Les neurones sérotoninergiques forment des réseaux complexes avec les autres systèmes de neurotransmission dans le système nerveux central. Le rôle du récepteur 5-HT2B dans ces réseaux est peu connu. L’ablation génétique ou la surexpression virale du récepteur 5-HT2B dans les neurones sérotoninergiques, nous ont permis de mettre en évidence sa participation à l’excitabilité de ces neurones. De fait, le récepteur 5-HT2B est nécessaire à l’action des antidépresseurs et de l'ecstasy qui provoquent une accumulation extracellulaire de sérotonine. Aussi, le récepteur 5-HT2B est capable d’agir tel un modulateur positif, à l’opposé des autorécepteurs 5-HT1A, sur l’activité des neurones sérotoninergiques. Ensuite, l’étude de la distribution du récepteur 5-HT2B et de son interaction avec la protéine de pontage CIPP nous a permis de décrire la distribution subcellulaire du récepteur 5-HT2B dans des cultures primaires de neurones d’hippocampe. La co-expression du récepteur 5-HT2B avec CIPP augmente significativement son adressage somatodendritique dans les synapses excitatrices. Au niveau fonctionnel, CIPP augmente la libération dendritique de calcium dépendante de la stimulation du récepteur 5-HT2B. En synergie avec CIPP, cette stimulation augmente le regroupement des récepteurs glutamatergiques NMDA suggérant un rôle dans la plasticité synaptique pouvant expliquer certains résultats précédents. / Serotonergic neurons are organized in complex networks interacting with other neurotransmitter systems in the brain. The 5-HT2B receptor contribution in these networks remains unclear. Using 5-HT2B receptor genetic ablation or a viral overexpression in the serotoninergic neurons, we have demonstrated its participation to the excitability of these neurons. In fact, 5-HT2B receptors are necessary for serotonin accumulation induced by ecstasy and antidepressants effects. Moreover, 5-HT2B receptors activation counteracts the 5-HT1A dependant inhibition on serotonergic neurons activity. Here we propose 5-HT2B receptor as positive modulator of serotonergic neurons. Then, studying 5-HT2B receptors and CIPP scaffold protein interaction allow us to identify the subcellular distribution of the receptor and a functional role of CIPP. Indeed, overexpression of both proteins in primary hippocampal cultures of neurons increases 5-HT2B receptors somatodendritic targeting at excitatory synapses. Thus CIPP increases dendritic calcium release dependent on 5-HT2B receptor stimulation. In synergy with CIPP, this stimulation increases NMDA receptors clustering suggesting a role in synaptic plasticity that could explain some of the previous findings.

Made available in DSpace on 2016-01-26T12:51:45Z (GMT). No. of bitstreams: 1 lucianasecchesdefreitas_tese.pdf: 1318047 bytes, checksum: 2f94fa7d973d746d2344caf42a9565ec (MD5) Previous issue date: 2011-09-08 / Introduction: Serotonin is an important neurotransmitter in the central nervous system. It has been suggested that serotoninergic dysfunction mediates the pathophysiology of temporomandibular dysfunction (TMD). Polymorphisms in HTR2A gene can alter the number of receptors in the serotoninergic system, causing nociceptive pain and hyperalgesia in the TMD. Objective: The aim of this study is to determine the prevalence of the 102T-C polymorphism of HTR2A in patients with and without TMD. Casuistic and Method: This cross-sectional study examined 100 patients as index cases and 100 persons as controls, of both genders. DNA was extracted from peripheral blood leukocytes, and the site that encompassed the polymorphism was amplified by PCR-RFLP. Results: There were significantly more females among index cases compared with the control group (p<0.05). The CC genotype of the 102T-C polymorphism was more frequent in patients with TMD versus controls (OR: 2.25; CI 95%: 1.13-4.46; p<0.05). Conclusions: The 102T-C polymorphism of HTR2A gene is linked to TMD in the studied population. / Introdução: A serotonina é um importante neurotransmissor no sistema nervoso central. Tem sido sugerido que a disfunção serotoninérgica é responsável pela fisiopatologia da disfunção temporomandibular (DTM). Polimorfismos no gene HTR2A podem alterar o número de receptores do sistema serotoninérgico, ocasionando a dor nociceptiva e hiperalgesia na DTM. Objetivo: Determinar a prevalência do polimorfismo 102T-C no gene HTR2A em pacientes com e sem DTM. Casuística e Método: Estudo em corte transversal no qual foram avaliados 100 pacientes como casos-índice e 100 indivíduos como controles, de ambos os gêneros. O DNA foi extraído dos leucócitos do sangue periférico e o local que abrange o polimorfismo foi amplificado por PCR-RFLP. Resultados: O gênero feminino foi significativamente maior nos casos do índice em comparação com o grupo controle (p <0,05). O genótipo CC do polimorfismo 102T-C foi mais frequente em pacientes com DTM em comparação aos controles (OR: 2,25 IC 95%: 1,13-4,46, p<0,05). Conclusões: O polimorfismo 102T-C no gene HTR2A está associado à DTM na população estudada.

