Maturation of glutamatergic transmission onto dorsal raphe serotonergic neurons.

Serotonergic neurons in the dorsal raphe nucleus (DRN) play important roles early in postnatal development in the maturation and modulation of higher-order emotional, sensory, and cognitive circuitry. The pivotal functions of these cells in brain development make them a critical substrate by which early experience can be wired into the brain. In this study, we investigated the maturation of synapses onto dorsal raphe serotonergic neurons in typically developing male and female mice using whole cell patch-clamp recordings in ex vivo brain slices. We show that while inhibition of these neurons is relatively stable across development, glutamatergic synapses greatly increase in strength between postnatal day 6 (P6) and P21-23. In contrast to forebrain regions, where the components making up glutamatergic synapses are dynamic across early life, we find that DRN excitatory synapses maintain a very high ratio of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) to N-methyl-d-aspartate (NMDA) receptors and a rectifying component of the AMPA response until adulthood. Overall, these findings reveal that the development of serotonergic neurons is marked by a significant refinement of glutamatergic synapses during the first three postnatal weeks. This suggests this time is a sensitive period of heightened plasticity for the integration of information from upstream brain areas. Genetic and environmental insults during this period could lead to alterations in serotonergic output, impacting both the development of forebrain circuits and lifelong neuromodulatory actions.NEW & NOTEWORTHY Serotonergic neurons are regulators of both the development of and ongoing activity in neuronal circuits controlling affective, cognitive, and sensory processing. Here, we characterize the maturation of extrinsic synaptic inputs onto these cells, showing that the first three postnatal weeks are a period of synaptic refinement and a potential window for experience-dependent plasticity in response to both enrichment and adversity.

Peripheral serotonergic neurons regulate gut motility and anxiety-like behavior.

Serotonergic circuits in the central nervous system play important roles in regulating mood and behavior, yet the functions of peripheral serotonergic neurons are less understood. Here, we engineered mice lacking the serotonin-producing enzyme Tph2 in peripheral neurons but with intact Tph2 in central neurons. In contrast to mice lacking Tph2 in all neurons, mice lacking Tph2 in peripheral serotonergic neurons did not exhibit increased territorial aggression. However, similar to the total body Tph2 knockout (KO) mice, the conditional KO animals exhibited reduced gut motility and decreased anxiety-like behavior. These observations reveal that peripheral serotonergic neurons contribute to control of intestinal motility and anxiety-like behavior and suggest that therapeutics targeting this subset of peripheral neurons could be beneficial.

Identification of a novel perifornical-hypothalamic-area-projecting serotonergic system that inhibits innate panic and conditioned fear responses.

The serotonin (5-HT) system is heavily implicated in the regulation of anxiety and trauma-related disorders such as panic disorder and post-traumatic stress disorder, respectively. However, the neural mechanisms of how serotonergic neurotransmission regulates innate panic and fear brain networks are poorly understood. Our earlier studies have identified that orexin (OX)/glutamate neurons within the perifornical hypothalamic area (PFA) play a critical role in adaptive and pathological panic and fear. While site-specific and electrophysiological studies have shown that intracranial injection and bath application of 5-HT inhibits PFA neurons via 5-HT1a receptors, they largely ignore circuit-specific neurotransmission and its physiological properties that occur in vivo. Here, we investigate the role of raphe nuclei 5-HT inputs into the PFA in panic and fear behaviors. We initially confirmed that photostimulation of glutamatergic neurons in the PFA of rats produces robust cardioexcitation and flight/aversive behaviors resembling panic-like responses. Using the retrograde tracer cholera toxin B, we determined that the PFA receives discrete innervation of serotonergic neurons clustered in the lateral wings of the dorsal (lwDRN) and in the median (MRN) raphe nuclei. Selective lesions of these serotonergic projections with saporin toxin resulted in similar panic-like responses during the suffocation-related CO2 challenge and increased freezing to fear-conditioning paradigm. Conversely, selective stimulation of serotonergic fibers in the PFA attenuated both flight/escape behaviors and cardioexcitation responses elicited by the CO2 challenge and induced conditioned place preference. The data here support the hypothesis that PFA projecting 5-HT neurons in the lwDRN/MRN represents a panic/fear-off circuit and may also play a role in reward behavior.

Serotonergic modulation of vigilance states in zebrafish and mice.

Vigilance refers to being alertly watchful or paying sustained attention to avoid potential threats. Animals in vigilance states reduce locomotion and have an enhanced sensitivity to aversive stimuli so as to react quickly to dangers. Here we report that an unconventional 5-HT driven mechanism operating at neural circuit level which shapes the internal state underlying vigilance behavior in zebrafish and male mice. The neural signature of internal vigilance state was characterized by persistent low-frequency high-amplitude neuronal synchrony in zebrafish dorsal pallium and mice prefrontal cortex. The neuronal synchronization underlying vigilance was dependent on intense release of 5-HT induced by persistent activation of either DRN 5-HT neuron or local 5-HT axon terminals in related brain regions via activation of 5-HTR7. Thus, we identify a mechanism of vigilance behavior across species that illustrates the interplay between neuromodulators and neural circuits necessary to shape behavior states.

