Der Hippocampus ist eine von zwei Gehirnregionen, in der zeitlebens kontinuierlich neue Nervenzellen gebildet werden. Er spielt eine wichtige Rolle bei der Gedächtniskonsolidierung und wird mit der funktionellen Entstehung neurodegenerativer Erkrankungen in Verbindung gebracht. Strukturveränderungen im erwachsenen Gehirn, die mit einer Depression einhergehen, sind laut Literatur auf einen geringen Serotoninspiegel und reduzierte hippocampale Neurogenese zurückzuführen. Selektive Serotonin-Wiederaufnahmehemmer (SSRI) erhöhen die Serotoninkonzentration im synaptischen Spalt und üben einen positiven Effekt auf die adulte Neurogenese aus. In der vorliegenden Arbeit wird untersucht, wie Veränderungen in der Serotonin (5-HT)-Neurotransmission durch einmalige oder chronische Gaben von Fluoxetin und speziellen Agonisten und Antagonisten für die Serotoninrezeptoren 5-HT1a und 5-HT2 in der erwachsenen Maus die Proliferation und Differenzierung von neugebildeten Nervenzellen im Gyrus dentatus beeinflussen. Die Ergebnisse zeigen, dass ein konträres Agieren beider Rezeptoren zu einem ausgewogenen Serotoninspiegel führt. 5-HT1a- und 5-HT2c-Rezeptoren haben einen Einfluss auf das Überleben neugebildeter Nervenzellen, wobei sie unterschiedliche Entwicklungsstadien innerhalb der adulten Neurogenese kontrollieren. Die vorliegende Arbeit bekräftigt außerdem, dass die chronische Gabe von Fluoxetin die adulte Neurogenese steigert. / The hippocampus as one region with ongoing neurogenesis throughout life contributes to the formation of long-term memory and has also been implicated in the pathology of major depression. Studies suggest that depression might be due to decreased levels of serotonin and reduced neurogenesis in the adult brain and that the beneficial effects of selective serotonin reuptake inhibitors would require adult hippocampal neurogenesis. Here, I investigated how modulation of serotonergic neurotransmission by acute and chronic treatment with the antidepressant fluoxetine, and selective serotonin receptor agonists and antagonists in adult mice influences precursor cell activity during development. I focused on 5-HT1a and 5-HT2 receptors as major mediators of serotonin action. The present findings suggest that an opposed action of 5-HT1a and 5-HT2c receptor subtypes result in a balanced regulation of serotonin levels in the dentate gyrus. Both receptors differentially affect intermediate cell stages in adult hippocampal neurogenesis and play an important role in the survival of newly generated neurons. Furthermore, this study confirms that chronic fluoxetine treatment increases adult neurogenesis. In conclusion, the latency of onset of fluoxetine action can be explained by a balanced interplay of 5-HT1a and 5-HT2c receptor subtypes.

O uso acentuado de fármacos e produtos de cuidado pessoal (FPCP) por grande parcela da população, associado ao aumento do número de habitantes, principalmente, em regiões costeiras, gera uma consequente e contínua entrada destas substâncias no ambiente. Com isso há uma necessidade crescente de se investigar a presença e o comportamento desta classe de contaminantes, principalmente em sedimentos, uma vez que estes são capazes de acumular e apresentar concentrações relativamente perigosas a organismos não-alvos. Assim, este estudo teve como objetivo avaliar o risco ambiental do fármaco fluoxetina (FLU) presente em sedimentos marinhos da região de Santos/SP, Brasil, por meio de ensaios ecotoxicológicos integrados à análises químicas para quantificação deste fármaco no ambiente marinho. Para tanto foram utilizados invertebrados marinhos, espécie Mytella charruana para a caracterização de citotoxicidade e atividade de biomarcadores, e as espécies Perna perna e Echinometra lucunter em ensaios de desenvolvimento embriolarval. Todos os orgismos-teste foram expostos à sedimentos marinhos previamente marcados com FLU. Por meio de técnicas de HPLC-ESI-MS/MS, foram identificadas e quantificadas concentrações da ordem de 10,4 ng.g-1 em sedimentos coletados no entorno do emissário submarino de esgoto de Santos (Baía de Santos, São Paulo - Brasil). A FLU apresentou efeitos sobre o desenvolvimento embriolarval de E. lucunter e P. perna e efeitos cito-genotóxicos para a espécie M. charruana, em concentrações ambientalmente relevantes. Segundo o método utilizado para avaliação de risco ambiental, a fluoxetina pode ser considerada como substância potencialmente perigosa para invertebrados aquáticos. / The high consumption of pharmaceutical and personal care products (PPCP) by a significant part of the