A serotonina (5-HT) é um neuro-hormônio com complexos efeitos em humanos e animais. Embora se acredite que a sinalização serotoninérgica promova o desenvolvimento de tumores de cólon, também tem sido observado que a redução dos níveis de 5-HT aumenta o risco de malignidades neste órgão. Assim, é necessário investigar como a síntese de 5-HT modula a carcinogênese de cólon. Esta hipótese será explorada em experimentos mecanísticos envolvendo a exposição ou não de camundongos a um agente carcinogênico (azoximetano). Estes experimentos revelaram que a exposição carcinogênica aumentou a síntese de 5-HT no cólon, uma vez que os processos de liberação e degradação de 5-HT foram reduzidos, enquanto que a sua síntese e recaptação aumentaram. Após 24 semanas da 1° exposição carcinogênica, a deleção da síntese de 5-HT promoveu a multiplicidade tumoral no cólon, enquanto que ao longo de 12 semanas ocorreu um aumento de lesões preneoplásicas e proliferação celular. É interessante que 72 hrs após a sexta e última exposição carcinogênica o número de criptas aberrantes foram detectadas reduzidas na ausência de 5-HT, o que ocorreu em conjunto com uma redução da atividade proliferativa, aumento de células apoptóticas, e maior dano de DNA. Finalmente, a 5-HT modulou mecanismos de reparo genômico. Concluímos que a síntese serotoninérgica parece ser um fator de proteção do cólon intestinal, que caso inibida facilitaria o desenvolvimento tumoral neste tecido. / Serotonin (5-HT) is a neurohormone with complex effects in humans and animals. Although serotonergic signaling has been suggested to promote the development of colon tumors, the reduction in 5-HT levels was reported to increase the risk of colon cancer. Here, we sought to investigate how 5-HT synthesis modulates colon carcinogenesis. This hypothesis was explored in mechanistic experiments that carcinogenically exposed or not mice to azoxymethane. It revealed that carcinogenic exposure increased the synthesis of 5-HT in the colon since 5-HT release and decay were inhibited, while its synthesis and reuptake are promoted. After 24 weeks from the first carcinogenic exposure, the deletion of 5-HT synthesis increased tumor multiplicity, while following 12 weeks it promoted the development of preneoplastic lesions, and cell proliferation in the colon. Interestingly, 72 hrs after the sixth and last carcinogenic exposures the number of aberrant crypts were detected reduced in the absence of 5-HT, which occurred together with a reduced proliferation, but increased apoptosis and DNA damage. Finally, 5-HT modulated genomic repair mechanisms. We conclude that serotonergic synthesis seems to be a protective factor of the intestinal colon, which inhibited case facilitates tumor development in this tissue.

