INTRODUÇÃO: Entre os tratamentos existentes para o transtorno obsessivocompulsivo (TOC) os mais eficazes são o farmacológico, com inibidores de recaptura de serotonina (IRS; inibidores seletivos de recaptura de serotonina [ISRS] e clomipramina), e o comportamental, baseado na técnica de exposição com prevenção de resposta (EPR). Ambas apresentam eficácia semelhante para os sintomas obsessivo-compulsivos e estudos demonstram que a EPR produz modificações neurobiológicas semelhantes às provocadas pelo tratamento com ISRS. Essas evidências sugerem que a resposta clínica à EPR está diretamente relacionada a um aumento da biodisponibilidade de 5HT no cérebro. A concentração de 5HT no sangue periférico é uma medida representativa do sistema serotonérgico central, e é utilizada como um marcador biológico indireto. O objetivo deste estudo foi comparar a concentração serotonérgica (basal e variação em 8 semanas) e a resposta à terapia comportamental baseada em EPR. MÉTODOS: Foram incluídos nesse estudo 30 pacientes com diagnóstico operacional de TOC. Destes, 29 iniciaram o tratamento, 27 chegaram até a quarta semana e 24 completaram o protocolo padronizado com 16 sessões (8 semanas) de terapia. As dosagens de 5-HT foram feitas nas semanas 0 e 8 e as avaliações clínicas pelas escalas Y-BOCS e CGI, bem como medidas de sintomas secundários (depressão, ansiedade e incapacidade) nas semanas 0, 4 e 8. RESULTADOS: Encontrou-se correlação positiva entre a concentração basal de 5HT e a resposta clínica em quatro semanas de EPR (p<0,05).Observouse maior concentração basal e maior redução em 8 semanas nos níveis de 5HT em pacientes respondedores comparados aos não respondedores. Entretanto não houve significância estatística. CONCLUSÃO: Na amostra estudada os dados sugerem que a alta concentração basal de 5-HT é um marcador biológico preditor de boa resposta clínica a quatro semanas de EPR. Amostras maiores talvez mostrassem a concentração de 5-HT no plasma rico em plaquetas como um preditor de resposta a 8 semanas de EPR. Protocolos com amostras maiores e com grupos controle são necessários para confirmar esses achados / INTRODUCTION: Both gold standard treatments for obsessive-compulsive disorder (pharmacotherapy with serotonin reuptake inhibitors, and behavioral with exposure and response prevention [ERP]) are equally effective. Studies have demonstrated similar neurobiological changes elicited by these different treatments in OCD patients. These findings are suggestive that the clinical response to ERP is directly related to an increase of the 5-HT concentration in the brain. The platelet 5-HT concentration have been shown as a representative measure of central serotonergic system and used as a biological marker of the synaptic transmition. OBJECTIVE: To compare the platelet 5-HT concentration (basal and variation in 8 weeks) and the clinical response to ERP treatment. METHODS: 30 OCD patients were included and 29 started the treatment. 27 patients compleated at list 4 weeks and 24 completed all 8 weeks (16 sesions) ERP protocol. Patients had the basal and final (after 8 weeks) platelet 5-HT concentrations dosed and the clinical response measured by Y-BOCS, CGI and measures of secondary symptoms as well (depression, anxiety and disability). RESULTS: Data shows a positive correlation between the basal concentration of 5-HT and the 4 week ERP response (p<0,05). There were higher basal concentration and reduction in 8 weeks of platelet 5-HT concentration in the responders group compared with non-responders. Nevertheless, this differences was not significant (p>0,05). CONCLUSION: In the studied sample data suggest that high basal 5-HT platelet concentration is a biologic predictor of fast onset (4 weeks) of clinical response to ERP. Probably larger samples would show the basal 5-HT platelet concentration as a predictor of 8 weeks ERP outcome. Controlled trials are needed to confirm these findings