human population, associated with the increase in the number of inhabitants, mainly in coastal regions, causes a continuous entry of these substances into the environment. Thus, there is a growing need to investigate the presence and behavior of this class of contaminants, especially in sediments, since they can accumulate and create relatively hazardous concentrations to non-target organisms. Therefore, the objective of this study was to evaluate the environmental risk of fluoxetine (FLU) present in marine sediments from the region of Santos/SP, Brazil, using ecotoxicological assays with chemical analyses so the amount of this pharmaceutical drug in the marine environment could be quantified. For this purpose, the marine invertebrates Mytella charruana species were used for the characterization of citotoxicity and endpoints using biomarkers, and the species Perna perna and Echinometra lucunter in embryo larval tests. All organisms used in the experiments were exposed to marine sediments previously spiked with known concentrations of FLU. Using LC-ESI-MS/MS, the environmental levels of FLU were quantified in marine sediments from the vicinities of the Santos submarine sewage outfall (Bay of Santos, São Paulo, Brazil) at 10.4ng.g-1. The fluoxetine has presented effects over the embryo larval development of E. lucunter and P. perna as such genotoxic and citotoxic effects for the M. charruana species at environmentally relevant concentrations. According to the employed ERA method, fluoxetine can be considered as a pontencially dangerous substance for acquatic invertebrates.

O desenvolvimento de síndrome metabólica como decorrência do uso de psicofármacos vem recebendo grande atenção da literatura nos últimos anos. O uso de antipsicóticos atípicos foi fortemente associado a ganho de peso, desenvolvimento de diabetes tipo 2 e aumento da mortalidade em pacientes esquizofrênicos. Já o uso de antidepressivos, embora associado a alterações de peso, não foi suficientemente estudado quanto ao risco de desenvolvimento de síndrome metabólica. Este estudo objetivou investigar alterações do peso corporal e de parâmetros relacionados à síndrome metabólica em pacientes com transtorno de pânico tratados com clomipramina, fluoxetina ou placebo. Foi realizado um estudo randomizado, duplo-cego e controlado com 83 pacientes seguidos ao longo de 24 semanas. Foram obtidas medidas de peso, relação cintura-quadril, glicemia, e níveis séricos de colesterol total, HDL e LDL colesteróis e triglicérides. Os resultados deste estudo permitiram concluir que, no tratamento do transtorno de pânico, não foram observadas alterações significativas de peso ou dos parâmetros bioquímicos associados à síndrome metabólica / The development of metabolic syndrome as a result of psychopharmacological treatment has been a highlight in medical literature on recent years. Atypical antipsychotics have been strongly associated with weight gain, type 2 diabetes and elevated mortality rates in schizophrenic patients. Although related to weight gain, antidepressants have not been as well studied concerning the risk of metabolic syndrome development. The objective of this study was to investigate changes in weight and in parameters associated with the metabolic syndrome in patients with panic disorder treated with clomipramine, fluoxetine or placebo. We conducted a randomized, double-blind, controlled study with 83 patients during 24 weeks. Measures were obtained for weight, waist-hip rate, glicemia and serum levels of total, HDL and LDL cholesterols, and triglycerides. The results of this study allowed the conclusion that, in the treatment of panic disorder, changes on weight or on the biochemical parameters related to metabolic syndrome were not significant

Estudos prévios avaliando domínios neuropsicológicos, especialmente funções executivas, indicam a presença de déficits em portadores do Transtorno Obsessivo Compulsivo (TOC). No entanto, achados neste sentido são muitas vezes contraditórios. Estas divergências podem, em parte, ser explicadas a partir de limitações metodológicas como pareamento inadequado de pacientes e controles e o uso de medicamentos no momento da avaliação neuropsicológica. Este estudo teve os seguintes objetivos: 1) verificar o funcionamento neuropsicológico, especialmente das funções executivas, de pacientes portadores de TOC sem tratamento prévio comparados a controles normais; 2) identificar fatores neuropsicológicos preditivos de resposta a tratamento com terapia cognitivo-comportamental em grupo (TCCG) ou fluoxetina. Pacientes portadores