Thesis (Ph. D.)--University of Wisconsin--Madison, 1990. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 107-128).

This paper provides evidence to support the hypothesis that the locus coeruleus – norephinephrine (LC-NE) system is the neurophysiological basis of both the attentional blink (AB) and the event related potential (ERP) component known as the P300. The LC-NE system is thought to provide a brief burst of processing facilitation in response to motivationally salient events. The AB refers to decreased accuracy for reporting the second of two targets (T1 and T2) inserted into a rapid serial visual presentation (RSVP). The LC-NE account of the AB holds that the AB is the result of a refractory-like period in LC-NE activity. The LC-NE account of the P300 suggests the P300 is the electrophysiological manifestation of the activity of the LC-NE system. I support the three-way link between these different aspects of brain activity by predicting differences in the AB dependent on characteristics of the P300 in response to T1 (T1-P300).

A glândula pineal de mamíferos não é uma estrutura oscilatória autônoma, exigindo a liberação de noradrenalina (Nor) na fase escura para que a melatonina seja circadianamente produzida. Na cultura padrão de glândula pineal, o órgão não expressa ritmicidade funcional e para mimetizar o padrão fisiológico de liberação de Nor, desenvolvemos a cultura temporizada com Nor. Logo, o objetivo desse trabalho foi investigar a manutenção do ritmo de expressão dos genes relógio pela cultura temporizada, e qual a via noradrenérgica envolvida. Para os estudos in vitro, realizaram-se culturas dos grupos: controle (sem Nor), agudo (cultura padrão) e temporizado (12h com Nor/12h sem Nor). Além disso, à cultura temporizada se adicionou Prasozin e/ou Propranolol. Analisou-se expressão dos genes relógio, atividade da enzima AANAT e conteúdo de melatonina no meio de cultura. No grupo temporizado, observou-se a manutenção da ritmicidade dos genes analisados, diferente do observado nos grupos controle, agudo e temporizado tratado com bloqueadores, além do aumento da atividade enzimática da AANAT e aumento do conteúdo de melatonina. Em suma, a cultura temporizada com Nor se mostra importante para evitar a arritmicidade encontrada na cultura padrão de glândula pineal. / The mammals pineal gland is not an autonomous oscillator, the circadian melatonin synthesis requires the release of norepinephrine (NE) on the dark phase. In standard pineal gland culture, the glands do not express any functional rhythmicity. To mimic the physiological pattern of NE release in the pineal gland culture, we developed a synchronized culture with NE. We aimed to investigate the maintenance of circadian clock genes expression within rat pineal gland under acute and synchronized culture and the noradrenergic pathway involved. In in vitro experiments, culture glands were under: control (without NE), acute (standard culture) and synchronized (12h with NE/12h without NE) conditions. Furthermore, in the synchronized group were added Prasozin and/or Propranolol. We investigated clock genes expression, AANAT activity and melatonin content. The synchronized culture was able to maintain the rhythmic clock genes expression, which didn´t occur in control, acute and synchronized treated with blockers groups, and was able to improve AANAT activity and melatonin synthesis. In conclusion, synchronized culture method showed as a useful approach to avoid disruption of rhythmic variations found in the standard culture.