La maladie de Parkinson (MP) est caractérisée par une dégénérescence progressive et irréversible des neurones dopaminergiques (DA) de la substance noire. Lorsque la perte DA atteint 60 à 80%, les patients vont développer des symptômes. Les traitements DA permettent de contrecarrer l'expression de ces symptômes mais induisent également à long terme l'apparition de complications invalidantes. De plus les patients développent également des symptômes non- moteurs pouvant émerger avant, pendant ou après l'apparition des symptômes moteurs. Parallèlement à la dégénérescence DA, les patients parkinsoniens présentent des altérations du système sérotoninergique (5-HT) qui ont été mises en évidence en post-mortem et plus récemment par imagerie par tomographie à émission de positons (TEP). Des corrélations ont également été démontrées entre l'altération du système 5-HT et la sévérité de certains symptômes parkinsoniens. Cependant, à ce jour, aucune étude n'a mis en évidence de lien causal direct entre l'altération 5-HT et l'expression des symptômes parkinsoniens. Il était donc crucial de clarifier le rôle exact de la 5-HT dans le développement des symptômes parkinsoniens ainsi que dans la réponse aux traitements dopaminergiques. Dans ce contexte, nous avons développé un nouveau modèle de la MP. Ce modèle nous a permis d'étudier l'impact de la lésion 5-HT sur la symptomatologie parkinsonienne. Ce travail a permis de démontrer l'implication du système sérotoninergique dans l'expression de la rigidité parkinsonienne. Par ailleurs, ce travail a également permis de démontrer le rôle causal des fibres 5-HT dans le développement de complications induites par un traitement chronique à la L- DOPA / Parkinson's disease (PD) is characterized by a progressive and irreversible degeneration of dopaminergic (DA) neurons localized in the substantia nigra, leading to the loss of dopamine within the target structures (mainly the striatum). When the DA loss reaches 60 to 80%, PD patients develop motor symptoms (rigidity, tremor, akinesia/bradykinesia). DA treatments allow counteracting symptoms expression but also induce after a certain time the appearance of disabling complications. Moreover, patients also develop non-motor symptoms that can emerge before, during or after the appearance of motor symptoms. ln addition to DA degeneration, PD patients present serotoninergic (5-HT) alteration evidenced in post-mortem and more recently by position emission tomography (PET) imaging. Correlations have been shown between the 5-HT alteration and the severity of some motor and non-motor symptoms as well as L-DOPA-induced dyskinesia. However, to date, none study evidenced a direct causal link between the 5-HT alteration and the expression of parkinsonian symptoms. lt was crucial to clarify the exact role of 5-HT in the development of parkinsonian symptoms. ln this context, we have developed a new model of PD. This model has allowed studying the impact of the 5-HT lesion on the parkinsonian symptomatology. We have evidenced the involvement of the 5-HT system in the expression of parkinsonian rigidity. Moreover, we have demonstrated the causal role of the 5-HT fibers in the development of complications induced by the L-DOPA treatment

