D-amino acid oxidase (DAO) is a flavin-dependent enzyme that is expressed in the mammalian brain. It is the metabolising enzyme of several D-amino acids, including D serine, which is an endogenous agonist at the glycine co-agonist site of the glutamatergic NMDA receptor. As such, regulation of D serine levels in the brain by DAO may indirectly modulate the activity of NMDA receptors. The expression and activity of DAO have been reported to be increased in schizophrenia. It has been identified as a putative susceptibility gene for the disorder, and as a potential therapeutic target. This thesis explored three aspects of the interface between DAO and the DA system. First, the expression of DA was investigated in the ventral tegmental area (VTA), the source of the dopaminergic mesocortical pathway. Traditionally, DAO was considered to be an enzyme confined to the hindbrain and to glia, but more recent studies have reported its expression in additional brain regions, and also in neurons. DAO mRNA and protein was found to be expressed in the VTA, and was present in both neurons and glia in this region, whereas in the cerebellum, DAO expression appeared solely glial. DA output from the VTA is regulated by NMDA receptors, and hence expression of DAO in the VTA suggests that it may serve a role in modulating cortical DA via regulation of D serine levels and NMDA receptor function. The second part of this thesis investigated the effects of DAO inhibition and D serine administration on DA levels in the prefrontal cortex (PFC) using in vivo microdialysis. Systemic DAO inhibition and D serine administration resulted in increases in extracellular levels of DA metabolites in the PFC, despite no detectable change in DA. Similarly, DA metabolites in the PFC increased after local application of D serine to the VTA, but no change was detected in DA. However, local DAO inhibition in the VTA resulted in increased levels of both DA and its metabolites, and DAO inhibition combined with D serine administration also produced increases in DA. This suggested that DAO and its regulation of D-serine levels may serve to indirectly modulate mesocortical DA function, and this may be mediated via the VTA. This notion was supported in the final section of this thesis, in which the expression of three DA genes was measured in the PFC of a novel line of DAO knockout mice. In this pilot study, there was evidence for an increase in Comt and Drd2 mRNAs in the knockout mice. As such, constitutive abolition of DAO activity may also alter mesocortical DA function. These studies provide new insights into the presence and role of DAO beyond the hindbrain, and point to a potentially important physiological function in modulating the activity of the mesocortical DA system via the VTA. This could be therapeutically relevant in the context of elevating cortical DA in the treatment of schizophrenia, and may provide supporting evidence for the clinical use of DAO inhibitors.

Dopamine is an important neurotransmitter that is involved in several human functions such as reward, cognition, emotions and movement. Abnormalities of the neurotransmitter itself, or the dopamine receptors through which it exerts its actions, contribute to a wide range of psychiatric and neurological disorders such as Parkinson’s disease and schizophrenia. Thus far, despite the great interest and extensive research, the exact role of dopamine and the causalities of dopamine related disorders are not fully understood. Here we have developed multimodal imaging methods, to investigate the release of dopamine and the distribution of the dopamine D2-like receptor family in-vivo in healthy humans. We use the [¹¹C]PHNO PET ligand, which enables exploration of dopamine-related parameters in striatal regions, and for the first time in extrastriatal regions, that are known to be associated with distinctive functions and disorders. Our methods involve robust approaches for the manual and automated delineation of these brain regions, in terms of structural and functional organisation, using information from structural and diffusion MRI images. These data have been combined with [¹¹C]PHNO PET data for quantitative dopamine imaging. Our investigation has revealed the distribution and the relative density of the D3R and D2R sites of the dopamine D2-like receptor family, in healthy humans. In addition, we have demonstrated that the release of dopamine has a functional rather than a structural specificity and that the relative densities of the D3R and D2R sites do not drive this specificity. We have also shown that the dopamine D3R receptor is primarily distributed in regions that have a central role in reward and addiction. A finding that supports theories that assigns a primarily limbic role to the D3R.