de TOC (n=50) foram pareados com controles saudáveis (n=35) por gênero, idade, escolaridade, nível socioeconômico e lateralidade manual. Estes foram avaliados a partir de uma bateria neuropsicológica investigando: quociente intelectual, funções executivas, memória verbal e não verbal, habilidades sociais e funções motoras. Os pacientes portadores de TOC foram alocados em dois subgrupos: 26 foram submetidos a tratamento medicamentoso com fluoxetina e 24 foram submetidos a um protocolo de TCCG por 12 semanas. Encontramos déficits nos pacientes portadores de TOC quando comparados a controles saudáveis quanto à flexibilidade cognitiva (segundo teste de Hayling), funções motoras (pelo teste de Grooved pegboard) e habilidades sociais (pelo inventário de Del Prette). Algumas medidas neuropsicológicas foram preditivas de melhor resposta a ambos os tratamentos: maior número de respostas corretas no teste do California verbal learning test (CVLT) (Trials 1-5); maior rapidez na parte D 14 (Dots) do Victoria stroop test (VST); maior lentidão na parte W (Word) no VST e menor número de erros na parte C (Colors) do VST (principalmente à TCCG). Maior quociente intelectual (QI) verbal se associou com melhor resposta à TCCG. Menor número de respostas perseverativas no CVLT se associou com melhor resposta à TCCG e pior resposta à medicação. Concluindo, neste estudo portadores de TOC apresentaram déficits na flexibilidade mental, habilidades sociais e funções motoras. Medidas neuropsicológicas como QI verbal, memória verbal e controle inibitório foram preditivas de resposta ao tratamento. Padrões específicos das habilidades verbais e perserveração se associaram de forma diferenciada á resposta a TCCG ou à fluoxetina. Assim, a avaliação neuropsicológica, pode auxiliar não só na indicação do melhor tratamento, mas também alertar o clínico para aqueles pacientes com maiores chances de não resposta ao tratamento de primeira escolha, nos quais medidas adicionais devem ser associadas. / Previous studies assessing neuropsychological domains, especially executive functions, indicate the presence of deficits in patients with Obsessive Compulsive Disorder (OCD). However, findings in this sense are often contradictory. These discrepancies may partly be explained by methodological limitations such as inadequate matching of patients and controls and use of medication at the time of neuropsychological assessment. This study had two aims: 1) to assess the neuropsychological functioning, especially in executive functions in OCD patients without prior treatment compared with healthy controls and 2) to identify neuropsychological predictors of response to treatment with fluoxetine or cognitivebehavioral therapy in group (CBTG). Patients with OCD (n=50) were matched with healthy controls (n=35) by gender, age, education, socioeconomic status and handedness. Patients and controls were evaluated with a neuropsychological battery investigating: intellectual quotient (IQ), executive functions, motor functions, verbal memory and non-verbal, social skills and motor function. OCD patients were allocated into two subgroups: 24 were submitted to GCBT for 12 weeks and 26 underwent treatment with fluoxetine. We found deficits in OCD patients compared to healthy controls in cognitive flexibility (Hayling test), motor functions (Grooved pegboard test) and social skills (inventory of Del Prette). Some neuropsychological measures were predictive of a better response to both treatments: greater number of correct answers on the California verbal learning test (CVLT) (Trials 1-5); greater speed on board D (Dots) of the Victoria stroop test (VST); greater slowness on board W (Word) of VST and fewer errors on the board C (Colors) of VST (primarily in TCCG). Greater verbal IQ was associated with better response to CBTG. Fewer perseveration answers in the 17 CVLT was associated with better response to CBTG and worse response to fluoxetine. In conclusion, patients with OCD showed deficits in cognitive flexibility, social skills and motor functions compared to healthy controls. Neuropsychological measures such as verbal IQ, verbal memory and inhibitory control were predictive of treatment response. Specific patterns of verbal abilities and mental flexibility predicted different treatment response to GCBT or fluoxetine. Thus, neuropsychological assessment may provide important information for treatment choice in clinical settings and may alert clinicians to those patients that are most likely non-responders, in whom additional treatment modalities should be implemented.