ALVES NETO, W.C. Efeitos do escitalopram sobre a identificação de expressões faciais. Ribeirão Preto, SP: Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo; 2008. Os inibidores seletivos da recaptura de serotonina (ISRS) têm sido utilizados com sucesso para o tratamento de diversas patologias psiquiátricas. Sua eficácia clínica é atribuída a uma potencialização da neurotransmissão serotoninérgica, mas pouco ainda é conhecido sobre os mecanismos neuropsicológicos envolvidos nesse processo. Várias evidências sugerem que a serotonina estaria envolvida, entre outras funções, na regulação do comportamento social, nos processos de aprendizagem e memória e no processamento de emoções. O reconhecimento de expressões faciais de emoções básicas representa um valioso paradigma para o estudo do processamento de emoções, pois são estímulos condensados, uniformes e de grande relevância para o funcionamento social. O objetivo do estudo foi avaliar os efeitos da administração aguda e por via oral do escitalopram, um ISRS, no reconhecimento de expressões faciais de emoções básicas. Uma dose oral de 10 mg de escitalopram foi administrada a doze voluntários saudáveis do sexo masculino, em modelo duplo-cego, controlado por placebo, em delineamento cruzado, ordem randômica, 3 horas antes de realizarem a tarefa de reconhecimento de expressões faciais, com seis emoções básicas raiva, medo, tristeza, asco, alegria e surpresa mais a expressão neutra. As faces foram digitalmente modificadas de forma a criar um gradiente de intensidade entre 10 e 100% de cada emoção, com incrementos sucessivos de 10%. Foram registrados os estados subjetivos de humor e ansiedade ao longo da tarefa e o desempenho foi avaliado pela medida de acurácia (número de acertos sobre o total de estímulos apresentados). De forma geral, o escitalopram interferiu no reconhecimento de todas as expressões faciais, à exceção de medo. Especificamente, facilitou a identificação das faces de tristeza e prejudicou o reconhecimento de alegria. Quando considerado o gênero das faces, esse efeito foi observado para as faces masculinas, enquanto que para as faces femininas o escitalopram não interferiu com o reconhecimento de tristeza e aumentou o de alegria. Além disso, aumentou o reconhecimento das faces de raiva e asco quando administrado na segunda sessão e prejudicou a identificação das faces de surpresa nas intensidades intermediárias de gradação. Também apresentou um efeito positivo global sobre o desempenho na tarefa quando administrado na segunda sessão. Os resultados sugerem uma modulação serotoninérgica sobre o reconhecimento de expressões faciais emocionais e sobre a evocação de material previamente aprendido. / ALVES NETO, W.C. Effects of escitalopram on the processing of emotional faces. Ribeirão Preto, SP: Faculty of Medicine of Ribeirão Preto, University of São Paulo; 2008. The selective serotonin reuptake inhibitors (SSRI) have been used successfully for the treatment of various psychiatry disorders. The SSRI clinical efficacy is attributed to an enhancement of the serotonergic neurotransmission, but little is known about the neuropsychological mechanisms underlying this process. Several evidences suggest that serotonin is involved with the regulation of social behavior, learning and memory process and emotional processing. The recognition of basic emotions on facial expressions represents an useful task to study the emotional processing, since they are a condensate, uniform and important stimuli for social functioning. The aim of the study was to verify the effects of the SSRI escitalopram on the recognition of facial emotional expressions. Twelve healthy males completed two experimental sessions each (crossover design), in a randomized, balanced order, double-blind design. An oral dose of 10 mg of escitalopram was administered 3 hours before they performed an emotion recognition task with six basic emotions angry, fear, sadness, disgust, happiness and surprise and neutral expression. The faces were digitally morphed between 10% and 100% of each emotional standard, creating a 10% steps gradient. The subjective mood and anxiety states through the task were recorded and the performance through the task was defined by the accuracy measure (number of correct answers divided by the total of stimuli presented). In general, except of fear, escitalopram interfered with all the emotions tested. Specifically, facilitated the recognition of sadness, while impaired the identification of happiness. When the gender of the faces was analyzed, this effect was seen in male, but not female faces, where it improves the recognition of happiness. In addition, improves the recognition of angry and disgusted faces when administered at the second session and impaired the identification of surprised faces at intermediate levels of intensity. It also showed a global positive effect on task performance when administered at the second session. The results indicate a serotonergic modulation on the recognition of emotional faces and the recall of previous learned items.