A fencanfamina (FCF) é um agonista indireto do sistema dopaminérgico que tem efeitos neurais e comportamentais similares aos observados com outras drogas estimulantes como a anfetamina ou a cocaína (COC). O presente trabalho teve como objetivo avaliar o efeito da administração aguda e repetida de FCF sobre o valor reforçador dos estímulos (Re). Foi usada a equação de igualação proposta por Herrnstein (1970) para avaliar esse efeito motivacional Foi também medido o efeito dessa droga sobre a taxa de respostas e a capacidade motora (k). Três experimentos foram realizados. Nos três experimentos o efeito da FCF foi testado em ratos treinados em um esquema múltiplo de sete componentes de diferentes Vls. Nos Experimentos 1 e 2 (E1 e E2, respectivamente) três doses agudas de FCF (0,88 mg/kg, 1,75 mg/kg e 3,5 mg/kg) foram administradas i.p. No E1 o reforçador foi água e no E2 reforçador foi sacarose. Em ambos os experimentos, o efeito da droga sobre os parâmetros estudados foi semelhante: as três doses de FCF aumentaram a taxa de respostas e diminuíram Re, sem alterar k. No Experimento 3, seis injeções de veiculo (Grupo VEI) ou de 1,75 mg/kg de FCF (Grupo DROGA) foram administradas i.p. intermitentemente aos sujeitos a fim de promover sensibilização comportamental. Após sete dias de suspensão da droga, foi administrada uma dose de 0,88 mg/kg de FCF em animais de ambos os grupos e foi medido o efeito sobre a taxa de respostas, k e Re. Os resultados obtidos mostraram que a administração repetida de FCF não alterou o efeito dessa droga sobre os parâmetros estudados. Os resultados são consistentes com os dados que mostram que a FCF tem efeitos sobre o comportamento similares aos de outros estimulantes, e apoiam a hipótese de que o aumento da taxa de respostas observado após a administração da FCF está relacionado a mudanças no valor reforçador dos estímulos, o que sugere um efeito motivacional e não motor. Além disso, os resultados sustentam as hipóteses que relacionam o sistema dopaminérgico ao processo do reforço. A falha na obtenção de sensibilização após a administração repetida de FCF poderia estar relacionada à dose utilizada ou ao numero de injeções administradas. / Fencanfamina (FCF) is an indirect dopaminergic agonist with neural and behavioral effects similar to those observed for other stimulant drugs such as the amphetamine or cocaine (COC). The aim of the present investigation was to evaluate the effect of acute and repeated administration of FCF on the reinforcing value (Re) taken as a motivational index. The Herrnstein hyperbole equation (1970) was used to evaluate this motivacional effect. The effects of FCF on response rate and motor capacity (k) where also observed. Three experiments were conducted. In all of them the effect of FCF was tested on rats trained on seven VI multiple schedule. In Experiments 1 and 2 (E1 and E2, respectively) three acute doses of FCF (0.88 mg/kg, 1.75 mg/kg and 3.5 mg/kg) were administered (i.p.) The reinforcer was water (E1) or sacarose (E2). In both experiments, the effect of the drug on the parameters studied was similar: the three doses of FCF increased the response rate, decreased Re and had no effect on k. In Experiment 3, six injections of vehicle (VEI Group) or 1.75 mg/kg of FCF (DROGA Group) were intermittently administered (i.p.) in order to promote sensitization. Seven days after drug withdrawal a single dose of 0.88 mg/kg of FCF was administered to animals in both groups and the effect on response rate, k and Re was measured. Results showed that repeated administration of FCF did not change the effect of this drug on the parameters investigated. These results are consistent with the evidence showing that FCF has behavioral effects similar to those reported for other stimulants and support the interpretation that increases in response rate are primarily related to changes in reinforcing value. Thus they probably reflect a motivational effect of the drug. Moreover, the results support the hypotheses that associate the dopaminergic system to the process of reinforcement. It is speculate that the failure to obtain sensitization after repeated administration of FCF could be related to dosage or number of injections.