Introdução: O choque séptico é complicação frequente e grave nos pacientes com câncer. Representa uma das principais causas de admissão em Unidade de Terapia Intensiva (UTI), com taxa de mortalidade em torno de 40% a 60%. O tratamento com vasopressor é parte fundamental do suporte hemodinâmico do paciente com choque séptico, sendo a norepinefrina o fármaco mais utilizado. Entretanto, aproximadamente 40% dos pacientes apresentam choque refratário a esse fármaco e vários eventos adversos são descritos, dentre eles vasoconstricção excessiva, redução do fluxo sanguíneo para os tecidos, distúrbios metabólicos e desequilíbrio imunológico. A vasopressina é um vasopressor não catecolaminérgico, que vem demonstrando ser eficiente vasopressor adjuvante no choque séptico. O objetivo desse estudo é avaliar se a vasopressina é superior à norepinefrina na mortalidade em 28 dias de pacientes com câncer e choque séptico. Métodos: Estudo unicêntrico, prospectivo, randomizado e duplo cego. Foram incluídos no estudo 250 pacientes com câncer e choque séptico no período de 20 de julho de 2013 a 6 de julho de 2016. Os pacientes foram randomizados para receber vasopressina (0,01 U/minuto a 0,06 U/minuto) ou norepinefrina (0,1 ug/kg/min a 1,0 ug/kg/min) como vasopressor no choque. A infusão dos fármacos foi titulada para manter a pressão arterial média (PAM) alvo ( >= 65 mmHg) após randomização. O desfecho primário foi mortalidade em 28 dias. Os desfechos secundários foram mortalidade em 90 dias, dias vivo e livres de ventilação mecânica, de vasopressores, e de terapia de substituição renal, e avaliação de disfunções orgânicas conforme o Sequential Organ Failure Assessment (SOFA) 24 horas e 96 horas após a randomização. Resultados: Foram elegíveis 1116 pacientes, sendo 250 pacientes incluídos no estudo e randomizados para vasopressina (n = 125) ou para norepinefrina (n = 125). Não houve perdas ou violação de protocolo. Não houve diferença na mortalidade em 28 dias (56,8% no grupo vasopressina vs. 52,8% no grupo norepinefrina, p = 0,525). A mortalidade em 90 dias também não foi diferente nos grupos, respectivamente nos grupos vasopressina e norepinefrina (72,0% vs. 75,2%, p = 0,566). Não houve diferença entre os grupos vasopressina e norepinefrina em relação aos dias vivos e livres de ventilação mecânica [20 (6-28) vs. 22 (7-28), p = 0,748], de dias livres de vasopressores [10 (1-23) vs. 12 (1-24), p = 0,669], e dias livres de terapia de substituição renal [20 (7- 28) vs. 21 (7-28), p = 0,819]. O escore SOFA não foi diferente entre os grupos vasopressina e norepinefrina 24 horas após a randomização [8 (5-11) vs. 7 (5-10), p = 0,425] e 96 horas após [7 (2-12) vs. 7 (3-12), p = 0,825]. Conclusão: A vasopressina não é superior à norepinefrina na mortalidade em 28 dias de pacientes com câncer e choque séptico / Background: Septic shock is a frequent complication in cancer patients. It is one of the most common admission causes in the intensive care unit (ICU), with mortality rates of 40% to 60%. Patients with septic shock often need the use of vasopressors for hemodynamic support and norepinephrine is the most used medication in this setting. However, 40% of patients have shock that is refractory to norepinephrine and lots of adverse effects are described, including excessive vasoconstriction, reduced blood flow to tissues and cells, and metabolic and immunologic disorders. Vasopressin is commonly used as an adjunct to catecholamines to support blood pressure in refractory septic shock. We hypothesized that the use of vasopressin would be more effective on the treatment of septic shock in cancer patients than norepinephrine, decreasing 28-day mortality. Methods: In this prospective and randomized, double-blind trial, we assigned patients who had cancer and septic shock to receive either vasopressin (0.01 U/minute to 0.06 U/minute) or norepinephrine (10 ?g/minute to 60 ?g/minute) in addition to open-label vasopressors. All vasopressor infusions were titrated and tapered according to protocols in order to maintain a target mean arterial pressure of 65 mmHg. The primary endpoint was 28-day mortality. Secondary outcomes included 90-day mortality, days alive and free of mechanical ventilation, free of vasopressors and renal replacement therapy, and SOFA 24 h and 96h after randomization. Results: 1116 patients were eligible to the study. 250 patients were included on the study and underwent randomization: 125 patients received vasopressin and 125, norepinephrine. There was no difference between groups in 28-day mortality (56.8% in vasopressin group vs. 52.8% in norepinephrine group, p = 0.525). In addition, 90-day mortality was not different between vasopressin and norepinephrine groups (72% vs. 75.2%, p = 0.566). There was also no difference between vasopressin and norepinephrine groups in days alive and free of mechanical ventilation [20 (6- 28) vs. 22 (7-28), p = 0.748], free of vasopressors [10 (1-23) vs. 12 (1-24), p = 0.669], and renal replacement therapy [20 (7-28) vs. 21 (7-28), p = 0.819]. SOFA score was not different between vasopressin and norepinephrine groups after 24 h [8 (5-11) vs. 7 (5-10), p = 0.425] and after 96h [7 (2-12) vs. 7 (3-12), p = 0.825]. Conclusion: Vasopressin is not superior to norepinephrine in 28-day mortality rate in cancer patients with septic shock

Only one third of depressed patients experience a beneficial therapeutic effect after using a first-line medication, leaving two-thirds of patients without effective treatment. It has been shown that a combination of two drugs with different modes of action result in an increase in the number of patients responding to treatment. One of the most effective strategies is the addition of low doses of an atypical antipsychotic. In depth evaluation of the neurobiological properties of atypical antipsychotics have revealed that these agents produce antidepressant effects and enhance the therapeutic response of first-line medications through antagonism of the 5-HT2A, 5-HT2C, 5-HT1B/D, 5-HT7 receptors and NET; agonism of the 5-HT1A receptor; and/or D2/3 partial agonism. The present experiments focused on determining the mode of action of this combination of drugs to help design better antidepressant treatment in the future. A series of electrophysiological experiments were proposed to assess 5-HT and NE neurotransmission in the rat hippocampus, as well as DA transmission in the rat forebrain.

No description available.

