundongos Swiss machos (peso: 20-25g) submetidos a dois protocolos de tratamento. No protocolo de prevenÃÃo (PP), os animais receberam CDS (0,1; 0,3; 1 ou 3 mg/Kg/dia), lÃtio (47,5 mg/Kg/dia) ou veÃculo por 14 dias e entre o 8 e o 14 dia receberam AMPH (2 mg/Kg/dia i.p) ou salina. No protocolo de reversÃo (PR), administrou-se AMPH ou salina por 14 dias e entre o 8 e o 14 dia os animais foram tratados com CDS, lÃtio ou veÃculo. No 14 dia, os animais foram submetidos aos testes comportamentais, campo aberto e Y Maze. Foram realizadas anÃlises neuroquÃmicos para avaliar o estresse oxidativo (TBARS e GSH) no vÃrmis cerebelar (VC), cÃrtex prÃ-frontal (PF), hipocampo (HPC) e corpo estriado (CE). AlÃm disso, foram avaliados os nÃveis de BDNF, TNF-α e fosfo-Ser9-GSK-3β para as doses de 0,3 e 1 mg/Kg de CDS. Os nÃveis de fosfo-Ser9-GSK-3β e BDNF foram avaliados apenas no HPC e os nÃveis de TNF-α no HPC e VC. Em ambos os protocolos de tratamento, observou-se aumento da atividade locomotora nos grupos que receberam apenas AMPH, que foi prevenida e revertida pela CDS. Os resultados obtidos nos animais tratados com CDS + AMPH foram semelhantes aos do grupo controle e dos animais que receberam LÃtio + AMPH. No teste de Y maze, a CDS conseguiu prevenir e reverter o prejuÃzo cognitivo causado pela AMPH e apenas as doses de CDS 0,1 no PP e 0,3 no PR nÃo tiveram efeito, assim como o tratamento com lÃtio em ambos os protocolos. A CDS aumentou os nÃveis de GSH no HPC e VC no PP e no PF, HPC e CE no PR. Os nÃveis de TBARS foram reduzidos pela CDS no PF, HPC e VC no PP e no PF, HPC e CE no PR. Em ambos os protocolos de tratamento, a AMPH reduziu os nÃveis hipocampais de BDNF e o lÃtio e ambas as doses de CDS avaliadas restauraram os nÃveis dessa neurotrofina. No PP, a AMPH e ambas as doses de CDS reduziram o nÃvel de fosfo-Ser9-GSK-3β que foi expressivamente aumentado pelo lÃtio. Os nÃveis de TNF-α foram aumentados pela AMPH e reduzidos pelo lÃtio no HPC e VC. Ambas as doses de CDS avaliadas tiveram efeito na prevenÃÃo do aumento de TNF-α no HPC e preveniram e reverteram esse aumento no VC. Juntos, os dados mostraram que a CDS, semelhante ao Li, à efetiva na prevenÃÃo e reversÃo de alteraÃÃes comportamentais e neuroquÃmicas induzidas pela AMPH, com exceÃÃo da fosfo-Ser9-GSK-3β, sugerindo que estudos sejam desenvolvidos para avaliaÃÃo da atividade antimanÃaca desse fÃrmaco em pacientes bipolares, porÃm mais estudos prÃ-clÃnicos sÃo necessÃrios. / The Bipolar Disorder (BD) is a highly prevalent and chronic psychiatric disorder, associated with functional disability and excessive cost to the health system. The pharmacological therapy of BD displays low efficacy due the complex and poorly understood etiology, which makes it imperative to find new therapeutic targets for this disorder. The renin-angiotensin system (RAS) has been studied concerning neurological diseases, and is currently recognized important role of angiotensin II in anxiety and mood disorders. The deregulation of SRA brain is associated with the formation of reactive oxygen species, activation of proinflammatory pathways, reduced neuroplasticity and mitochondrial dysfunction. It is noteworthy that all these events are related to the pathophysiology of BD. Thus, this study aimed to evaluate the effect of candesartan (CDS) in an animal model of mania induced by d-amphetamine (AMPH). The animals were submitted to two treatment protocols. In prevention protocol, animals received CDS (0.1; 0.3; 1 or 3 mg/kg/day), lithium (47.5 mg/kg/day) or vehicle for 14 days and between the 8th and 14th day received AMPH (2 mg/kg/day ip) or saline. In reversal protocol, was administered AMPH or saline for 14 days and between the 8th and 14th day the animals were treated with CDS, lithium or vehicle. The effect of CDS was evaluated on 14th day by exploratory behavior of animals in the open field test used for pre-clinical study of antimanic drugs. The working memory was also evaluated by Y Maze test. Neurochemical analisis of oxidative stress (TBARS and GSH), was assessed in cerebellar vÃrmix (CV), prefrontal cortex (PF), hippocampus (HPC) and striatum (ST). For evaluate the levels of BDNF, TNF-α e fosfo-Ser9-GSK-3β,we used CDS 0,3 and CDS 1. BDNF and fosfo-Ser9-GSK-3β was assessed only in HPC and TNF-α in HPC and CV. In both treatment protocols, there was an increase in locomotor activity in the animals that received only AMPH, which was prevented and reversed by CDS, whose results were similar to the control group and the animals that received AMPH and lithium. In the memory test, the CDS prevented and reversed the cognitive impairment caused by AMPH and only the CDS doses of 0.1 in prevention protocol and 0.3 in reversal protocol were not successful. Lithium treatment neither prevented nor reversed the cognitive impairment. The CDS increased GSH levels in HPC and CV in the prevention protocol and in PF, HPC and ST in the reversal protocol. The TBARS levels were reduced by CDS in PF, HPC and CV in the prevention protocol and in PF, HPC and ST in the reversal protocol. However, MDA level was increased by higher dose of CDS in ST in prevention protocol and by the two lower doses of CDS in CV in reversal protocol. In both treatment protocols, AMPH reduced BDNF and lithium and both doses of CDS restored the levels of this neurotrophin. In the prevention protocol, AMPH and both doses of CDS reduced the level of phospho-Ser9-GSK-3β that was significantly increased by lithium. The levels of TNF-α were increased by AMPH and reduced by lithium in HPC and VC. CDS prevented the increase of TNF-α in HPC and prevented and reversed this increase in CV. Our findings showed that CDS, similarly to Li, is effective in reversing and preventing AMPH-induced behavioral and neurochemical alterations, providing a rationale for evaluating CDS as a novel antimanic agent, however new pre-clinical studies are necessary.