The Amphetamine Years is a history of psychostimulant drugs and their clinical applications in post-World War II American medicine. Comprising such well-known substances as the amphetamines (Benzedrine, Dexedrine), methylphenidate (Ritalin), and phenmetrazine (Preludin), this class of pharmaceuticals has been among the most widely consumed in the past half-century. Their therapeutic uses for a variety of indications such as depression, obesity, and attention-deficit/hyperactivity disorder (ADHD) in children, not to mention their relevance for a number of different medical specialties, reveals that psychostimulants have occupied an important, if underappreciated role in the practice of modern medicine. In this dissertation, I illuminate the various ways in which physicians, particularly psychiatrists, put these drugs to work in clinical practice. In short, I contend that physicians exploited the wide range of physiological and psychological effects of psychostimulants and made a place for them in different therapeutic settings, even ones characterized by competing views and theories about the workings of the human body and mind. My dissertation is distinguished by two prominent themes. First, I emphasize the clinician perspective as a vehicle for understanding the history of the psychostimulants, as well as related developments in psychiatry, pharmacotherapy, and the political economy of drugs, in the second half of the twentieth century. Scholars such Nicolas Rasmussen, David Courtwright, and Ilina Singh have elucidated the history of psychostimulants by emphasizing how pharmaceutical companies positioned their products in the medical marketplace. My dissertation takes a different, yet complimentary approach by studying clinicians, themselves, to further historical comprehension of the place of these pharmaceuticals within postwar medicine, society, and culture. Second, I advance the concept of "therapeutic versatility" to explain their historical trajectories. The complex set of psychological and physical effects these drugs produced made them ideal for a diverse range of therapeutic applications, which explains why they were embraced by many different medical specialties, why they were marketed by manufacturers for a variety of indications, and why they have enjoyed an enduring therapeutic lifespan, in spite of increasing efforts since the mid-1960s to regulate their availability and control their consumption. In addition to these two overarching themes, I advance five specific arguments in my dissertation. First, I contend that pharmaceutical markets were simultaneously created by the drug industry and clinicians. Pharmaceutical firms' efforts to develop markets for their products have been well documented by historians, but in my dissertation, I underscore the role also played by clinicians in discerning drugs' applications. Second, I argue that twentieth-century psychiatry's conception of illness and therapeutics may not be served best by strictly dividing its history along lines of institutional and outpatient treatment. Third, I demonstrate how the use of psychostimulants by analytically oriented psychiatrists during the 1950s complicates historical notions of paradigm shift from a psychodynamic to biological orientation. Psychotherapy and psychopharmacology were not competing paradigms; in practice, doctors often employed both. Fourth, I assert that an appreciation of psychiatrists' empirical and eclectic approaches to the use of drugs is necessary to comprehend the rise of psychiatric pharmacotherapy in the postwar era. Finally, I contend that in order to understand the relationship between medical applications of psychostimulants and their extramedical consumption, it is necessary to conceive of a plurality of distinct "amphetamine cultures," each characterized by a unique set of relationships between physician-prescribers, patient-consumers, pharmaceutical firms, and political authorities.

The aim of this thesis was to investigate the input-specificity of sensory-induced plasticity in humans. This was achieved by varying the characteristics of sine gratings so that they selectively targeted distinct populations of neurons in the visual cortex. In Experiments 1-3, specificity was investigated with electroencephalography using horizontally- and vertically-oriented sine gratings (Experiment 1) or gratings of differing spatial frequency (Experiments 2 & 3). Increases in the N1b potential were observed only for sine gratings that were the same in orientation or spatial frequency as that used as the tetanus, suggesting that the potentiation is specific to the visual pathways stimulated during the induction of the tetanus. However, the increase in the amplitude of the N1b in Experiment 1 was not maintained when tested again at 50 minutes post-tetanus. This may have been due to depotentiation caused by the temporal frequency of stimulus presentation in the first post-tetanus block. To try to circumvent this potential confound, immediate and maintained (tested 30 minutes post-tetanus) spatial-frequency-specific potentiation were tested separately in Experiments 2 and 3, respectively. Experiment 3 demonstrated that the increased N1b was maintained for up to half an hour post-tetanus. In addition, the findings from Experiment 1, as well as the pattern of results from Experiments 2 and 3, indicate that the potentiation must be occurring in the visual cortex rather than further upstream at the lateral geniculate nucleus. In Experiment 4 functional magnetic resonance imaging was used to more accurately localise where these plastic changes were taking place using sine gratings of differing spatial frequency. A small, focal post-tetanic increase in the blood-oxygen-level-dependent (BOLD) response was observed for the tetanised grating in the right temporo-parieto-occipital junction. For the non-tetanised grating, decreases in BOLD were found in the primary visual cortex and bilaterally in the cuneus and pre-cuneus. These decreases may have been due to inhibitory interconnections between neurons tuned to different spatial frequencies. These data indicate that tetanic sensory stimulation selectively targets and potentiates specific populations of neurons in the visual cortex.