Electroconvulsive therapy (ECT) effectively treats depression by administration of repeated seizure-inducing electrical stimuli. Sprague-Dawley rats were administered 6 electroconvulsive shocks (ECS) over 2 weeks, and in vivo single unit extracellular electrophysiological activity was recorded after 48 hours. Overall firing activity in the locus coeruleus and ventral tegmental area was unchanged, suggesting the therapeutic efficacy of ECT may not be attributed to increased norepinephrine and dopamine release. There were more spontaneously active neurons in the substantia nigra pars compacta (SNc), indicating greater dopamine tone in the nigrostriatal motor pathway, which may contribute to alleviation of psychomotor retardation. In the facial motor nucleus (FMN), locally administered norepinephrine, but not serotonin, facilitated greater glutamate-induced firing, which may contribute to improved facial motricity. Current results indicate that repeated ECS enhances postsynaptic norepinephrine neurotransmission in the FMN and SNc dopamine neurotransmission, which could represent the mechanism behind the alleviation of depressive symptoms including psychomotor retardation.

Introduction: major depressive disorder is a common psychiatric disorder associated with high economic cost, severe human suffering, and low remission rates. Imbalanced neurotransmission of the monoaminergic serotonin (5-HT), dopamine (DA) and norepinephrine (NE) systems is implicated in this disorder. However, the etiology underlying this presumed imbalance and the mechanism by which antidepressant strategies restore this imbalance requires further exploration. Accordingly, the present work assessed the effects of depressogenic and antidepressant-like conditions on these systems. Methodology: Electrophysiological extracellular single unit recordings from 5-HT, DA, NE, and hippocampal pyramidal neurons were obtained in adult male chloral hydrate anaesthetized Sprague-Dawley rats. Effects on relevant receptors were characterized using established electrophysiological and/or pharmacological strategies. Prenatal stress was used to model depressogenic-like conditions. The effects on monoamine systems of asenapine and brexpiprazole, two atypical antipsychotics with antidepressant potential, were characterized after acute (brexpiprazole) and sustained administration. These sustained regimens resulted in clinically relevant blood plasma levels. Results: Prenatal stress exposure altered monoamine system activities but did not produce detrimental effects on behavior. Asenapine and brexpiprazole had unique effects on the activities of monoamine systems. Unlike other antipsychotics, both agents did not produce a cessation of the firing of dopamine neurons in the ventral tegmental area, thereby providing novel insights in the role of this system in the treatment of mood disorders. Furthermore, both agents enhanced the tonic activation of postsynaptic 5-HT1A receptors, similarly to the effects of all antidepressant strategies. Conclusion: Prenatal stress altered the activities of 5-HT, NE and DA neurons. Since these central changes were obtained in animals displaying normal behavior, they presumably reflect adaptations to depressogenic-like conditions. The characterization of asenapine and brexpiprazole contributed to a further understanding of their mechanisms of action. Together, these studies provide insight in neural substrates presumably relevant to the antidepressant response.

The establishment of physiological norms for psychologically hardy vs. non-hardy individuals was attempted by examination of levels of salivary cortisol and urinary norepinephrine before and after a mid-term examination stressor. Normative data was collected on the reported frequency of stressors and their severity one week prior to the examination, and self-reported ratings of stress immediately prior to the examination. Performance on the examination as a function of hardiness was explored. Associations between demographic variables and psychological hardiness were also studied. Results from this study were inconclusive in establishing physiological norms for psychologically hardy individuals. Associations were found between: 1) hardiness and frequency of stressors; 2) hardiness and age; and 3) self-reported ratings of stress and anxiety as measured by the State-Trait Anxiety Inventory (STAI).

Rationale Many studies demonstrate down-regulation of the norepinephrine transporter (NET) by desipramine (DMI) in vitro and in stress-naive rats. Little is known regarding regulation of the NET in stressed animals. Objective The present study was designed to investigate effects of DMI on the expression of NET and protein kinases in the stress rat. Methods Adult Fischer 344 rats were subjected to chronic social defeat (CSD) for 4 weeks. DMI (10 mg/kg, intraperitoneal (i.p.)) was administered concurrently with CSD or 1 or 2 weeks after cessation of CSD. Sucrose consumption, NET expression, and protein kinases were measured. Results CSD significantly increased messenger RNA (mRNA) and protein levels of NET in the locus coeruleus, as well as NET protein levels in the hippocampus, frontal cortex, and amygdala. These effects were nearly abolished when DMI was administered concurrently with CSD. CSD-induced upregulation of NET expression in the locus coeruleus, hippocampus, and amygdala lasted at least 2 weeks after cessation of CSD, an effect that was significantly attenuated by 1 or 2 weeks of DMI treatment starting from cessation of the CSD. Concurrent administration of DMI with CSD did not markedly interfere with CSD-induced decreases in protein levels of protein kinases A and C in these brain regions, but it did reverse the CSD-induced reduction in phosphorylated cAMP response element-binding (pCREB) protein levels in most brain regions. Conclusion These findings suggest that NET regulation by DMI occurs in both stressed and behaviorally naive rats, and DMI-induced changes in pCREB may be involved.