Estudos com microinjeções de drogas vêm sendo realizados na tentativa de se compreender a participação da neurotransmissão serotonérgica do hipocampo na modulação de comportamentos defensivos relacionados à ansiedade. Nesse sentido, observou-se que a ativação dos receptores do tipo 5-HT1A do hipocampo dorsal (HD) promoveu efeito do tipo ansiogênico sobre a resposta de esquiva inibitória, sem alterar a resposta de fuga, em ratos submetidos ao labirinto em T elevado (LTE). Essa alteração seletiva na resposta de esquiva inibitória sustenta a hipótese da participação do hipocampo na fisiopatologia do transtorno de ansiedade generalizada, uma vez que, as respostas defensivas de esquiva inibitória e fuga, expressas no LTE, têm sido relacionadas respectivamente ao transtorno de ansiedade generalizada e ao transtorno do pânico. Além de receptores do tipo 5- HT1A, destaca-se no HD a presença de receptores do tipo 5-HT2C. Tem sido observado que a estimulação desses últimos em áreas límbicas associadas à ansiedade, como a amígdala, promove efeito do tipo ansiogênico em diferentes modelos animais de ansiedade. Porém, ainda é desconhecida a participação desses receptores presentes no HD sobre as resposta de esquiva inibitória e fuga, geradas no LTE. Assim, o presente estudo procurou avaliar a participação dos receptores serotonérgicos do tipo 5-HT2C na modulação de respostas defensivas relacionadas à ansiedade generalizada e ao transtorno do pânico. Os resultados mostram que injeções bilaterais intra-HD dos agonistas de receptores 5-HT2C MK-212 ou RO600175 prejudicaram a aquisição da resposta de esquiva inibitória, em ratos testados no LTE, indicando um efeito do tipo ansiolítico. Por outro lado, a administração do antagonista de receptores 5-HT2C SB-242084 promoveu efeito oposto sobre essa mesma resposta. Adicionalmente administração do agonista preferencial de receptores 5-HT2A DOI não foi capaz de promover efeito em nenhuma das doses utilizadas. Nenhum dos tratamentos empregados alterou a resposta de fuga no LTE. O efeito ansiolítico da ativação dos receptores 5-HT2C, bem como o efeito ansiogênico resultante do seu bloqueio, foram confirmados no teste do beber punido de Vogel. Em suma, nossos resultados sugerem que os receptores do tipo 5-HT2C do hipocampo dorsal estão envolvidos na modulação de comportamentos defensivos relacionados ao transtorno de ansiedade generalizada, mas não ao transtorno do pânico. / Studies using intracerebral microinfusion of drugs have been performed to unveil the role of the hippocampus serotonergic system in the modulation of anxiety-related defensive behaviors. For instance, it has been shown that activation of 5-HT1A receptors in the dorsal hippocampus (DH) facilitated inhibitory avoidance acquisition, suggesting an anxiogenic effect, without altering escape expression in rats tested in the elevated T-maze (ETM). This selective effect on inhibitory avoidance response is consistent with the notion that the hippocampus is critically involved in the pathophysiology of generalized anxiety disorder. Besides 5-HT1A receptors, expressive levels of 5-HT2C receptors are also reported in hippocampus. Compelling evidence from animal studies shows that facilitation of 5-HT2C receptor-mediated neurotransmission increases anxiety. In this study we evaluated the involvement the 5-HT2C receptors of the DH in the regulation of defensive behaviors that have been associated with generalized anxiety and panic. Male Wistar rats were tested in the ETM after intra-DH injection of the 5-HT2C receptor agonists MK-212, RO-600175, or the preferential 5-HT2A receptor agonist DOI, or the 5-HT2C receptor antagonist SB242084. For comparative reason, the effect of MK-212, RO-600175 and SB-242084 was also evaluated on another generalized anxiety-associated model, the Vogel conflict test. Our results showed that while intra-DH microinjection of both MK-212 and RO-600175 facilitated inhibitory avoidance acquisition, suggesting an anxiolytic effect, SB-242084 had the opposite effect. Injections of DOI did not affected performance in ETM. None of these drugs affected escape performance in the ETM. The anxiolytic-like effects of the 5-HT2C receptor agonists and anxiogenic-like effect of the SB-242084 were also observed in the Vogel conflict test. Our findings indicate that 5-HT2C receptors in DH are selectively involved in the regulation of defensive behaviors associated with generalized anxiety, but not panic.

The importance of social behaviour is evident in human society, but there are both costs and benefits associated with cooperation and sociality throughout the animal kingdom. At what point do the benefits outweigh the costs, and when do selective pressures favour sociality and colonization over solitude and independence? To investigate these questions, we have focused on an anomalous species of spider, Anelosimus studiosus, also known now as the northern social spider. Throughout its broad range, A. studiosus is solitary and aggressive, but recently, colonies of cooperative and social individuals have been observed at northern latitudes. This leads to two research questions: 1) what characteristics differentiate the two variants behaviourally, and, 2) how are they different physiologically? Colonies and individuals were collected from multiple populations throughout the Tennessee River watershed area and maintained in a laboratory environment for quantitative and qualitative assessment of behavioural traits as well as specific neurochemical analysis by high performance liquid chromatography with electrochemical detection. After classifying individuals as social or aggressive, I looked at the influence of factors such as age, reproductive state, nutritional state, and time of day on behaviour and neurophysiology. I found correlations between social behaviours and serotonin, aggressive behaviours and octopamine (invertebrate counterpart of norepinephrine), and several other compounds associated with an increase or decrease in aggression. These studies combine techniques from multiple disciplines to contribute to the greater understanding of the proximate control of social and aggressive behaviours as well as factors influencing the evolution of sociality.

Prior work using a contractility bioassay determined that the serotonin (5-HT) receptor subtype 5-HT2A is present in bovine lateral saphenous veins and plays a role in ergot alkaloid-induced vascular contraction in steers grazing endophyte-infected (Epichloë coenophiala) tall fescue (Lolium arundinaceum). A study was conducted to determine what 5-HT receptors are involved in vasoconstriction of bovine gut vasculature. The findings of this study indicate that 5-HT2A is present and may play a role in ergot alkaloid induced vasoconstriction. A second study was conducted to determine if ergot alkaloids were transported in the small intestine. The active transporter, peptide transporter 1 (PepT1), was evaluated for its role in the transport of various concentrations of ergot alkaloids across Caco-2 cell monolayers. Results indicate that CEPH, ERT, EXT, and LSA do move across Caco-2 cell monolayers, but appear to utilize PepT1 at larger concentrations. Overall, the demonstrated presence of 5-HT2A receptors in the bovine gut vasculature established a potential for vascular interference by ergot alkaloids entering the bloodstream through transepithelial absorption.