Role of α1-GABAA receptors in the serotonergic dorsal raphe nucleus in models of opioid reward, anxiety, and depression.

BACKGROUND: The serotonin (5-hydroxytryptamine (5-HT))-mediated system plays an important role in stress-related psychiatric disorders and substance abuse. Our previous studies showed that stress and drug exposure can modulate the dorsal raphe nucleus (DRN)-5-HT system via γ-aminobutyric acid (GABA)A receptors. Moreover, GABAA receptor-mediated inhibition of serotonergic DRN neurons is required for stress-induced reinstatement of opioid seeking. AIM/METHODS: To further test the role of GABAA receptors in the 5-HT system in stress and opioid-sensitive behaviors, our current study generated mice with conditional genetic deletions of the GABAA α1 subunit to manipulate GABAA receptors in either the DRN or the entire population of 5-HT neurons. The GABAA α1 subunit is a constituent of the most abundant GABAA subtype in the brain and the most highly expressed subunit in 5-HT DRN neurons. RESULTS: Our results showed that mice with DRN-specific knockout of α1-GABAA receptors exhibited a normal phenotype in tests of anxiety- and depression-like behaviors as well as swim stress-induced reinstatement of morphine-conditioned place preference. By contrast, mice with 5-HT neuron-specific knockout of α1-GABAA receptors exhibited an anxiolytic phenotype at baseline and increased sensitivity to post-morphine withdrawal-induced anxiety. CONCLUSIONS: Our data suggest that GABAA receptors on 5-HT neurons contribute to anxiety-like behaviors and sensitivity of those behaviors to opioid withdrawal.

Serotonergic neuromodulation of synaptic plasticity.

Synaptic plasticity constitutes a fundamental process in the reorganization of neural networks that underlie memory, cognition, emotional responses, and behavioral planning. At the core of this phenomenon lie Hebbian mechanisms, wherein frequent synaptic stimulation induces long-term potentiation (LTP), while less activation leads to long-term depression (LTD). The synaptic reorganization of neuronal networks is regulated by serotonin (5-HT), a neuromodulator capable of modify synaptic plasticity to appropriately respond to mental and behavioral states, such as alertness, attention, concentration, motivation, and mood. Lately, understanding the serotonergic Neuromodulation of synaptic plasticity has become imperative for unraveling its impact on cognitive, emotional, and behavioral functions. Through a comparative analysis across three main forebrain structures-the hippocampus, amygdala, and prefrontal cortex, this review discusses the actions of 5-HT on synaptic plasticity, offering insights into its role as a neuromodulator involved in emotional and cognitive functions. By distinguishing between plastic and metaplastic effects, we provide a comprehensive overview about the mechanisms of 5-HT neuromodulation of synaptic plasticity and associated functions across different brain regions.

Physical exercise-induced fatigue: the role of serotonergic and dopaminergic systems

Brain serotonin and dopamine are neurotransmitters related to fatigue, a feeling that leads to reduced intensity or interruption of physical exercises, thereby regulating performance. The present review aims to present advances on the understanding of fatigue, which has recently been proposed as a defense mechanism instead of a "physiological failure" in the context of prolonged (aerobic) exercises. We also present recent advances on the association between serotonin, dopamine and fatigue. Experiments with rodents, which allow direct manipulation of brain serotonin and dopamine during exercise, clearly indicate that increased serotoninergic activity reduces performance, while increased dopaminergic activity is associated with increased performance. Nevertheless, experiments with humans, particularly those involving nutritional supplementation or pharmacological manipulations, have yielded conflicting results on the relationship between serotonin, dopamine and fatigue. The only clear and reproducible effect observed in humans is increased performance in hot environments after treatment with inhibitors of dopamine reuptake. Because the serotonergic and dopaminergic systems interact with each other, the serotonin-to-dopamine ratio seems to be more relevant for determining fatigue than analyzing or manipulating only one of the two transmitters. Finally, physical training protocols induce neuroplasticity, thus modulating the action of these neurotransmitters in order to improve physical performance.

Mecanismos regulatorios del tono vascular pulmonar neonatal: una perspectiva molecular / Regulatory mechanisms of neonatal pulmonary vascular tone: a molecular perspective