Até o momento, são escassos os estudos que se propuseram a investigar o funcionamento cognitivo das crianças e adolescentes com Transtorno Obsessivo-Compulsivo (TOC). Os estudos disponíveis apontam que essa população apresenta pior desempenho nos testes neuropsicológicos que avaliam as funções executivas, a memória não-verbal, o funcionamento visuoespacial e a velocidade de processamento, em comparação aos sujeitos saudáveis. Mesmo com esses achados, poucos autores averiguaram a influência dos tratamentos de primeira linha para o TOC [Terapia Cognitivo- Comportamental (TCC) e inibidores de recaptura de serotonina (IRS)] na cognição. Vale ressaltar que tais estudos expressam resultados divergentes, não havendo um consenso sobre a melhora ou manutenção dos déficits no desempenho dos jovens após o tratamento. Diante deste contexto, o presente estudo teve como objetivos: A) Comparar as características sociodemográficas e clínicas e o funcionamento cognitivo de uma amostra pediátrica com TOC e sujeitos saudáveis; B) Verificar as modificações no funcionamento cognitivo do grupo TOC após 14 semanas de tratamento farmacológico ou psicoterápico. Para isso, foram avaliados 82 crianças e adolescentes com TOC e 82 controles saudáveis, com idades entre 6-17 anos, com questionários para avaliação de sintomas psiquiátricos e uma bateria de testes neuropsicológicos. Todos os participantes do estudo foram submetidos às avaliações na linha de base. Os pacientes, após randomização para TCC em grupo ou fluoxetina (FLX), foram reavaliados findadas 14 semanas de tratamento. A análise dos dados indicou que os pacientes apresentam desempenho cognitivo global pior que os controles, havendo diferenças significativas no QI de execução, nas habilidades visuoconstrutivas, na memória episódica não verbal e na flexibilidade mental. Variáveis clínicas, como idade de início dos sintomas, gravidade dos sintomas do TOC, dimensões dos sintomas obsessivo-compulsivos e comorbidades, não correlacionaram com o pior desempenho dos pacientes nos diferentes testes neuropsicológicos. Após 14 semanas de tratamento, embora os pacientes tenham apresentado melhora clínica dos sintomas obsessivo-compulsivos, o mesmo não ocorreu com as diferentes funções neuropsicológicas, mesmo naquelas que estavam prejudicadas na linha de base. De acordo com os resultados do presente estudo, as crianças e adolescentes com TOC apresentam pior desempenho cognitivo global em provas neuropsicológicas quando comparados aos controles saudáveis. O fato da melhora dos sintomas não ser acompanhada da melhora do desempenho neuropsicológico dos pacientes, sugere que as alterações cognitivas observadas no grupo TOC sejam relacionadas à própria neurobiologia do transtorno, independentemente da gravidade dos sintomas. Futuros estudos longitudinais serão necessários para aumentar a compreensão do funcionamento cognitivo dos jovens com TOC e as implicações do tratamento na sua cognição no longo prazo / To date, only a few studies have investigated the cognitive functioning of children and adolescents with Obsessive-Compulsive Disorder (OCD). These studies indicate that youth with OCD present a worse performance in neurocognitive tests that assess the executive functions, nonverbal memory, visuospatial functioning and processing speed. Despite these findings, only a few authors have investigated the influence of Cognitive-Behavioral Therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs) on the cognition of youth with OCD. It is worth noting that these studies express divergent results, and there is no consensus on the improvement or maintenance of the cognitive deficits after treatment. In this context, the present study aimed: A) To compare the sociodemographic/ clinical characteristics and the cognitive functioning of youth with OCD and healthy controls; B) To verify the changes in cognitive functioning of children and adolescents with OCD after 14 weeks of randomized pharmacological or cognitive-behavioral treatment. Eighty-two children and adolescents with OCD and 82 healthy controls, aged between 6 and 17 years, were evaluated by means of structured questionnaires and a battery of neuropsychological tests. All participants underwent assessments at baseline. The OCD group, after being randomized to group CBT or Fluoxetine (FLX), was re-evaluated after 14 weeks of treatment. Data analyses indicated that patients presented a worse cognitive performance when compared to the healthy controls, with significant differences in performance IQ, visuoconstructive skills, nonverbal memory, and mental flexibility. Clinical variables, such as age of onset, severity of OCD symptoms, OCD dimensions and comorbidities, did not correlate with poorer performance on neuropsychological tests. Although patients had clinical improvement after 14 weeks of treatment, the same did not occur with the cognitive performance, even in those functions which were impaired at baseline. According to the results of the present study, youth with OCD present a worse cognitive performance when compared to controls. The fact that the improvement of the symptoms is not followed by the improvement of the neuropsychological performance suggests that the cognitive deficits observed in the OCD group may be related to the neurobiology of the disorder, regardless of the symptom severity. Future longitudinal studies will be needed to further clarify the cognitive functioning of youth with OCD and the implications of treatment on their cognition in the long run