The aim of this thesis was to investigate the input-specificity of sensory-induced plasticity in humans. This was achieved by varying the characteristics of sine gratings so that they selectively targeted distinct populations of neurons in the visual cortex. In Experiments 1-3, specificity was investigated with electroencephalography using horizontally- and vertically-oriented sine gratings (Experiment 1) or gratings of differing spatial frequency (Experiments 2 & 3). Increases in the N1b potential were observed only for sine gratings that were the same in orientation or spatial frequency as that used as the tetanus, suggesting that the potentiation is specific to the visual pathways stimulated during the induction of the tetanus. However, the increase in the amplitude of the N1b in Experiment 1 was not maintained when tested again at 50 minutes post-tetanus. This may have been due to depotentiation caused by the temporal frequency of stimulus presentation in the first post-tetanus block. To try to circumvent this potential confound, immediate and maintained (tested 30 minutes post-tetanus) spatial-frequency-specific potentiation were tested separately in Experiments 2 and 3, respectively. Experiment 3 demonstrated that the increased N1b was maintained for up to half an hour post-tetanus. In addition, the findings from Experiment 1, as well as the pattern of results from Experiments 2 and 3, indicate that the potentiation must be occurring in the visual cortex rather than further upstream at the lateral geniculate nucleus. In Experiment 4 functional magnetic resonance imaging was used to more accurately localise where these plastic changes were taking place using sine gratings of differing spatial frequency. A small, focal post-tetanic increase in the blood-oxygen-level-dependent (BOLD) response was observed for the tetanised grating in the right temporo-parieto-occipital junction. For the non-tetanised grating, decreases in BOLD were found in the primary visual cortex and bilaterally in the cuneus and pre-cuneus. These decreases may have been due to inhibitory interconnections between neurons tuned to different spatial frequencies. These data indicate that tetanic sensory stimulation selectively targets and potentiates specific populations of neurons in the visual cortex.

The aim of this thesis was to investigate the input-specificity of sensory-induced plasticity in humans. This was achieved by varying the characteristics of sine gratings so that they selectively targeted distinct populations of neurons in the visual cortex. In Experiments 1-3, specificity was investigated with electroencephalography using horizontally- and vertically-oriented sine gratings (Experiment 1) or gratings of differing spatial frequency (Experiments 2 & 3). Increases in the N1b potential were observed only for sine gratings that were the same in orientation or spatial frequency as that used as the tetanus, suggesting that the potentiation is specific to the visual pathways stimulated during the induction of the tetanus. However, the increase in the amplitude of the N1b in Experiment 1 was not maintained when tested again at 50 minutes post-tetanus. This may have been due to depotentiation caused by the temporal frequency of stimulus presentation in the first post-tetanus block. To try to circumvent this potential confound, immediate and maintained (tested 30 minutes post-tetanus) spatial-frequency-specific potentiation were tested separately in Experiments 2 and 3, respectively. Experiment 3 demonstrated that the increased N1b was maintained for up to half an hour post-tetanus. In addition, the findings from Experiment 1, as well as the pattern of results from Experiments 2 and 3, indicate that the potentiation must be occurring in the visual cortex rather than further upstream at the lateral geniculate nucleus. In Experiment 4 functional magnetic resonance imaging was used to more accurately localise where these plastic changes were taking place using sine gratings of differing spatial frequency. A small, focal post-tetanic increase in the blood-oxygen-level-dependent (BOLD) response was observed for the tetanised grating in the right temporo-parieto-occipital junction. For the non-tetanised grating, decreases in BOLD were found in the primary visual cortex and bilaterally in the cuneus and pre-cuneus. These decreases may have been due to inhibitory interconnections between neurons tuned to different spatial frequencies. These data indicate that tetanic sensory stimulation selectively targets and potentiates specific populations of neurons in the visual cortex.

