Submitted by Ismael Pereira (ismael@neuro.ufrn.br) on 2017-11-03T14:45:12Z No. of bitstreams: 1 Tese_AdrianoTort_2005.pdf: 1861214 bytes, checksum: 93eb092dffbce7414f26253895b0ad28 (MD5) / Approved for entry into archive by Ismael Pereira (ismael@neuro.ufrn.br) on 2017-11-03T14:46:05Z (GMT) No. of bitstreams: 1 Tese_AdrianoTort_2005.pdf: 1861214 bytes, checksum: 93eb092dffbce7414f26253895b0ad28 (MD5) / Made available in DSpace on 2017-11-06T11:41:34Z (GMT). No. of bitstreams: 1 Tese_AdrianoTort_2005.pdf: 1861214 bytes, checksum: 93eb092dffbce7414f26253895b0ad28 (MD5) Previous issue date: 2005-12 / Os objetivos da presente tese de doutorado foram os de buscar novos antipsic?ticos at?picos de baixo pre?o comercial e tamb?m procurar entender o mecanismo de a??o que leva a um perfil antipsic?tico at?pico. Os resultados da tese s?o divididos em duas partes, de acordo com sua natureza, em experimentais (primeira parte) e te?ricos (segunda parte). Para o desenvolvimento da primeira parte, foi necess?ria primeiramente a programa??o de um software para medir locomo??o em roedores ap?s filmagem com webcam. A seguir, foram investigados os efeitos da guanosina, flunarizina e cinarizina em modelos animais de psicose, bem como em outros paradigmas comportamentais. A guanosina foi escolhida para estudo uma vez que tem se mostrado que ela interage com o sistema glutamat?rgico ? que sabidamente est? envolvido na fisiopatologia da esquizofrenia ? promovendo a capta??o astrocit?ria de glutamato. J? a flunarizina e a cinarizina, dois bloqueadores de canal de c?lcio empregados para tratar enxaqueca e vertigem foram escolhidas pelo fato delas produzirem sinais e sintomas extrapiramidais em pacientes idosos, o que posteriormente foi relacionado ?s suas propriedades como antagonistas moderados dos receptores dopamin?rgicos do tipo D2. A guanosina diminuiu o aumento de locomo??o induzido por um antagonista NMDA (MK-801), enquanto que n?o apresentou efeito sobre o aumento de locomo??o induzido por anfetamina, de forma que sua utilidade como potencial antipsic?tico deve ser ainda melhor estudada. Tanto a flunarizina quanto a cinarizina foram capazes de diminuir o aumento de locomo??o induzido por MK-801 e por anfetamina em doses que n?o causam efeitos catal?pticos importantes. Portanto, foi conclu?do que estes dois compostos apresentam um potencial perfil de antipsic?tico at?pico, com as vantagens de j? estarem dispon?veis para uso comercial, boa tolerabilidade e baixo custo quando comparados com os antipsic?ticos at?picos dispon?veis comercialmente nos dias de hoje. A segunda parte da tese apresenta alguns resultados te?ricos matem?ticos que podem ser derivados da teoria da lei de a??o das massas aplicada ao binding de receptores, utilizando tamb?m resultados experimentais j? conhecidos de PET. Estes resultados apresentam insights ao entendimento das diferen?as entre os perfis antipsic?ticos at?picos e t?picos em rela??o ? gera??o de sinais extrapiramidais. ? discutido que fatores culturais e comerciais relacionados ? posologia atual empregada no tratamento com antipsic?ticos t?picos podem ser os respons?veis pelas diferen?as de perfis, uma vez que alguns deles s?o prescritos em doses proporcionalmente maiores em rela??o ? sua afinidade, atingindo assim maiores n?veis de bloqueio dopamin?rgico no estriado. Uma curta meia-vida plasm?tica tamb?m ? apontada como um poss?vel par?metro importante na gera??o de um perfil at?pico. ? mostrado ainda alguns erros de concep??o relacionados ao curso temporal da ocupa??o dopamin?rgica que tem sido atualmente cometidos na literatura cient?fica, como o conceito de meia-vida de ocupa??o de receptores. Como um ?ltimo resultado te?rico, ? proposto um algoritmo para a redu??o de dose em pacientes tratados com antipsic?ticos apresentando sinais e sintomas extrapiramidais. / The aims of this work were the search for new atypical antipsychotics presenting low cost and the understanding of the mechanism of action leading to atypical antipsychotic profile. The results obtained are presented in two distinct parts based on their nature, namely, experimental (first part) or theoretical (second part). For the development of the first part, a webcam based software to measure locomotion of rodents was programmed. After that, it was investigated the effect of guanosine, flunarizine and cinnarizine on animal models of psychosis, as well as in other behavioral tasks. Guanosine was chosen because it has been shown to interact with the glutamatergic system ? which is known to be involved in the pathophysiology of schizophrenia ? by promoting astrocytic glutamate reuptake. Flunarizine and cinnarizine, two calcium channel blockers commonly used in many countries to treat vertigo and migraine, were chosen because they were shown to induce extrapyramidal signs in elder patients, which was later related to moderate antagonist properties at dopamine D2 receptors. Guanosine was able to reduce a NMDA antagonist (MK-801) induced hyperlocomotion, whereas it had no effect on the hyperlocomotion induced by amphetamine, and it is discussed that its utility as antipsychotic drug should be further evaluated. Both cinnarizine and flunarizine were able to reduce the hyperlocomotion induced by MK-801 and amphetamine at doses that presented no significant cataleptic behavior. It was therefore concluded that these compounds have a potential atypical antipsychotic profile, with the advantage of already approved for commercial use, presenting well tolerability and very low cost when compared to current commercially available atypical antipsychotics. The second part of this thesis presents some theoretical mathematical results that can be derived from the law of mass action theory applied to receptor binding linked with known PET experimental data. These results present insights to the understanding of the differences between typical and atypical profile of antipsychotics regarding the generation of extrapyramidal syndrome. It is argued that cultural and commercial aspects related to the nowadays employed posology of typical antipsychotics can be responsible for the difference seen in profile, once some typical antipsychotics are prescribed in proportionally higher doses in relation to their affinities, leading therefore to higher dopaminergic blockade. A short plasmatic half-life is also pointed as a possible important factor leading to an atipical profile. Moreover, the second part of this thesis also points to some misconception currently being used in the scientific literature regarding the time-course of dopaminergic occupation, such as the concept of receptor occupation half-life. As a last theoretical based result, it is proposed an algorithm for antipsychotic dose reduction in patients presenting extrapyramidal signs and symptoms.