La adaptación al medio extrauterino incluye un aumento considerable de la PaO2, que induce especialmente cambios estructurales y vasoactivos en la circulación pulmonar, que llevarán a una circulación previamente pobremente irrigada, a recibir ∼100% del gasto cardíaco del recién nacido, permitiendo el normal intercambio gaseoso. La regulación local de la circulación arterial pulmonar neonatal basal, es mantenida por un delicado equilibrio entre agentes vasoconstrictores y vasodilatadores. Este equilibrio, permite mantener la circulación pulmonar como un territorio de gran flujo sanguíneo y baja resistencia. La acción de los vasoconstrictores permite la formación de las interacciones entre actina y la cadena liviana de la miosina, esta es inducida en la célula muscular lisa principalmente por dos vías: a) dependiente de calcio, que consiste en aumentar el calcio intracelular, facilitando finalmente la unión de actina y miosina, y b) independiente de calcio, la cual a través de consecutivas fosforilaciones logra sensibilizar a las proteínas involucradas promoviendo la unión de actina y miosina. Estas acciones son mediadas por agonistas generados principalmente en el endotelio pulmonar, como endotelina-1 y tromboxano, o por agonistas provenientes de otros tipos celulares como la serotonina. Los agentes vasodilatadores regulan la respuesta vasoconstrictora, principalmente inhibiendo la señalización que induce la vasocontricción independiente de calcio, a través de la activación de proteínas quinasas que inhibirán la función de la ROCK quinasa, uno de los últimos efectores de la vasocontricción antes de la formación de la unión de actina y miosina. Esta revisión describe estos mecanismos de primordial importancia en las primeras horas de nuestra vida como individuos independientes.

The extrauterine-milieu adaptation includes a considerable increase in PaO2, that specifically induces structural and vasoactive changes at pulmonary circulation. Such changes transform a poor irrigated circulation into a circulation that receive ∼100% of neonatal cardiac output, supporting the normal alveolar-capillary gas exchange. Local regulation of basal neonatal pulmonary circulation is maintaining by a delicate equilibrium between vasoconstrictor and vasodilator agents. This equilibrium, allows to maintain the pulmonary circulation as an hemodynamic system with a high blood flow and a low vascular resistance. Vasocontrictors action allows actin and light-chain myosin interaction. Two main pathways induced this effect in smooth muscle cell: a) a calcium dependent pathway, that increases intracellular calcium, facilitating actin - myosin binding, and b) the independent calcium pathway, which achieves through consecutive phosphorylation reactions sensitize the proteins involved, promoting the binding of actin and light-chain myosin. These actions are mediated by agonists produced mainly in the pulmonary endothelium, such as endothelin-1 and thromboxane, or by agonists from other cell types such as serotonin. Vasodilator agents regulate the vasoconstrictor response, mainly by inhibiting signals that induce calcium-independent vasoconstriction, through activation of protein kinases, which in turn will inhibit the function of ROCK kinase, one of the last effectors of vasoconstriction before formation of the actin and light-chain myosin binding. This review will focus on describing these mechanisms of primal importance in the first hours of our lives as independent individuals.

Psiconeuroinmunología en el síndrome del intestino irritable / Psychoneuroimmunology in irritable bowel síndrome

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Serum interleukin-17 levels are associated with nephritis in childhood-onset systemic lupus erythematosus

OBJECTIVES: To determine the serum interleukin-17 (IL-17) levels in childhood-onset systemic lupus erythematosus patients and to evaluate the association between IL-17 and clinical manifestations, disease activity, laboratory findings and treatment. METHODS: We included 67 consecutive childhood-onset systemic lupus erythematosus patients [61 women; median age 18 years (range 11-31)], 55 first-degree relatives [50 women; median age 40 years (range 29-52)] and 47 age- and sex-matched healthy controls [42 women; median age 19 years (range 6-30)]. The childhood-onset systemic lupus erythematosus patients were assessed for clinical and laboratory systemic lupus erythematosus manifestations, disease activity [Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)], cumulative damage [Systemic Lupus International Collaborating Clinics/American College of Rheumatology (ACR) Damage Index] and current drug use. Serum IL-17 levels were measured by an enzyme-linked immunosorbent assay using commercial kits. RESULTS: The median serum IL-17 level was 36.3 (range 17.36-105.92) pg/mL in childhood-onset systemic lupus erythematosus patients and 29.47 (15.16-62.17) pg/mL in healthy controls (p=0.009). We observed an association between serum IL-17 levels and active nephritis (p=0.01) and migraines (p=0.03). Serum IL-17 levels were not associated with disease activity (p=0.32), cumulative damage (p=0.34), or medication use (p=0.63). CONCLUSION: IL-17 is increased in childhood-onset systemic lupus erythematosus and may play a role in the pathogenesis of neuropsychiatric and renal manifestations. Longitudinal studies are necessary to determine the role of IL-17 in childhood-onset systemic lupus erythematosus. .

Influência do uso de fluoxetina sobre o tempo de corrida em esteira ergométrica em ratos não treinados / Influence of using fluoxetine on run-time in treadmill in rats un trained / Efecto de la fluoxetina sobre el tiempo de ejecución en una cinta en ratas no entrenadas

Trabalhos de diferentes autores constataram que, um aumento na concentração de serotonina (5-HT) no cérebro, durante exercício físico intenso e prolongado, está diretamente relacionado a um prejuízo na função do Sistema Nervoso Central (SNC), com correspondente desenvolvimento da fadiga e consequente diminuição do desempenho. No presente trabalho, 10 ratos Wistar foram submetidos a sessões de corrida até o esgotamento físico em esteira rolante. Os protocolos experimentais foram divididos em quatro fases: Fase 1 - avaliação do tempo médio de corrida dos animais até o esgotamento físico; Fase 2 - avaliação do tempo médio de corrida dos animais até o esgotamento físico, sob tratamento com fluoxetina; Fase 3 - "washout" de sete dias; Fase 4 - "washout" de 14 dias. Este estudo sugere que a administração crônica de fluoxetina aumenta substancialmente o tempo médio de corrida até o esgotamento físico em ratos submetidos a exercício em esteira rolante.