Thermogenic brown and beige adipocytes convert chemical energy to heat by metabolizing glucose and lipids via uncoupling protein 1 (Ucp1), a process known as non-shivering thermogenesis. Serotonin (5-HT) neurons in the ventral medulla are known to regulate sympathetic efferent neurons in the intermediolateral nucleus (IML) necessary to maintain brown adipose tissue (BAT) activity. Previous studies show that mice lacking central 5-HT neurons are incapable of maintaining body temperature in cold, ambient conditions. Due to this direct linkage between 5-HT and thermoregulation, we hypothesized that central 5-HT neurons may be vital to the regulation of brown and beige adipocyte activity. Given that BAT consumes large amounts of substrate when active, we also hypothesized that inactivation of BAT due to deletion of the regulatory neural circuitry (5-HT neurons) would cause metabolic dysregulation. To test this, we generated mice in which the human diphtheria toxin (DT) receptor was selectively expressed in central 5-HT neurons under control of a Pet-1 promoter. Pet-1 is a transcription factor selectively located in mature, central 5-HT neurons. Coincidentally, some cells within pancreatic islets also express Pet-1, and contain adequate machinery to produce, release, and uptake 5-HT. Systemic treatment with DT eliminated 5-HT neurons and caused loss of thermoregulation, BAT steatosis, and a >50% decrease in Ucp1 expression in BAT and beige fat, indicative of reduced thermal production. In parallel, blood glucose increased 3.5-fold, free fatty acids 13.4-fold and triglycerides 6.5-fold. Intracerebroventricular (ICV) treatment with 1/30th the systemic dose of DT induced an even greater thermoregulatory impairment. The metabolic deficits following systemic DT treatment indicate that central 5-HT neurons are essential for proper metabolic regulation. However, such high levels of glucose and lipids also indicate failure of the pancreatic endocrine program following systemic treatment, likely due to moderate destruction of β-cells expressing Pet-1 and the DT receptor. Because ICV treatment caused even greater thermoregulatory and metabolic deficits, where little, if any, of the toxin would spread systemically, central 5-HT neurons are clearly essential for normal central regulation of metabolism. Interestingly, similar BAT and beige fat defects occurred in Lmx1bf/f/p mice, in which 5-HT neurons fail to develop in utero. Assessment of systemically treated animals using a euglycemic/hyperinsulinemic clamp showed extensive fasting hyperglycemia and systemic insulin resistance, coinciding with reduced glucose uptake in skeletal muscle and BAT. The hyperinsulinemic clamp failed to suppress hepatic glucose and fatty acid production, leading to the conclusion that loss of central 5-HT neurons disrupts central hepatic regulation. In attempts to induce BAT thermogenesis and metabolism, we optogenetically stimulated 5-HT neurons in the rostral raphe pallidus and measured BAT and body temperature along with blood glucose. Unfortunately, these stimulations were incapable of increasing BAT temperature and lowering blood glucose, perhaps limiting therapeutic potential of these 5-HT neurons. We conclude that 5-HT neurons are major players in central regulation of metabolic homeostasis, in part through recruitment and activation of brown and beige adipocytes and hepatic substrate production. Data also suggest that 5-HT neurons regulate glucose homeostasis via undefined neural mechanisms independently of BAT activity and pancreatic insulin secretion. Cumulative data on central 5-HT neurons indicate they are master regulators of whole-body metabolism.