O uso de fármacos durante a lactação é uma prática comum; porém, os tratamentos farmacológicos impõem grandes dúvidas tanto aos profissionais quanto às nutrizes sobre a segurança do uso destes durante este período. A amamentação é uma forma de vínculo entre mãe e bebê e está associada a diversos benefícios nutricionais, imunológicos, cognitivos, psicoafetivos, econômicos e sociais. A depressão é um problema clínico importante durante o período pós-parto, e a vulnerabilidade para o início ou recorrência de sintomas depressivos aumenta a possibilidade de uso de psicofármacos enquanto ocorre a lactação. Os antidepressivos inibidores seletivos da recaptação da serotonina são comumente prescritos para o tratamento destes quadros depressivos, entre eles fluoxetina, sertralina, citalopram e paroxetina, sendo que a maioria destes é excretada no leite materno e há grande variabilidade na quantidade de analitos que pode ser recebida pelo lactente. Bupropiona é um fármaco antidepressivo utilizado para o tratamento do tabagismo e quadros depressivos e tem sua excreção ao leite materno relatada em literatura. Métodos bioanalíticos para determinação da excreção de fármacos antidepressivos foram desenvolvidos e validados por cromatografia líquida acoplada a espectrômetro de massas e cromatografia líquida com detecção ultravioleta. Estes métodos demonstraram serem seletivos, lineares, precisos e exatos, com limites de quantificação de 5 ng/mL (fluoxetina, citalopram e bupropiona) e 20 ng/mL (sertralina e paroxetina) para método por LC-MS e de 200 ng/mL para todos os analitos no método por CLAE-UV. As amostras de leite materno foram coletadas em Banco de Leite de mães que declararam utilizar fluoxetina ou sertralina ou paroxetina e analisados. Os dados de concentração encontrados para os fármacos referidos estão dentro da faixa encontrada em literatura confirmando sua excreção no leite materno. Paroxetina apresentou valores abaixo do limite de quantificação. Das concentrações encontradas no leite materno, foram estimadas as doses absolutas e relativas no lactante, sendo que os resultados demonstraram baixos valores em relação a estas estimativas, podendo os fármacos analisados ser considerados seguros para manutenção do uso durante a lactação. Foi também detectada nas análises por LC-MS a presença de norfluoxetina, metabólito da fluoxetina, confirmando sua excreção nesta matriz. / The use of medications during lactation is a common practice; however pharmacological treatments impose serious doubts to both, professionals and nursing mothers, about the safety of drugs use during this period. Breastfeeding is a natural form of bonding between mother and baby and it is associated with many nutritional, immunological, cognitive, psychoemotional, social and economic benefits. Depression is a major clinical problem during the postpartum period and the vulnerability to onset or recurrence of depressive symptoms increases the possibility of psychotropic drug use during lactation. Selective inhibitors of serotonin reuptake are commonly prescribed for the treatment of depressive disorders, including fluoxetine, sertraline, citalopram and paroxetine. Most of these drugs are excreted in breast milk and there is great variability in the amount of analytes that can be received by the infant. Bupropion is an antidepressant used for tabagism treatment and for depression symptoms; it is also described in literature its excretion into breast milk. Bioanalytical methods for determining the excretion of antidepressants were developed and validated by liquid chromatography coupled to mass spectrometry and liquid chromatography with ultraviolet detection. These methods proved to be selective, linear, precise and accurate with quantification limits of 5 ng/mL (fluoxetine, citalopram e bupropion) and 20 ng/mL (sertraline e paroxetine) for LC-MS method and 200 ng/mL for all analytes in the CLAE-UV method. Human milk samples were collected in milk banks from mothers to which the antidepressants fluoxetine or sertraline or paroxetine were administered, and the concentrations in this matrix were verified. Found concentrations were within the range described in the literature confirming their excretion in the breast milk. Paroxetine presented values less than limit of quantification. From the found concentrations, the absolute and relative doses in nursing were estimated. The results showed low values for these estimates and so the analyzed drugs can be considered safe to continue use during lactation. The presence of norfluoxetine, a metabolite of fluoxetine, was also detected by LC-MS, confirming its excretion in this matrix.