Works of different authors have been shown that an increase in the concentration of serotonin (5-HT) in the brain during intense and long-term physical exercise, is directly associated with a harm in the function of the Central Nervous System (CNS), with corresponding development of the fatigue and consequence decrease of the performance. In the present work, 10 rats Wistar were submitted to run-sessions until the exhaustion in treadmill. The experimental protocols were splited in 4 phases: Phase 1: evaluation of the range run-time of the animals until the physical exhaustion. Phase 2: evaluation of the range run-time of the animals until the physical exhaustion on treatment with fluoxetine. Phase 3: washout seven days. Phase 4 washout 14 days. The present study suggest that chronic administration of fluoxetine increase substantially the run-time until the physical exhaustion in rats submitted to exercises in treadmill.

Las obras de diferentes autores encontraron que un aumento en la concentración de la serotonina (5-HT) en el cerebro durante el ejercicio intenso y prolongado está directamente relacionado con deterioro de la función del Sistema Nervioso Central (SNC), con el correspondiente desarrollo de la fatiga y su consecuente reducción en el rendimiento. En este estudio, 10 ratas Wistar fueron sometidas a la ejecución de sesiones en una cinta hasta el agotamiento físico. Los protocolos experimentales fueron divididos en cuatro fases: Fase 1 - Evaluación de la carrera media de los animales al agotamiento físico, la Fase 2 - Evaluación de la carrera media de los animales al agotamiento físico, están en tratamiento con fluoxetina, la Fase 3 - "lavado "de siete días; Fase 4 -" lavado "de 14 días. Este estudio sugiere que la administración crónica de fluoxetina incrementa sustancialmente la tarifa media del agotamiento físico en ratas sometidas a ejercicio en una caminadora.

New perspective on the pathophysiology of panic: merging serotonin and opioids in the periaqueductal gray

Panic disorder patients are vulnerable to recurrent panic attacks. Two neurochemical hypotheses have been proposed to explain this susceptibility. The first assumes that panic patients have deficient serotonergic inhibition of neurons localized in the dorsal periaqueductal gray matter of the midbrain that organize defensive reactions to cope with proximal threats and of sympathomotor control areas of the rostral ventrolateral medulla that generate most of the neurovegetative symptoms of the panic attack. The second suggests that endogenous opioids buffer normal subjects from the behavioral and physiological manifestations of the panic attack, and their deficit brings about heightened suffocation sensitivity and separation anxiety in panic patients, making them more vulnerable to panic attacks. Experimental results obtained in rats performing one-way escape in the elevated T-maze, an animal model of panic, indicate that the inhibitory action of serotonin on defense is connected with activation of endogenous opioids in the periaqueductal gray. This allows reconciliation of the serotonergic and opioidergic hypotheses of panic pathophysiology, the periaqueductal gray being the fulcrum of serotonin-opioid interaction.

Evidencia de asociación entre el gen SLC6A4 y efectos epistáticos con variantes en HTR2A en la etiología del autismo en la población antioqueña / Evidence for association and epistasis between the genetic markers SLC6A4 and HTR2A in autism etiology

Introducción. El espectro autista constituye un grupo de trastornos graves del neurodesarrollo, con un fuerte componente genético. Se ha sugerido un papel importante del sistema serotoninérgico en el desarrollo de este grupo de trastornos, con base en los estudios de respuesta a medicamentos y la hiperserotoninemia, característica común en el autismo. Se han implicado múltiples moléculas en el metabolismo y la neurotransmisión de la serotonina; sin embargo, los resultados de los estudios han tenido poca congruencia entre diferentes poblaciones. Objetivos. Evaluar la relación entre el autismo y el polimorfismo de nucleótido simple (Single Nucleotide Polymorphism, SNP) en los genes SLC6A4, HTR2A e ITGB3, en una muestra de la población antioqueña. Materiales y métodos. Se genotipificaron 42 núcleos familiares con autismo para 10 variantes en los genes SLC6A4, ITGB3 y HTR2A. Se evaluó la asociación utilizando la prueba de desequilibrio en la transmisión. Se exploró el impacto de la interacción entre estos genes y el autismo, utilizando la reducción multidimensional. Resultados. Se encontró asociación de las variantes rs4583306 (OR=2,6, p=0,004) y rs2066713 (OR=2,2 p=0,03), en el gen SLC6A4, y asociación de combinaciones genotípicas entre los genes SLC6A4 y HTR2A y el riesgo de autismo (p=0,0001). Conclusiones. Se encontró asociación significativa con variantes en el gen transportador de serotonina con el autismo, al igual que interacción entre variantes en los genes HTR2A con SLC6A4. Estos resultados concuerdan con los de estudios previos en otras poblaciones y son pruebas a favor del papel del sistema serotoninérgico en la etiología del espectro autista.