Thesis (M.S.)--Auburn University, 2008. / Abstract. Vita. Includes bibliographical references (p. 50-52).

Background: A dysfunctional mesocorticolimbic dopamine system has been reported in alcohol dependence and major depressive disorder. Probing mesocorticolimbic dopamine function in severe depression using dextroamphetamine revealed an altered behavioural response and a disrupted mesocorticolimbic circuitry in behavioural and functional magnetic resonance imaging (fMRI) studies. The purpose of this study was to use a similar approach in alcohol dependence. Behavioural Study: to assess dextroamphetamine subjective effects in alcohol-dependent and depressed alcohol-dependent participants. FMRI Study: to assess how the mesocorticolimbic circuitry would respond to a dextroamphetamine challenge in alcohol-dependent participants exposed to alcohol cues. Methods: In both studies, a single oral 30 mg dose of dextroamphetamine was the pharmacological intervention. Behavioural Study: randomized, double-blind, placebo-controlled, between-subject study. Eighteen alcohol-dependent and 22 depressed alcohol-dependent participants were compared using validated self-report drug effect tools (e.g. Addiction Research Center Inventory). FMRI Study: single-blind, between-subject study. FMRI blood oxygen level–dependent (BOLD) activation was measured in 14 alcohol-dependent and 9 healthy control participants during an alcohol-cue exposure task pre- and post-drug. Results: Behavioural Study: DRUG (F1,40=18.6; p<0.001) and GROUP (F1,40=16.6; p<0.001) main effects but no GROUPxDRUG interaction effects (F1,40=0.02; p=0.88) were detected, even when only severely depressed alcohol-dependent individuals were included (F1,30=0.04; p=0.84). FMRI Study: Alcohol-dependent participants exhibited greater ventral striatal activation compared to controls pre-drug and post-drug effect (F1,40=20.1; z=3.8; p<0.001; k>10; (x=10;y=-2;z=-14)). A GROUPxDRUG interaction effect was detected in the medial orbitofrontal cortex (mOFC) (F1,40=21.5; z=4.0; p<0.001; k>10; (x=-12;y=28;z=-20). The alcohol-dependent group exhibited a negligible mOFC response across both pre- and post-drug scanning sessions. In contrast, controls exhibited attenuation of mOFC response post-drug. Conclusion: The lack of significant GROUPxDRUG interaction effects in the Behavioural Study may suggest different neurobiological mechanisms underlying alcohol dependence and depression mesocorticolimbic dysfunction. Alcohol dependence appeared to mitigate the impact of depression severity on participants’ behavioural responses to dextroamphetamine. The FMRI Study data suggest there may be ventral striatal and mOFC disruption in alcohol-dependent participants. We suggest the mOFC may be involved in the reported loss of prefrontal modulation of dopamine cell activity in alcohol dependence. This supports a key role for the mOFC in mesocorticolimbic dysfunction in alcohol dependence.