O objetivo deste trabalho foi investigar alterações comportamentais produzidas por etanol (ET) e estresse crônico imprevisível (ECI) em camundongos adolescentes (ADL) e adultos (AD), estudando a participação da enzima nNOS. Em camundongos AD também estudamos a atividade da nNOS via receptor NMDA na sensibilização cruzada entre estresse por imobilização (EI) e ET, utilizando dizocilpina (DZP) como pré-tratamento. Os resultados demonstraram haver sensibilização cruzada entre ECI e ET, tanto nos ADL quanto nos AD. Houve aumento da atividade da nNOS em hipocampo (HP) e córtex frontal (CF) de AD submetidos ao ECI. ET atenuou este efeito. A sensibilização cruzada em ADL aumentou atividade da nNOS em CF. O pré-tratamento com 7-nitroindazol inibiu sensibilização cruzada entre ECI e ET em ADL e AD, sinalizando a participação da nNOS. DZP potencializou sensibilização cruzada entre EI e ET e diminuiu a atividade da nNOS em HP e CF de animais submetidos ao EI. ECI e EI induzem sensibilização comportamental ao ET e nNOS participa na sensibilização cruzada entre ECI/EI e ET. / The objective of this work was to investigate behavioral alterations produced by ethanol (ET) and chronic unpredictable stress (CUS) in adolescent (ADL) and adult (AD) mice, studying the nNOS enzyme activity. In AD mice was also studied the nNOS activity through the NMDA receptor in the cross-sensitization between immobilization stress (IS) and ET, by using dizocilpine (DZP) as a pretreatment. The results demonstrate cross-sensitization between CUS and ET in the ADL and AD mice. There was an increase in the nNOS activity in hippocampus (HP) and frontal cortex (FC) of AD submitted to CUS. This effect was attenuated by ET. The cross-sensitization in ADL increased the nNOS activity in FC. The 7-nitroindazole pretreatment inhibit cross-sensitization between CUS and ET in ADL and AD, signaling the nNOS participation. DZP potentiates cross-sensitization between IS and ET and decreased the nNOS activity in HP and FC of animals submitted to IS. CUS and IS induce behavioral sensitization to the ET and nNOS participate in the cross-sensitization between CUS/IS and ET.