Introduction. Autism spectrum disorders are severe neurodevelopmental disorders with a strong genetic component. The potential role of the serotoninergic system in the development of autistic disorder has been based on the observation of hyperserotoninemia in autistic subjects and the results of drug treatment studies. Multiple molecules involved in serotonin metabolism and neurotransmission have been studied; however, replication studies have been inconsistent. This may be partially related to the marked genetic heterogeneity of autism in different populations. Objectives. The relationship between autism and single nucleotide polymorphisms of SLC6A4, HTR2A and ITGB3 genes was evaluated in an urban population of northwestern Colombia. Materials and methods. In Antioquia, Colombia, 42 families with history of autism were screened for 10 SNPs in SLC6A4, HTR2A and ITGB3 genes and evaluated for associations with the transmission disequilibrium test. The interactions among these genes and autism was assessed with multidimensional reduction methods. Results. A significant main effect was seen among the SLC6A4 gene variants rs4583306 (OR=2.6, p=0.004) and rs2066713 (OR=2.2, p=0.03). No main effect of the ITGB3 or HTR2A variants was found, however, in the interaction effects, the SLC6A4 and HTR2A genes demonstrated significant evidence of association with autism (p<0.001). Conclusion. Significant association of markers were discovered within the SLC6A4 gene and the combination of SLC6A4 and HTR2A (S-A) genes to autism. These results were consistent with previous studies conducted in other populations and provide further evidence for the implication of the serotoninergic system in the etiology of autistic disorders.

Serotonina e controle hipotalâmico da fome: uma revisão / Serotonin and hypothalamic control of hunger: a review

Este trabalho revisa a participação do sistema serotonérgico no controle da ingestão de alimentos e saciedade. É de grande interesse compreender a relevância desse sistema para o controle fisiológico do balanço energético e da obesidade. Mais de 35 anos de pesquisas sugerem que a serotonina (5-HT) desempenha um importante papel na saciedade. Assim, o sistema serotonérgico tem sido um alvo viável para o controle de peso. A 5-HT apresenta controle sobre a fome e a saciedade através de diversos receptores, com diferentes funções. O receptor 5-HT2C parece ser o mais importante na relação entre ingestão alimentar e balanço energético. Nesta revisão serão discutidos os mecanismos do sistema serotonérgico envolvidos no controle da ingestão de alimentos e saciedade.

This paper reviews involvement of the serotonergic system in the control of food intake and satiety. It is of great interest to understand the relevance of this system for physiological control of energy balance and obesity. Over 35 years of research suggest that serotonin (5-HT) plays an important role in satiety. Thus, the serotonergic system has been a viable target for weight control. The 5-HT has control over hunger and satiety through different receptors with distinct functions. The 5-HT2C receptor may be more important in the relationship between food intake and energy balance. This review will discuss the mechanisms of the serotonergic system involved in the control of food intake and satiety.

El cerebro social: bases neurobiológicas de interés clínico / The social brain: neurobiological bases of clinical interest

Introducción. Las capacidades sociales humanas son evolutivamente tardías y únicas. Permiten una especialización que mejora la disponibilidad de recursos y facilita la reproducción. Nuestra complejidad social descansa en circuitos y mecanismos específicos, que analizamos. Desarrollo. A esos efectos, resultan operativos: el conocimiento del otro mediante la empatía, mecanismos específicos que nos dotan de capacidad para detectar defraudadores, factores genéticos y bioquímicos, y el sistema nervioso autónomo. La empatía es el mecanismo básico de la sociabilidad. Reconoce niveles de complejidad (emocional, cognitiva, de atribución), con diferenciación anatómica específica. Lo social va ligado a lo emocional, y esto a lo homeostático. Así, dolor físico y social comparten matriz anatómica y terapias. Somos seres sociales de naturaleza biológica egoísta, que ajustamos gracias a una capacidad especial para detectar defraudadores, dominante sobre las de planificación o abstracción. La oxitocina es el mediador neuroquímico prosocial esencial. La serotonina y la enzima MAO se consideran con capacidad antisocial, dependiente de la interacción con ambientes adversos. Finalmente, el sistema vagal más reciente filogenéticamente y mielinizado, el del núcleo dorsal del vago, es requisito para la interacción social acogedora y lúdica. Conclusiones. La neurobiología de lo social permite reconocer trastornos de esta conducta en lesiones estructurales (vasculares, de la sustancia blanca, demencias...), alteraciones del neurodesarrollo (autismo), enfermedades psiquiátricas (esquizofrenia) o trastornos de la personalidad. Existen posibilidades de intervención terapéutica (estimulación magnética transcraneal, fármacos) prometedoras. La adición de factores culturales y ambientales a los neurobiológicos introduce complejidad ecológica, sin restar validez a lo expuesto (AU)