In humans and other organisms, monoaminergic systems are crucial in neuronal function and behavior. The monoamine transporters (MATs), which can be found on the presynaptic plasma membrane of neurons in the central nervous system (CNS), are crucial in the regulation of neurotransmitter concentration in the synaptic cleft. As the duration and concentration of neurotransmitters in the cleft affect further downstream signaling responses, these proteins are important targets for both understanding neuronal physiology and compounds of interest. Multiple theories exist proponing the contribution of MATs to a variety of mental and neurological disorders, including depression. This theory establishes that depression is caused by imbalances in monoamine neurotransmitters. Compounds such as Fluoxetine (FLX) are classified as selective serotonin reuptake inhibitors (SSRIs), these drugs selectively block the reuptake of neurotransmitters at the serotonin transporter (SERT). Since differences in MAT selectivity of inhibitory compounds are influential to selecting efficacious antidepressant treatments, we utilized a unique fluorescent analysis technique to explore three therapeutic compounds of interest (in-vitro) which contain structural similarity to FLX. Our results confirm the selectivity of FLX at SERT, and classify the novel compounds studied into different potential categories of reuptake inhibitors. We hope these compounds will be studied further to elucidate their potentially therapeutic roles and mitigation of undesired side effects seen in other medications.

La maladie de Parkinson (MP) se caractérise par une dégénérescence progressive et irréversible des neurones dopaminergiques de la substance noire induisant une perte de dopamine (DA) dans les structures cibles. Lorsque cette perte DA se situe entre 60 % et 80 %, les patients présentent des symptômes moteurs (rigidité, tremblement, akinésie) et non-moteurs très variés (dépression, anxiété, apathie). Ces derniers apparaissent avant et/ou en même temps que les symptômes moteurs. La dopathérapie permet de contrecarrer certains symptômes, mais tous ne sont pas sensibles à cette médication. Parallèlement à la dégénérescence DA, le système sérotoninergique (5-HT) serait aussi altéré de façon précoce dans la maladie. Cette dégénérescence est liée par l’expression de symptômes moteurs et non-moteurs. Néanmoins, aucun lien causal n’a été mis en évidence entre cette lésion 5-HT et la symptomatologie parkinsonienne. Ainsi, il était primordial de déterminer le rôle de la 5-HT dans 1) l’expression des troubles moteurs et non-moteurs 2) dans la réponse au traitement sérotoninergique et dopaminergique. Nous avons utilisé un nouveau modèle animal primate ayant une lésion 5-HT (via la MDMA) puis une lésion DA (via le MPTP). Ce modèle nous permet de mettre en évidence l’impact d’une lésion 5-HT précoce dans la symptomatologie. Des approches comportementales, pharmacologiques, d’imagerie et de neuroanatomie ont été utilisées. La lésion 5-HT a induit un trouble anxieux chez les animaux lésés à la MDMA, qui ne sont pas contrecarrer avec un traitement sérotoninergique (antidépresseur). Cette lésion a également induit une sévérité et une progression plus rapide des symptômes moteurs induits par la lésion DA / Parkinson’s disease (PD) is characterized by a progressive and irreversible degeneration of dopaminergic (DA) neurons localized in the substantia nigra, leading to a loss of dopamine within the target structures. When the loss of DA reaches 60 to 80 %, PD patients develop a wide range of motor (rigidity, tremor, akinesia fro example) and non-motor (depression, anxiety, apathy for example) symptoms. Dopatherapy allows the reduction of symptoms expression. But some motor and non-motor symptoms are not counteracted by those DA drugs. In addition to DA degeneration, patients present an early serotonergic (5-HT) lesion. This lesion is linked to the severity of some motor and non-motor symptoms. However, there is no causal link established between 5-HT lesion and parkinsonian symptoms. Therefore, it was essential to determine the role of 5-HT 1) in the expression of motor and non-motor symptoms 2) and in the response of DA and 5-HT treatments. For that, we used a new monkey model of PD, exhibiting a 5-HT lesion (with MDMA ‘”ecstasy”)) followed by a DA lesion (with MPTP). This model allowed us to evaluate the impact of an early 5-HT lesion on parkinsonian symptoms. We used different approaches: PET imaging, pharmacology, behavioral and neuroanatomy. The MDMA-driven early 5-HT lesion induced an anxious-like behavior on MDMA treatedmonkeys. This behavioral modification was not counteracted by 5-HT drugs (antidepressant). This MDMA lesion has also increased the severity and the progression of parkinsonian symptoms induced by DA lesion with MPTP