The aim of this thesis was to investigate the input-specificity of sensory-induced plasticity in humans. This was achieved by varying the characteristics of sine gratings so that they selectively targeted distinct populations of neurons in the visual cortex. In Experiments 1-3, specificity was investigated with electroencephalography using horizontally- and vertically-oriented sine gratings (Experiment 1) or gratings of differing spatial frequency (Experiments 2 & 3). Increases in the N1b potential were observed only for sine gratings that were the same in orientation or spatial frequency as that used as the tetanus, suggesting that the potentiation is specific to the visual pathways stimulated during the induction of the tetanus. However, the increase in the amplitude of the N1b in Experiment 1 was not maintained when tested again at 50 minutes post-tetanus. This may have been due to depotentiation caused by the temporal frequency of stimulus presentation in the first post-tetanus block. To try to circumvent this potential confound, immediate and maintained (tested 30 minutes post-tetanus) spatial-frequency-specific potentiation were tested separately in Experiments 2 and 3, respectively. Experiment 3 demonstrated that the increased N1b was maintained for up to half an hour post-tetanus. In addition, the findings from Experiment 1, as well as the pattern of results from Experiments 2 and 3, indicate that the potentiation must be occurring in the visual cortex rather than further upstream at the lateral geniculate nucleus. In Experiment 4 functional magnetic resonance imaging was used to more accurately localise where these plastic changes were taking place using sine gratings of differing spatial frequency. A small, focal post-tetanic increase in the blood-oxygen-level-dependent (BOLD) response was observed for the tetanised grating in the right temporo-parieto-occipital junction. For the non-tetanised grating, decreases in BOLD were found in the primary visual cortex and bilaterally in the cuneus and pre-cuneus. These decreases may have been due to inhibitory interconnections between neurons tuned to different spatial frequencies. These data indicate that tetanic sensory stimulation selectively targets and potentiates specific populations of neurons in the visual cortex.

The aim of this thesis was to investigate the input-specificity of sensory-induced plasticity in humans. This was achieved by varying the characteristics of sine gratings so that they selectively targeted distinct populations of neurons in the visual cortex. In Experiments 1-3, specificity was investigated with electroencephalography using horizontally- and vertically-oriented sine gratings (Experiment 1) or gratings of differing spatial frequency (Experiments 2 & 3). Increases in the N1b potential were observed only for sine gratings that were the same in orientation or spatial frequency as that used as the tetanus, suggesting that the potentiation is specific to the visual pathways stimulated during the induction of the tetanus. However, the increase in the amplitude of the N1b in Experiment 1 was not maintained when tested again at 50 minutes post-tetanus. This may have been due to depotentiation caused by the temporal frequency of stimulus presentation in the first post-tetanus block. To try to circumvent this potential confound, immediate and maintained (tested 30 minutes post-tetanus) spatial-frequency-specific potentiation were tested separately in Experiments 2 and 3, respectively. Experiment 3 demonstrated that the increased N1b was maintained for up to half an hour post-tetanus. In addition, the findings from Experiment 1, as well as the pattern of results from Experiments 2 and 3, indicate that the potentiation must be occurring in the visual cortex rather than further upstream at the lateral geniculate nucleus. In Experiment 4 functional magnetic resonance imaging was used to more accurately localise where these plastic changes were taking place using sine gratings of differing spatial frequency. A small, focal post-tetanic increase in the blood-oxygen-level-dependent (BOLD) response was observed for the tetanised grating in the right temporo-parieto-occipital junction. For the non-tetanised grating, decreases in BOLD were found in the primary visual cortex and bilaterally in the cuneus and pre-cuneus. These decreases may have been due to inhibitory interconnections between neurons tuned to different spatial frequencies. These data indicate that tetanic sensory stimulation selectively targets and potentiates specific populations of neurons in the visual cortex.