Introduction. Human social capacities are developmentally late and unique. They allow for a specialisation that enhances the availability of resources and facilitates reproduction. Our social complexity rests on specific circuits and mechanisms, which are analysed here. Development. The following are put into operation for those purposes: knowledge of the other by means of empathy, specific mechanisms that endow us with the capacity to detect defrauders, genetic and biochemical factors, and the autonomic nervous system. Empathy is the basic mechanism in sociability. It has different levels of complexity (emotional, cognitive, attribution), with specific anatomical differentiation. Social matters are linked to emotional ones, and this in turn to the homeostatic aspects. Hence, physical and social pain share an anatomical matrix and therapies. We are social beings of a selfish biological nature, which we adjust thanks to a special capacity to detect defrauders, which is dominant over those involving planning or abstraction. Oxytocin is the essential prosocial neurochemical mediator. Serotonin and the enzyme MAO are considered as having an antisocial capacity, which is dependent on the interaction with adverse environments. Finally, the vagal system, which is more recent phylogenetically speaking and myelinated, that of the dorsal nucleus of the vagus nerve, is a requirement for warm and leisurely social interaction. Conclusions. The neurobiology of social matters makes it possible to recognise disorders affecting this behaviour in structural injuries (vascular, of the white matter, dementias, etc.), neurodevelopmental disorders (autism), psychiatric illnesses (schizophrenia) or personality disorders. There are a number of promising therapeutic interventions (transcranial magnetic stimulation, drugs). The addition of cultural and environmental factors to the neurobiological ones introduces a greater amount of ecological complexity, but without lessening the validity of what it outlined (AU)

Neurobiologia dos transtornos do controle dos impulsos / The neurobiology of impulse control disorders

OBJETIVO: Revisar os artigos sobre substratos neurobiológicos dos transtornos do controle dos impulsos. O jogo patológico é o foco central desta revisão na medida em que a maioria dos estudos biológicos dos formalmente classificados como transtornos do controle dos impulsos examinou este transtorno. MÉTODO: Foi feita uma busca no banco de dados Medline de artigos publicados de 1966 até o presente para identificar aqueles relevantes para serem revisados neste artigo. DESFECHOS: Estudos pré-clínicos sugerem que a neuromodulação das monoaminas cerebrais está associada à tomada de decisões impulsivas e aos comportamentos de risco. Os estudos clínicos implicam diversos sistemas de neurotransmissores (serotoninérgico, dopaminérgico, adrenérgico e opióide) na fisiopatologia do jogo patológico e de outros transtornos do controle dos impulsos. Estudos de neuroimagem preliminares têm indicado o córtex pré-frontal ventromedial e o estriato ventral como atuantes na fisiopatologia do jogo patológico e de outros transtornos do controle dos impulsos. As contribuições genéticas para o jogo patológico parecem substanciais e os estudos iniciais têm relacionado esse transtorno a polimorfismos alélicos específicos, ainda que os achados de varredura genômica ainda tenham que ser publicados. CONCLUSÃO: Mesmo que tenham sido logrados avanços significativos em nossa compreensão sobre os transtornos do controle dos impulsos, mais pesquisas são necessárias para ampliar o conhecimento existente e traduzir esses achados em avanços clínicos.

OBJECTIVE: To review the neurobiological substrates of impulse control disorders. Pathological gambling is a main focus of the review in that most biological studies of the formal impulse control disorders have examined this disorder. METHOD: The medical database Medline from 1966 to present was searched to identify relevant articles that were subsequently reviewed to generate this manuscript. RESULTS: Preclinical studies suggest that differential brain monoamine neuromodulation is associated with impulsive decision-making and risk-taking behaviors. Clinical studies implicate multiple neurotransmitter systems (serotonergic, dopaminergic, adrenergic, and opioidergic) in the pathophysiology of pathological gambling and other impulse control disorders. Initial neuroimaging studies have implicated the ventromedial prefrontal cortex and ventral striatum in the pathophysiology of pathological gambling and other impulse control disorders. Genetic contributions to pathological gambling seem substantial and initial studies have implicated specific allelic polymorphisms, although genome-wide analyses have yet to be published. CONCLUSION: Although significant advances have been made in our understanding of the neurobiology of impulse control disorders, more research is needed to extend existing knowledge and translate these findings into clinical advances.