Synthetic cathinones and related agents represent an international drug abuse problem, and at the same time an important class of clinically useful compounds. Structure-activity relationship studies are needed to elucidate molecular features underlying the pharmacology of these agents. Illicit methcathinone (i.e., MCAT), the prototype of the synthetic cathinone class, exists as a racemic mixture. Though the differences in potency and target selectivity between the positional and optical isomers of synthetic cathinones and related agents have been demonstrated to have important implications for abuse and therapeutic potential, the two MCAT isomers have never been directly compared at their molecular targets: the monoamine transporters (MATs). Additionally, previous studies have found that the carbonyl oxygen atom can be replaced with a methoxy group, but this results in two chiral centers (i.e., four possible optical isomers for synthesis and evaluation). Here, the individual isomers of MCAT, their racemate, and achiral MCAT analogs were prepared where necessary, and examined in vitro and in silico at the MATs. All agents were active as substrates, with a rank order of potency suggesting that α-position chirality, in either configuration, is favored but not required, with the S(-) configuration slightly preferred. Either chiral center removal approach resulted in a reduction in potency, suggesting both favorable interactions with the α-methyl, and limited bulk tolerance. To further investigate this possibility, docking studies were conducted using homology models of the MATs. Common binding modes were identified that were similar to the binding mode of S(+)amphetamine co-crystallized at drosophila DAT. Taken together, these studies supported our conclusions, as steric hindrance was observed in the α-methyl region of the proposed binding site for the R(+)MCAT isomer. Inclusion of the original synthetic cathinones among Schedule I controlled substances has driven the clandestine development of a second generation of agents, resulting in an array of new synthetic cathinones diverse in structure and effect.Pyrrolidinophenones are a major constituent of second-generation bath salts. Little is known about their structure-activity relationships. Here, we have synthesized and examined a series of aryl-substituted pyrrolidinophenone analogs, as well as an achiral pyrrolidinophenone analog, utilizing novel synthetic chemistry and an innovative cell-based epifluorescence Ca2+ imaging technique. Herein, we evaluated the neurochemical properties of these novel compounds at the dopamine transporter (DAT), considered to exert a major role in actions of drugs of abuse. For future structure-activity relationship studies, additional analogs of synthetic cathinone-related agents were produced using novel synthetic approaches, including analogs and isomers of known amphetamine drugs of abuse. Finally, though much has been learned about the role of the dopamine and serotonin transporters in the mechanisms of action of synthetic cathinones, the role of the norepinephrine transporter is poorly understood. Homology models of the human norephinephrine transporter were built and docking studies conducted to inform the study of MAT ligand selectivity, activity, and binding. In conclusion, these studies represent progress towards the establishment of comprehensive structure-activity relationships for synthetic cathinones and related agents. Particular emphasis was placed on the SAR of the phenylalkylamine α-carbon in the synthetic cathinone context, and the role of the norepinephrine transporter in their activity.

Psychedelics are a subset of hallucinogenic drugs that exert their characteristic effects through agonist activity at the serotonin receptor 2A (5-HT2A). In this study, I aimed to characterize the modulatory role of the metabotropic glutamate subtype 2 receptor (mGluR2) in the 5-HT2A-specific rodent model of hallucinogenic action, head-twitch response (HTR). Secondly, I aimed to explore if 5-HT2A agonist-induced deficits in prepulse inhibition (PPI) of the startle response, an additional model of hallucinogenic action, could be produced in mice. Though 5-HT2A agonist-induced PPI deficits, which represent interruptions in normal sensorimotor gating, have been described in both rats and humans, attempts to translate this behavior to mice are rare. In contrast to prior gene knockout studies suggesting the mGluR2 is necessary for 5-HT2A agonist-induced HTR, mGluR2 knockout (Grm2-/-) mice still displayed HTR upon administration of the psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI). Additionally, DOI and lysergic acid diethylamide (LSD) produced unexpected improvements in PPI in male 126S6/Sv wild-type mice, depending on the experimental protocol used and the origin of the animals. Sex differences were observed as DOI-induced improvements in PPI were present in female 129S6/Sv mice of the same origin and tested with the same protocol as their male counterparts; this effect in females was absent in 5-HT2A knockout (Htr2a-/-) mice. The results of this study shed light on issues with replicability and reproducibility in science, the importance of highlighting the origin and background of animal subjects, and potential sex differences in hallucinogenic drug action.