Background: A dysfunctional mesocorticolimbic dopamine system has been reported in alcohol dependence and major depressive disorder. Probing mesocorticolimbic dopamine function in severe depression using dextroamphetamine revealed an altered behavioural response and a disrupted mesocorticolimbic circuitry in behavioural and functional magnetic resonance imaging (fMRI) studies. The purpose of this study was to use a similar approach in alcohol dependence. Behavioural Study: to assess dextroamphetamine subjective effects in alcohol-dependent and depressed alcohol-dependent participants. FMRI Study: to assess how the mesocorticolimbic circuitry would respond to a dextroamphetamine challenge in alcohol-dependent participants exposed to alcohol cues. Methods: In both studies, a single oral 30 mg dose of dextroamphetamine was the pharmacological intervention. Behavioural Study: randomized, double-blind, placebo-controlled, between-subject study. Eighteen alcohol-dependent and 22 depressed alcohol-dependent participants were compared using validated self-report drug effect tools (e.g. Addiction Research Center Inventory). FMRI Study: single-blind, between-subject study. FMRI blood oxygen level–dependent (BOLD) activation was measured in 14 alcohol-dependent and 9 healthy control participants during an alcohol-cue exposure task pre- and post-drug. Results: Behavioural Study: DRUG (F1,40=18.6; p<0.001) and GROUP (F1,40=16.6; p<0.001) main effects but no GROUPxDRUG interaction effects (F1,40=0.02; p=0.88) were detected, even when only severely depressed alcohol-dependent individuals were included (F1,30=0.04; p=0.84). FMRI Study: Alcohol-dependent participants exhibited greater ventral striatal activation compared to controls pre-drug and post-drug effect (F1,40=20.1; z=3.8; p<0.001; k>10; (x=10;y=-2;z=-14)). A GROUPxDRUG interaction effect was detected in the medial orbitofrontal cortex (mOFC) (F1,40=21.5; z=4.0; p<0.001; k>10; (x=-12;y=28;z=-20). The alcohol-dependent group exhibited a negligible mOFC response across both pre- and post-drug scanning sessions. In contrast, controls exhibited attenuation of mOFC response post-drug. Conclusion: The lack of significant GROUPxDRUG interaction effects in the Behavioural Study may suggest different neurobiological mechanisms underlying alcohol dependence and depression mesocorticolimbic dysfunction. Alcohol dependence appeared to mitigate the impact of depression severity on participants’ behavioural responses to dextroamphetamine. The FMRI Study data suggest there may be ventral striatal and mOFC disruption in alcohol-dependent participants. We suggest the mOFC may be involved in the reported loss of prefrontal modulation of dopamine cell activity in alcohol dependence. This supports a key role for the mOFC in mesocorticolimbic dysfunction in alcohol dependence.

Thesis (M.D.)--University of Adelaide, 1986. / Includes bibliographical references (leaves 317-350).

Presynaptic and postsynaptic actions of dextroamphetamine (DEX) were studied on dopamine (DA) sensitive neurons of the subesophageal ganglion of the garden snail Helix aspersa utilizing standard microelectrode techniques. Dextroamphetamine (5.5 × 10-7-10-4 M) produced effects on DA-sensitive neurons similar to that caused by DA (5.5 × 10-7-10-4 M). On cells excited by DA, surfused DEX (5.5 × 10-7 M) caused an excitation that could be blocked by chlorpromazine (0.5-1 × 10-6 M) or haloperidol (0.5-1 × 10-6 M). Elevating the extracellular Mg2+ from 4 to 20 mM reduced the depolarization caused by DEX from 11 to 2.5 mV without affecting the response to DA. The response remaining is attributed to a direct response to DEX on DA receptors. Surfused DEX caused an inhibition of cells inhibited by DA. Both DA and DEX effects were selectively blocked by dihydroergotamine (0.5-1 × 10-6 M). Elevating the [Mg2+] decreased the hyperpolarization caused by DEX from 11 to 3 mV without affecting the DA response. The effect of elevated magnesium in decreasing responses to surfused DEX suggests that the primary action of DEX is at the nerve terminal to cause DA release. Iontophoretic application of DEX caused minimal excitation or inhibition of DA neurons. This is attributed to the fact that DA receptors at the site of drug application are not associated with synaptic innervation. The response obtained with iontophoretically applied DEX suggest a weak direct action on DA receptors.