Unsere Bemühungen die Natur individueller Unterschiede der Emotionsregulation zu verstehen, involviert das Verständnis der Gene. In dieser Arbeit werden Gene (Kandidatengene), die für Proteine als Rezeptoren, Transporter oder Enzyme im Neurotransmitterstoffwechsel Serotonin und Dopamin kodieren, untersucht. Serotonin und Dopamin sind mit Angststörungen in verschiedener Weise assoziiert. Sie sind wichtige Neurotransmitter in Teilen des Gehirns, die mit Angstkonditionierung im Zusammenhang stehen. Polymorphismen in diesen Genen verändern die Struktur und Funktion der Genprodukte und nehmen damit Einfluss auf die Funktion von Hirnstrukturen und -systemen. Phobien sind äußerst intensive und persistente Furchtreaktionen, welche durch spezifische Situationen oder Objekte ausgelöst werden und von dem zwingenden Wunsch begleitet sind, diese Situationen oder Objekte zu vermeiden. Die Intensität der Furchtreaktion erscheint einem Außenstehenden, entsprechend der realen Gefahr dieser Situation, unangemessen und eigentümlich. Zumeist hat der Phobiker selbst auch Einsicht in diese Irrationalität seiner Furchtreaktion, vermag sie aber nicht willentlich unter Kontrolle zu halten. In dieser Arbeit wurden als Beispiel einer assoziierten Angst die Zahnbehandlungsphobie und als Beispiel einer nicht-assoziierten Angst die Spinnenphobie untersucht. Es wurden 53 Zahnbehandlungsängstliche, 52 Spinnenphobiker und 37 Kontrollpersonen mittels Fragebogen (SPF,FAS,STAI trait, DCQ, DFS, ASI, PANAS, R-IDCI) getestet. Die Probanden wurden durch PCR-Analyse von Mundschleimhautabstriche je einem Polymorphismus der untersuchten Kandidatengene zugeordnet. Es handelte sich dabei um die Gene für den Serotonintransporter 5HTT, den Serotoninrezepor 5HT1A, den Dopaminrezeptor DRD4, den Dopamintransporter DAT, BDNF und das in den Katecholaminabbau involvierte COMT-Enzym. Die untersuchten Polymorphismen weisen in der Literatur einen Einfluss auf die Angstausprägungen auf. In der statistischen Auswertung wurde auf signifikante Zusammenhänge zwischen einem Polymorphismus und der Ausprägung einer Phobie geachtet. Desweiteren wurden die verschiedenen Polymorphismen mit den Ergebnissen der Fragebogentests in Zusammenschau gebracht. Ein direkter Einfluss eines der untersuchten Gene auf die Ausprägung einer Phobie konnte nicht nachgewiesen werden. In der Gruppe der Dentalphobiker zeigten sich Hinweise auf einen Einfluss des BDNF G-Allels und des COMT G-Allels auf erhöhte Ängstlichkeit. / Understanding of individual differences in emotions is related to the understanding of genes. This paper analyses genes (candidate genes) that code for proteins as receptors, transporters or enzymes in the metabolism of neurotransmitter serotonin and dopamine. Serotonin and dopamine are in different ways associated with anxiety disorders. They are important neurotransmitter in parts of the brain that are associated with anxiety conditioning. Polymorphisms in these genes change the structure and function of gene products and have effect on the function of brain structures. In literature the analysed polymorphisms show influence on characteristics of anxiety. Phobias are very intense and persistent fearreactions, which are triggered by specific situations or objects. They are accompanied by the desire to avoid these specific objects/situations. The intensity of this fearreactions seems inadequate according to real danger. The phobic person himself realises the irrationality of the reaction, but cannot control it. In this paper dental phobia, as an example for associated anxiety, and spider phobia, as an example for non-associated anxiety, are analysed. 53 dentalphobic, 52 spiderphobic and 37 control persons are tested by questionnaires (SPF,FAS,STAI trait, DCQ, DFS, ASI, PANAS, R-IDCI). The test persons were related to each one polymorphism of a candidate gene by PCR-analysing of mouth mucosa samples. Analysed candidate genes are serotonin-transporter 5HTT, serotonin-receptor 5HT1A, COMT, dopamine-receptor DRD4, dopamine-transporter and neutrophin BDNF. The relationship between a polymorphism and the characteristics of a phobia was examined statistically. Further the questionnaire results and polymorphisms were analysed for relations. No direct influence could be shown for candidate genes on phobia characteristics. In the group of dental phobia, hints for influence of the BFNF G-allele and COMT G-allele on anxiety could be made.