Elevated mazes as animal models of anxiety: effects of serotonergic agents

This article reviews reported results about the effects of drugs that act upon the serotonergic neurotransmission measured in three elevated mazes that are animal models of anxiety. A bibliographic search has been performed in MEDLINE using different combinations of the key words X-maze, plus-maze, T-maze, serotonin and 5-HT, present in the title and/or the abstract, with no time limit. From the obtained abstracts, several publications were excluded on the basis of the following criteria: review articles that did not report original results, species other than the rat, intracerebral drug administration alone, genetically manipulated rats, and animals having any kind of experimental pathology. The reported results indicate that the effect of drugs on the inhibitory avoidance task performed in the elevated T-maze and on the spatio temporal indexes of anxiety measured in the X and plus mazes correlate with their effect in patients diagnosed with generalized anxiety disorder. In contrast, the drug effects on the one-way escape task in the elevated T-maze predict the drug response of panic disorder patients. Overall, the drug effects assessed with the avoidance task in the T-maze are more consistent than those measured through the anxiety indexes of the X and plus mazes. Therefore, the elevated T-maze is a promising animal model of generalized anxiety and panic disorder.

No presente artigo, revisamos resultados publicados relatando efeitos de drogas que atuam na neurotransmissão serotonérgica medidos em três labirintos elevados, que são modelos animais de ansiedade. Realizamos uma busca bibliográfica no MEDLINE, usando diferentes combinações das palavras-chave: X-maze, plus-maze, T-maze, serotonin e 5-HT, presentes no título ou no resumo, sem limite de tempo. Dos resumos obtidos, vários foram excluídos com base nos seguintes critérios: artigos de revisão que não continham resultados originais, espécies diferentes do rato, apenas injeções intracerebrais, ratos geneticamente manipulados, animais com algum tipo de patologia experimental. Os resultados relatados indicam que o efeito de drogas na tarefa de esquiva inibitória desempenhada no labirinto em T elevado, bem como nos índices espaciais de ansiedade nos labirintos em X ou em forma de cruz se correlacionam com os efeitos em pacientes diagnosticados com o transtorno de ansiedade generalizada. Por outro lado, os efeitos de drogas na tarefa de fuga unidirecional do labirinto em T predizem a resposta a drogas dos pacientes com o transtorno de pânico. De modo geral, os efeitos de drogas sobre a tarefa de esquiva no labirinto em T são mais consistentes que os medidos pelos índices de ansiedade calculados nos labirintos em X e em forma de cruz. Portanto, o labirinto em T-elevado é um modelo promissor dos transtornos de ansiedade generalizada e de pânico.

Modulación de los receptores ionotrópicos de tipo cys-loop por proteincinasas A y C / Cys-loop ligand-gated ion channels modulation by protein kinases A and C

Introducción. En el sistema nervioso, la neurotransmisión química rápida es mediada por receptores ionotrópicos que se activan por la unión de su ligando. La unión del ligando a su receptor, favorece la entrada selectiva de iones a la célula que cambia el potencial eléctrico de la membrana celular. Los receptores de tipo cys-loop pertenecen a la superfamilia de receptores ionotrópicos activados por ligando que comprende a los receptores nicotínicos de acetilcolina, del ácido gamma-aminobutírico, glicina, serotonina y zinc. En diversos estudios se demostró que la actividad de estos receptores se modifica en respuesta a la activación de las proteincinasas A y C; los diferentes resultados, aparentemente contradictorios, podrían explicarse por la participación de diversos factores como el tipo de subunidades que forman a los receptores, componentes del citoesqueleto y subtipos de cinasas y fosfatasas presentes en el tejido nervioso de estudio. Objetivo. Presentar una revisión del efecto que las proteincinasas A y C ejercen sobre la actividad de los receptores ionotrópicos de tipo cys-loop. Desarrollo. En esta revisión se describen los experimentos obtenidos en diversas regiones en las que se ha determinado el efecto que tiene la activación de estas cinasas sobre la función de los receptores de neurotransmisores mayormente distribuidos en el sistema nervioso central y que han sido objeto de estudio. Conclusiones. La regulación de los receptores de tipo cys-loop por proteincinasas ocurre por medio de la activación de otros receptores (cross-talk) que se expresan en diversas etapas del desarrollo y áreas del sistema nervioso (AU)

Introduction. In the nervous system, rapid chemical neurotransmission is mediated by ionotropic receptors that are activated by ligand binding. Ligand binding to its receptor promotes the selective flow of ions into the cell which changes the electrical potential of the cell membrane. Cys-loop type receptors belong to the ligand-gated ion channel superfamily including the nicotinic acetylcholine receptor, the gamma-aminobutyric acid, glycine, serotonin and zinc. Several studies showed that the activity of these receptors was modified in response to protein kinases A and C activation; the different results, apparently contradictory, could be explained by the involvement of several factors such as the type of subunits that make up these receptors, components of the cytoskeleton and sub-types of kinases and phosphatases present in nerve tissue studied. Aim. To review the effect of protein kinases A and C on the activity of cys-loop receptors. Development. In this review we describe experiments conducted in different regions where it was determined the effect of these kinases on the function of neurotransmitter receptors mostly distributed in the nervous system. Conclusions. The cys-loop receptors regulation by protein kinases occurs through the activation of other receptors (crosstalk) that are expressed at different stages of development and nervous system areas (AU)

Evidence indicating participation of the serotonergic system in controlling feeding behavior in Coturnix japonica (Galliformes: Aves)