Bibliography: leaves 317-350 / 350 leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (M.D.)--University of Adelaide, 1986

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.

Plusieurs articles scientifiques et manuels de référence en médecine comportementale distinguent l'hyperactivité ou hyperkinésie de l’activité excessive en évaluant la réponse physiologique et comportementale des chiens suite à l’administration per os de 0.2 à 1.0 mg/kg de dextroamphétamine. Selon ces références, le chien atteint d’un syndrome hyperactif ou hyperkinésie, répondra de façon paradoxale à cette médication par une diminution de l’activité motrice accompagnée d’une réduction minimale de 15% de la fréquence respiratoire et de la fréquence cardiaque. L’objectif de la présente étude était de mesurer la variation de la température corporelle, de la fréquence cardiaque, de l’activité motrice et de différents comportements spécifiques chez un groupe de Beagles ayant reçu de la dextroamphétamine. La fiabilité d'un accéléromètre comme mesure objective d’activité motrice a aussi été évaluée. Dans le cadre de cette étude croisée contrôlée par placebo, douze Beagles de la colonie de recherche âgés entre 13 et 20 mois ont reçu une dose orale de 0.2 mg/kg de dextroamphétamine. Le moniteur cardiaque Polar® et un accéléromètre Actical® ont été utilisés pour enregistrer la fréquence cardiaque et l’activité motrice avant et après l’administration de la médication. La durée de chacun des comportements spécifiques a été compilée à l’aide du logiciel Noldus® et la température corporelle a été prise par thermomètre rectal. Le modèle équilibré de mesures répétées indique que les sujets ayant reçu la dextroamphétamine montrent une réduction significative (p = 0.044) de leur fréquence cardiaque comparativement aux chiens ayant reçu le placebo. Aucune variation significative n'a été observée concernant la température corporelle, l'activité motrice, et les autres comportements (léchage des babines, halètements, et bâillements) suite à l’administration de la dextroamphétamine. Une corrélation significative, linéaire et positive (p < 0,0001) entre les périodes de mouvements observées (vidéo) et les mesures d’activité enregistrées par l’accéléromètre a été observée. Les résultats de cette étude indiquent que les Beagles peuvent afficher des effets paradoxaux dans les 90 minutes suivant l’administration per os de dextroamphétamine à raison de 0.2 mg/kg. / Several veterinary behaviour texts/handbooks used in practice, distinguish hyperactivity or hyperkinesis from over-activity by using the physiological and behavioural responses of dogs given amphetamines. It is presumed that true hyperactive or hyperkinetic dogs given 0.2 - 1.0 mg/kg dextroamphetamine orally will paradoxically calm down, and have at least a 15% reduction in heart and respiratory rates. The purpose of the study was to measure the effects of an oral dose of 0.2 mg/kg dextroamphetamine on heart rate, body temperature, motor activity, and discrete behaviour sequences in Beagle dogs. Reliability of a collar mounted accelerometer, Actical® as an objective measure of motor activity was also investigated. The study design was a placebo controlled cross-over study. Twelve research colony Beagle dogs (13 - 20 months old) received an oral dose of 0.2 mg/kg dextroamphetamine as treatment. Baseline and post-treatment values for body temperature, heart rate, motor activity, and general behavioural changes, were obtained using rectal temperature, video recordings and Noldus® software, Polar® monitor (heart rate), and a collar mounted Actical®. A repeated measures model indicates that dogs receiving an oral dose of 0.2 mg/kg dextroamphetamine had a significantly (p = 0.044) reduced heart rate compared to placebo. There was no effect of treatment on the dogs’ body temperature, motor activity, or other behaviours such as “lip-licking”, “panting” and “yawning”. There is a significant linear and positive relationship between the gross motor activity as measured by observational video and the Actical® counts (p < 0.0001). Results from this study indicate that Beagle dogs may display some paradoxical effects in the 90 minutes following an oral dose of 0.2 mg/kg dextroamphetamine.