Passive exposure of children to drugs is common, but difficult to ascertain as direct studies are in many cases not possible, and currently available indirect measures of drug exposure, such as maternal reports, are likely to be inaccurate. Novel, indirect methods to evaluate drug exposure in the uterus and early life are needed, and may provide risk estimates that can be later correlated with clinical outcomes. In the studies presented here, I have applied novel methods such as measurement of hair drug concentrations and population pharmacokinetics modeling and simulation to evaluate fetal and infant exposure to drugs and potential associated risks. Testing for methamphetamine allowed demonstration, for the first time, that it freely crosses the human placenta. In contrast, analysis of paired maternal–infant hair showed limited cocaine placental transfer, in agreement with animal models. Results of hair tests from children found in marihuana grow houses and other drug operations showed that passive exposure tends to be higher in infants, likely due to higher dependence on, and proximity to care givers. We also demonstrated the importance of measuring drug metabolites to distinguish between systemic exposure to MDMA and simple external hair contamination secondary to drug present in the home environment. Finally, we developed a population pharmacokinetics and simulation approach to accurately estimate drug excretion into breast milk. This novel technique was applied to fluoxetine and to nifurtimox. Use of our approach allowed us to define, for the first time, the limited extent to which fluoxetine and nifurtimox would be expected to cross into breast milk and estimate potential degree of exposure of breastfed infants. In summary, results presented here support the value of these novel methods for the evaluation of fetal and infant drug exposure and suggest a promising value in estimating risks to children passively exposed to drugs.

Passive exposure of children to drugs is common, but difficult to ascertain as direct studies are in many cases not possible, and currently available indirect measures of drug exposure, such as maternal reports, are likely to be inaccurate. Novel, indirect methods to evaluate drug exposure in the uterus and early life are needed, and may provide risk estimates that can be later correlated with clinical outcomes. In the studies presented here, I have applied novel methods such as measurement of hair drug concentrations and population pharmacokinetics modeling and simulation to evaluate fetal and infant exposure to drugs and potential associated risks. Testing for methamphetamine allowed demonstration, for the first time, that it freely crosses the human placenta. In contrast, analysis of paired maternal–infant hair showed limited cocaine placental transfer, in agreement with animal models. Results of hair tests from children found in marihuana grow houses and other drug operations showed that passive exposure tends to be higher in infants, likely due to higher dependence on, and proximity to care givers. We also demonstrated the importance of measuring drug metabolites to distinguish between systemic exposure to MDMA and simple external hair contamination secondary to drug present in the home environment. Finally, we developed a population pharmacokinetics and simulation approach to accurately estimate drug excretion into breast milk. This novel technique was applied to fluoxetine and to nifurtimox. Use of our approach allowed us to define, for the first time, the limited extent to which fluoxetine and nifurtimox would be expected to cross into breast milk and estimate potential degree of exposure of breastfed infants. In summary, results presented here support the value of these novel methods for the evaluation of fetal and infant drug exposure and suggest a promising value in estimating risks to children passively exposed to drugs.