The purpose of this study was to identify the effects of the neurotransmitter, serotonin (SE), on the immune function of peripheral blood mononuclear cells (PBMC) of normal, healthy subjects. This was done as a preliminary investigation to studies on the association of SE with immune changes in autistic subjects. The PBMC isolated from normal male subjects were treated with various concentrations of SE for 48 hrs. Their incubation in SE at a concentration of 10-3 M induced about a 35% decrease in DNA synthesis. However, incubation of the cells in lower concentrations (10-4 to 10-10) of SE produced no significant effect. The ability of natural killer (NK) cells to lyse K562 target cells was also examined after incubation with SE for 48 hrs. The NK activity was almost completely eliminated following incubation in 10-3M of SE, but the activity was not significantly decreased by exposure to lower concentrations of SE. The viability of PBMC was not altered following incubation with SE under identical conditions as those utilized in the NK assay. Preliminary analysis using a fluorescence-activated cell sorter (FACS) of monoclonal antibodies directed against Tll (total T cell), T4 (helper T cell), T8 (suppressor and cytotoxic T cells), B-cell and NK cell markers indicated that the suppressive effect exerted by SE could be attributed to a decrease in the density of these markers or receptors on the cell surface. These findings provide additional evidence for a possible link between neurotransmitters, specifically SE, and immune function.

Opioids, such as oxycodone, morphine, and fentanyl, are commonly used medications in the treatment of moderate to severe pain. In spite of their efficacious analgesic properties, their increased prescribing rates by physicians and inherent abuse-related effects have led to the ongoing opioid epidemic. Their clinical utility is limited by the risk of adverse dose-dependent side effects, such as constipation and respiratory depression, and the development of tolerance and dependence. Opioid-sparing adjunctive therapies are sought to address these issues by reducing the dose of opioid needed to achieve analgesia through alternative non-opioidergic mechanisms and as a result, reduce the incidence of the previously mentioned side effects. Serotonin type-2C receptor agonists have demonstrated antinociceptive efficacy in preclinical models of chronic pain. Lorcaserin is a selective 5-HT2C receptor agonist and was reported to attenuate the abuse-related effects of oxycodone. The antinociceptive properties of 5-HT2C receptor agonists and their potential to alter the abuse-related effects of commonly abused drugs suggest that lorcaserin may be a potential opioid-sparing therapeutic. The goal of these studies was to evaluate the utility of lorcaserin, in combination with opioids, in a preclinical model of acute pain. Based on previous studies demonstrating the antinociceptive activity of 5-HT2C agonists, the hypotheses for these studies were that lorcaserin would increase the acute antinociceptive effects of opioids and would attenuate the development of tolerance associated with chronic opioid consumption. The results demonstrate that the acute antinociceptive effects and the time-course of activity of opioids were enhanced by doses of lorcaserin. These effects were mediated through activation of the 5-HT2C receptor and were not blocked by administration of naloxone. Additionally, the acute effects of lorcaserin to increase opioid potency and time course was not mediated through changes in opioid distribution in the blood or central tissues. Opioid tolerance was evaluated in vivo, and tolerance was developed using two methods of treatment: an acute (single dose administration) model of tolerance and a multiple-injection model. Testing the effect of lorcaserin in these models was important because current research suggests that the mechanisms that underlie both models of tolerance are distinct from one another. The results demonstrate that lorcaserin significantly blocked the development of acute tolerance in the whole animal and on a single cell level in dorsal root ganglion cell cultures. In the multiple-day tolerance model, lorcaserin partially attenuated the development of opioid antinociceptive tolerance. Chronic administration of an opioid is associated with desensitization of the MOR, and the effect of lorcaserin on opioid tolerance may be mediated through changes in MOR functional activity. Upon further investigation using agonist-stimulated [35S]GTPyS, the results showed that lorcaserin altered basal binding of [35S]GTPyS but not agonist-stimulated binding in mice that received chronic opioid treatment. These data suggest that the effect of lorcaserin on opioid tolerance, in the multiple-injection model, is not mediated through changes in MOR functional activity. Collectively, the tolerance studies suggest that the effect of 5-HT2C receptor activation by lorcaserin has differential effects on the stages of opioid tolerances and further supports the notion that the mechanisms that underlie the stages of opioid tolerance are distinct. Given the efficacy of lorcaserin to increase the acute antinociceptive effects of opioids and its ability to impair the development of opioid tolerance, collectively, these data suggest that lorcaserin may be a useful opioid-sparing adjunctive therapy.