Investigamos a participação do sistema serotonérgico cerebral no controle da ingestão de alimento em codornas (Coturnix japonica) por meio da administração oral e sistêmica de precursores da serotonina. A suplementação dietética com triptofano (0,1-50,0 g/kg de ração) provocou inibição dose-dependente da ingestão de alimento em 5 h de avaliação, que se manteve ao final de 24 h com doses de 30,0 e 50,0 g/kg. Codornas tratadas com hidroxitriptofano (12,5-50,0 mg/kg, via intracoelomática) exibiram aguda inibição da ingestão alimentar, tanto as normoalimentadas quanto as submetidas ao jejum. Nas aves em jejum, a resposta hipofágica foi efetiva apenas quando a administração do precursor foi feita imediatamente antes da oferta de alimento. Resposta similar foi alcançada com a administração de serotonina (0,125-2,5 mg/kg, sc). Nos minutos iniciais após a administração desenvolveu-se resposta hipnogênica, implicando assunção de que essa amina atravessa a barreira hemato-encefálica em codornas, diferentemente do observado em mamíferos. A administração de hidroxitriptofano em todas as doses utilizadas induziu intensa resposta dipsogênica, não obstante o desenvolvimento concomitante de resposta hipnogênica. Os resultados sugerem o envolvimento de vias serotonérgicas no controle da ingestão de alimento em codornas e mostram pela primeira vez as ações hipnógena, induzida pela serotonina e hiperdipsética, pelo hidroxitriptofano.

Efectos contráctiles dependientes del calcio intracelular inducidos por la serotonina en la arteria umbilical humana / Intracellular calcium-dependent contractile effects of serotonin in the human umbilical artery

Antecedentes: Los vasos umbilicales humanos se caracterizan por la ausencia de inervación y por consecuencia, las diferentes sustancias vasoactivas y la respuesta contráctil a través de los iones de calcio son los factores que determinan el flujo sanguíneo al espacio intervelloso en condiciones normales y patológicas, como es el caso de la preeclampsia eclampsia. Objetivo: Aportar información adicional de la respuesta contráctil de la serotonina en relación al calcio intracelular en la arteria umbilical humana. Material y métodos: Se utilizaron vasos umbilicales procedentes de mujeres con embarazo normoevolutivo, los cuales una vez disecados se cortaron en anillos de 5 mm y se montaron en cámara de órgano aislado, utilizando solución de Krebs con y sin calcio, burbujeada con carbógeno y la temperatura controlada. Se evaluó el efecto contráctil inducido por serotonina a diferentes concentraciones molares y se contrastó con verapamil, lantano y ácido ciclopiazónico, cuantificando la respuesta contráctil mediante un polígrafo biopac acoplado a un sistema computacional. Resultados: No se observaron diferencias significativas en la magnitud de la respuesta obtenida en presencia y ausencia de calcio extracelular. Se apreció el efecto contráctil a la serotonina que disminuyó significati vamente como respuesta a la estimulación repetida a la misma; así mismo, se incrementó el tono basal posterior a la adición del calcio al medio de incubación, lo que dependió del tiempo de exposición. También se observó la inhibición parcial del incremento en el tono basal con vera pamil y lantano. Finalmente, el pretratamiento con ácido ciclopiazónico no modificó la respuesta contráctil a la serotonina en un medio sin calcio. Conclusiones: La contracción inducida por serotonina en la arteria umbilical humana, depende principalmente de calcio intracelular y favorece el ingreso capacitativo de este ion, el cual se incrementa gradualmente a través del tiempo. El ingreso capacitativo del calcio secundario al vaciamiento de los depósitos intracelulares de este ion con serotonina se efectúa a través de canales tipo L y no-L, y no parecen ser sensibles al ácido ciclopiazónico.

Background: Absence of innervation is a hallmark of human umbilical vessels. Intervillous space blood flow is regulated by vasoactive substances and calcium dependent contractility, both in normal and pathological conditions such as preeclampsia eclampsia. Objective: To obtain additional information on the intracellular calcium contractile effects of serotonin in human umbilical arteries. Materials and Methods: Umbilical arteries from normal pregnancies were dissected, cut in 5 mm rings and mounted in a temperature controlled isolated organ chamber, using calciumfree Krebs solution. The contractile effects of serotonin, lantane, verapamil and cyclopiazonic acid were evaluated at different concentrations using a computer coupled biopac polygraph. Results: No differences in response were observed in the presence and absence of intracellular calcium. The positive contractile effects observed with serotonin were significantly decreased with repeated stimulation. An increase in the basal tone of the vessel was observed after calcium supplementation was added to the solution. This effect was minimized in the presence of verapamil and lantane. The contractile effects of serotonin in the calcium free solution were not affected by the presence of cyclopiazonic acid. Conclusions: Serotonin contractile effects in the human umbilical artery depend mainly on intracellular calcium levels which favor the gradual entrance of this ion over time. Calcium influx induced by serotonin is possible through L and Non-L channels apparently insensitive to cyclopiozonic acid.