Made available in DSpace on 2015-07-22T20:49:52Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-03-31 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A alimentação vem sofrendo uma série de modificações, tanto na forma de obtenção, quanto de preparo dos alimentos. Este processo atinge as comunidades indígenas, e traz como consequência, carências nutricionais e alterações culturais. Muitas culturas não fazem distinção entre alimento e medicamento. No Brasil, vários trabalhos focando a atividade biológica das plantas vêm sendo desenvolvidos nas últimas décadas. Este trabalho teve como objetivo registrar a alteração alimentar ao longo do tempo, relatada pelos entrevistados da aldeia Guarani Tenondé Porã, bem como observar suas percepções a respeito desta alteração e sua influência na saúde. Para tanto, foram utilizados técnicas e métodos da etnografia como diários de campo, entrevistas informais, não-estruturadas e observação participante. Foram entrevistados 15 indígenas que relataram alterações na forma de obtenção dos alimentos, o que levou a substituições e, até mesmo, ao abandono de alguns espécimes vegetais, bem como a incorporação de novos alimentos e alterações nas receitas. Algumas plantas mantiveram seu uso, principalmente aquelas utilizadas em contextos rituais. Seu uso crônico, bem como os benefícios à saúde que promovem, incluindo a prevenção e/ou tratamento de doenças, sugerem sua equivalência aos alimentos nutracêuticos. O milho (Zea mays L. ssp.), o tabaco (Nicotiana spp. L.) e a erva-mate (Ilex paraguariensis St. Hil.), são alguns exemplos e foram destacados no estudo pois são considerados pelos indígenas como os alimentos, tanto para o corpo quanto para a alma, mais importantes nessa aldeia. As doenças também são divididas naquelas do corpo e da alma pelos indígenas. Segundo relatos dos indígenas, ambos tipos de doenças têm aumentado a sua freqüência ao longo do tempo devido a vários fatores, sempre ligados ao abandono de certas tradições do Povo Guarani, tais como: alteração alimentar, que envolve tanto à perda quanto a inserção do uso de novos alimentos e a alteração na forma de preparo; falta de obediência a Nhanderu (“Deus” dos Guarani) e finalmente, a falta de espaço adequado para as atividades diárias como o cultivo e a caça, que acabam promovendo o sedentarismo. / The food has suffered a series of changes both in the form of taking, the food preparation. This process affects the indigenous communities, and brings as a consequence, nutritional deficiencies and cultural changes. Many cultures do not distinguish between food and medicine. In Brazil, several studies focusing on the biological activity of the plants have been developed in recent decades. This study aimed to register the change food over time, reported by respondents from village Guarani Tenondé Porã, and to observe their perceptions regarding this change and its influence on health. We used techniques and methods of ethnography and field diaries, informal interviews, unstructured and participant observation. We interviewed 15 Indians who reported changes in the way of obtaining food, which led to replacements, and even abandonment of some plant specimens, and the incorporation of new foods and changes in revenue. Some plants maintained its use, especially those used in ritual contexts. Its chronic use as well as the health benefits they advertise, including the prevention or treatment of diseases, suggesting their equivalence to food nutraceuticals. Corn (Zea mays L. ssp.), Tobacco (Nicotiana spp. L.) and yerba mate (Ilex paraguariensis St. Hil.) Are some examples and were highlighted in the study because they are considered by the natives as food, for both the body and the soul, the most important in this village. The diseases are also divided into those of body and soul by indigenous people. According to reports of the natives, both types of diseases have increased its frequency over time due to several factors, always linked to the abandonment of certain traditions of the Guarani people, such as changing food, which involves both the loss as the insertion of use new food and change in the way of preparation, lack of obedience to Nhanderu ("God" in Guarani) and finally, lack of adequate space for daily activities as farming and hunting, you end up promoting a sedentary lifestyle. / TEDE / BV UNIFESP: Teses e dissertações