<p>Eukaryotic gene transcription plays a regulatory role in mammalian developmental processes. It has been shown that transcriptional control is an important mechanism for specification of neurotransmitter phenotypes. In the mammalian central nervous system, the transcription factor AP-2 family is one of the critical regulatory factors for neural gene expression and neuronal development. It has been shown that several genes in the monoaminergic systems have AP-2 binding sites in regulatory regions, suggesting a regulatory role of AP-2 also in the adult brain. Brainstem monoamines are implicated in the expression of personality traits and imbalances in these systems may give rise to psychiatric disorders. </p><p>The gene encoding AP-2β includes a polymorphic region consisting of a tetranucleotide repeat of [CAAA]_4-5 in intron 2. Studies on AP-2β genotype in relation to personality and platelet MAO activity, a trait-dependant marker for personality, are presented in this thesis. Furthermore, correlations between brainstem levels of AP-2α and AP-2β and monoamine turnover in projection areas in rat forebrain are reported. These results strengthen the notion that the AP-2 family is important regulators of the monoaminergic systems in the adult brain. Furthermore, two studies are presented in this thesis with analyses indicating a role for AP-2 in the molecular mechanism of antidepressant drugs.</p><p>Altogether, this thesis presents data supporting our notion that the transcription factor AP-2 family is involved in the regulation of the monoaminergic systems both pre- and postnatally, and, therefore, might be involved in the pathophysiology of neuropsychiatric disorders.</p>

<p>The CNS monoaminergic systems are considered as the head engine regulating neuropsychiatric functions and personality. Transcription factor AP-2 is known to be essential for the development of the brainstem including the monoaminergic nuclei, and has the ability to regulate many genes in the monoaminergic systems. The ability of transcription factors to regulate specific gene expression, has lately made them hot candidates as drug targets. In this thesis, results indicating a role of AP-2 in the molecular effects of the antidepressant drugs citalopram and phenelzine, are presented. </p><p>A polymorphism in the second intron of the gene encoding AP-2ß has previously been associated with anxiety-related personality traits as estimated by the Karolinska Scales of Personality (KSP). In this thesis, results confirming this association, gained by using a larger material and several different personality scales, are presented. Furthermore, data is presented showing an association between the activity of platelet monoamine oxidase, a trait-dependent marker for personality, and the genotype of the AP-2ß intron 2 polymorphism. </p><p>The functional importance of the AP-2ß intron 2 polymorphism has not yet been elucidated. Included in this thesis are results showing that the AP-2ß intron 2 polymorphism is not in linkage disequilibrium with the only other described polymorphism in the AP-2ß gene, i.e. in the AP-2ß promoter (-67 G/A). Introns have in several studies been shown to include binding sites for regulatory proteins, and thus, to be important in transcriptional regulation. Results are presented demonstrating that one human brain nuclear protein binds only to the long variant of the AP-2ß intron 2 polymorphism. If this protein is involved in the regulation of the AP-2ß gene, it would affect the expression levels of the AP-2ß protein. </p><p>In general, this thesis further establishes the role of transcription factor AP-2 as a regulatory factor of importance for personality and monoaminergic functions.</p>