The problem with which this investigation was concerned is that of treating agoraphobia with cognitive-behavioral group therapy and cognitive-behavioral group therapy combined with the drug alprazolam (Xanax). The purpose of the research was twofold. The first goal was to determine the relative effectiveness of the two treatment conditions on phobic behavior, anxiety, and depression. A second goal was to analyze the results and make recommendations concerning each of these modalities available to agoraphobics, their families, and to treatment specialists. The research design of this study was a randomized, pretest-posttest, experimental group design. The sample (N = 15) consisted of Group I (N = 7), who received behavioral-cognitive group therapy combined with the medication alprazolam, and Group II (N = 8), who received behavioral-cognitive group therapy only. The treatment included 15, 2-hour weekly group sessions, with the addition of a brief medication evaluation prior to each group meeting for Group I. During these sessions, the subjects received information about agoraphobia in the form of brief didactic segments, treatment materials, homework assignments, group interaction, and various forms of desensitization. Based on the findings of this study, the following conclusions were drawn: 1. Multidimensional behavioral-cognitive group therapy can significantly reduce phobic avoidance, anxiety, and depression associated with agoraphobia; and 2. Multidimensional behavioral-cognitive group therapy in combination with administration of alprazolam, can significantly reduce phobic avoidance and anxiety associated with agoraphobia.

This thesis explores the discourses that surround psychopharmacological stimulant use in the online forum on reddit.com. The focus is on the negotiations of variable effects that people ascribe to the medication use. In the collective search for explanations and remedies, individuals become responsible for different aspects of their life in order to reach a balanced state. This state is constantly at flux and dependent on many variables, that are to be taken under control. Users thus have to monitor themselves and acquire self-knowledge, that is a based on listening to their embodied experience, and they have to adjust their bodies and daily routines. The idea of finding the right balance, that is informed by the embodied experiences, is closely connected to the ancient humoralist forms of governmentality. However, unlike in ancient humoralism, where balance necessarily meant adapting to the environment, biotechnologies have expanded the horizon of posssible modulations of bodies and selves, that may be achieved by the individuals themselves.

Tho present thesis represents a summary or research done by the author (and others) that was conducted with heroin addicts and drug abusers undergoing behavioral and pharmacological therapy at Stockton State Hospital, Stockton, California. From June 1970 to December 1970 the Research Department of Stockton State Hospital, in conjunction with the Drug Abuse Program at Stockton State Hospital, conducted research investigating a number of difference facets relating to inpatient programs for heroin addicts undergoing methadone maintenance and drug abusers. These facets included the investigation and evaluation of (a) motivational factors; affecting the voluntary participation of inpatient heroin addicts and drug abusers in behavioral and pharmacological therapy, (b) the effectiveness of the synthetic narcotic methadone hydrocloride as a primary reinforcing technique for appropriate behavior, (c) the effectiveness of various therapeutic approaches used in conjunction with behavioral modification techniques, and (d) the effect of methadone on perceptual and motor functioning in the heroin addict under-going methadone maintenance. The present thesis is a compilation cf these research projects.