Le développement de radiotraceurs (18F) des récepteurs de la sérotonine 5-HT6 et 5-HT7 pour l'imagerie TEP (tomographie par émission de positons) permettrait d'étudier la fonction et l'implication de ces récepteurs dans des maladies neurodégénératives telles que la schizophrénie ou la maladie d'Alzheimer. A partir des structures et pharmacophores déjà décrits dans la littérature, nous nous sommes orientés vers des dérivés pyrrolidiniques pour les récepteurs 5-HT7 et quinolines pour les récepteurs 5-HT6. 7 radioligands des récepteurs 5-HT7 marqués au fluor 18 ont pu être étudiés par autoradiographie et imagerie μTEP sur le rat et ont montrés des fixations intéressantes, mais avec une sélectivité moyenne du récepteur. 16 ligands du récepteur 5-HT6 ont été synthétisés et 4 d'entre eux ont été radiomarqués afin d'identifier le 2FNQ1P comme radioligand sélectif vis-à-vis du récepteur 5-HT2A (principal récepteur en compétition). Les premières images TEP réalisées sur le chat ont montrées un marquage sélectif dans les zones cérébrales riches en 5-HT6. La poursuite des études biologiques menées en collaboration avec le CERMEP – Imagerie du vivant permettront d'approfondir les caractéristiques de ces nouveaux radioligands synthétisés / Development of fluorine 18 labeled radiotracer of 5-HT6 and 5-HT7 receptors for PET imaging (positron emission tomography) allows the study of those receptors in various neurodegenerative diseases such as schizophrenia and Alzheimer disease. Description of structures and pharmacophores in literature led to pyrrolidine derivatives for 5-HT7 receptors and quinolones for 5-HT6. After their synthesis, 7 radioligands of 5-HT7 receptors have been studied by autoradiography and μPET. These radioligands have shown interesting binding on rat, with more or less selectivity for the receptor. 14 ligands of 5-HT6 receptors have been synthesized and 4 have been radiolabeled to select 2FNQ1P as a selective radioligand toward 5-HT2A. First PET images on cat have shown a selective binding in 5- HT6 rich area in brain. Pursue of biological studies, in collaboration with CERMEP – Imagerie du vivant will give more information on those new radioligands

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

<p>In this study, metastasizing serotonin-producing ileocaecal carcinoid tumours (MSPCs) were examined for biological characteristics that could be used to define clinically relevant subgroups within this patient population. Possible targets for new treatment options were also explored.</p><p>It was found that MSPCs share several biological characteristics such as expression of serotonin, tachykinins (TKs), chromogranin A, islet autoantigen-2 and connective tissue growth factor (CTGF). TKs and serotonin were demonstrated in the same endocrine tumours in the gut and lung. IA-2 expression was shown to be up-regulated in MSPCs, possibly in connection with active hormone secretion. CTGF expression was high in tumour areas adjacent to extensive stroma expressing alpha-smooth muscle actin. This indicated myofibroblast differentiation, which may be associated with fibrosis-related complications prevalent in patients with MSPCs. When compared with other endocrine tumours, MSPCs behaved as a relatively homogeneous group, though within the MSPC population several subgroups could be defined. Patients with tumours displaying either a solid growth pattern and/or a Ki67 index ≥1% had a less favourable prognosis than those who did not. Another group of patients, who had increased plasma TK concentrations, were more likely to suffer from severe diarrhea. This information should be considered when discussing clinical treatment and when undertaking tumour biological studies. New treatment possibilities, such as drugs that specifically target TK receptors and antibodies to CTGF, are also discussed.</p><p>In conclusion, MSPCs comprise a clinically relevant tumour group with similar biological features that are distinct from other endocrine tumours. Subgroups of patients within this patient category can be defined which may be relevant when establishing prognosis and when selecting future treatment modalities.</p>