Cannabis (and its main psychoactive component, THC) is one of the most widely-used drugs in the world, and recent expansion of its legal status has made it available in a variety of formulations and at a potency unrivaled in history. While its medicinal properties are gaining scientific support, so too is its potential to lead to abuse and dependence. Both initiation of cannabis use and frequent cannabis use are most prevalent in adolescence, and compared to adults, cannabis use by adolescents is associated with a greater likelihood of developing cannabis dependence and cannabis use disorder. Given the ethical limitations surrounding research that provides cannabis to non-users or non-adults, animal models of drug use can be valuable tools for the study of causes and consequences related to drug use, as well as allowing for investigating brain mechanisms underlying these factors. However, only recently have models in which animals reliably use cannabis (THC) at levels above its respective vehicle and at levels which produce consistent behavioral and physiological effects become available, and in no case has age-related differences in this use been examined. Thus, one goal of the current study was to directly compare the self-administration of edible THC (a route of administration used by humans and a formulation increasing in popularity) between adolescent and adult mice.<br><div> Adolescents also appear to be differentially sensitive to various effects of several classes of drugs, and they have been shown to be less sensitive to the aversive effects of cannabis, thereby putting them at greater risk for elevated and continued use. Evidence also suggests that, in addition to the risk associated with adolescent cannabis use, having initial positive subjective experiences resulting from its use is a strong predictor of subsequent cannabis dependence. Thus, the second goal of the current study was to use the place conditioning paradigm to examine the reward- (or aversion-) inducing properties of THC in adolescent and adult C57BL/6J mice, using both the traditional experimenter-administered THC (via injection) as well as edible THC self-administration.</div><div> Prior to initiating these THC studies, sensitivity of the place conditioning procedure to age-related differences in drug-induced reward was validated using cocaine, yielding locomotor stimulation in both ages and a decreased sensitivity to cocaine’s rewarding properties in adolescent mice. When provided limited access to edible THC dough in doses ranging from 0.0 to 6.0 mg/kg, mice showed a dose-dependent reduction in consumption across access sessions, and this reduction was more rapid in adult mice at the highest doses, suggesting that adolescent mice might have been less sensitive to its aversive properties. These same mice, as well as a separate group of mice receiving injection (also 0.0 to 6.0 mg/kg THC), were given place conditioning sessions, alternating between THC dough and control dough or THC injection and vehicle injection, for 6 days per week and were tested once per week across a total of 3 weeks. Mice conditioned using edible THC showed a neutral response (neither reward nor aversion) at all doses. However, mice conditioned using injected THC showed a conditioned place aversion to the highest dose, which was more pronounced in adult mice. Interestingly, in mice self-administering edible THC, the dose of THC consumed was related to the outcome of place conditioning, such that a conditioned place preference was observed for adult mice which shifted their consumption of 3.0 mg/kg edible THC downward relative to those mice with full consumption of 3.0 mg/kg, and for adolescent mice which had the highest degree of consumption of 6.0 mg/kg edible THC relative to those mice with the lowest consumption of 6.0 mg/kg. Furthermore, initial place preference outcomes at the individual level at test 1 predicted subsequent doses of edible THC consumed, suggesting mice adjust their self-administration of edible THC based on the subjective experience it produces. Besides its impact in place conditioning, THC also had differential effects on body weight and locomotor activity based on age and route of administration. Collectively, this project demonstrates that adolescent mice are less sensitive to the hedonic properties of both cocaine and THC, and that differences in edible THC self-administration between ages, and between individuals within an age, are likely related the subjective experience of its rewarding and aversive properties.</div>

No description available.

Yes / In this chapter we will review experimental evidence related to pharmacological moral enhancement. Firstly, we will present our recent study in which we found that a drug called propranolol could change moral judgements. Further research, which also investigated this, found similar results. Secondly, we will discuss the limitations of such approaches, when it comes to the idea of general “human enhancement”. Whilst promising effects on certain moral concepts might be beneficial to the development of theoretical moral psychology, enhancement of human moral behaviour in general – to our current understanding – has more side-effects than intended effects, making it potentially harmful. We give an overview of misconceptions when taking experimental findings beyond the laboratory and discuss the problems and solutions associated with the psychological assessment of moral behaviour. Indeed, how is morality “measured” in psychology, and are those measures reliable?

The glymphatic system (GS) is primarily a neural waste clearance system that relies on cerebrospinal fluid (CSF) to transport neuronal byproducts and nutrients. Studies demonstrate that sleep facilitates movement within the GS to clear metabolites and maintain cerebral homeostasis. However, functions of the GS during sleep and its implications have predominantly been examined in animals, clinical/at-risk, and ageing populations. Our understanding of the neural mechanisms underlying GS during sleep in typically developing human infants is limited. The objective of this study was to investigate the relationship between GS imbalance (characterized by extra-axial CSF [EA-CSF] from MRI structural images) and sleep problems in early development. Data from 75 infants were obtained from the Baby Connectome Project. Sleep was indexed with the Brief Infant Sleep Questionnaire. Multilevel models were utilized to explore the associations of EA-CSF volumes and EA-CSF/total cerebral volume (TCV) ratios with age and sleep. We replicated previous findings on lower TCV and overall CSF volumes in infants with dysregulated sleep compared to infants with regulated sleep. Results also demonstrated a decline in EA-CSF/TCV ratios from 9 to 34 months of age (b = -0.0005, <i>t</i> = -2.19, <i>p</i> = .032). Sleep problems were not associated with differential developmental trajectories of EA-CSF volumes or EA-CSF/TCV ratios. Findings from the present study do not support sleep problems as a mechanism through which CSF disbursement within the GS is altered. Although elevated EA-CSF is associated with developmental and neurodegenerative pathology, in early typical development, its links with sleep dysregulation are not robust.

The theme of this project was synthesis and the thesis encompasses knowledge generation and knowledge translation. Systematic review methodology was employed. The initial two systematic reviews compared antidepressant medication and cognitive-behaviour therapy for the acute treatment of depression. A further comparison of a combination of the two interventions with each treatment on its own was also conducted, with the bulk of the evidence favouring the psychotherapy. Moving to the topic of knowledge translation, the main theme of the thesis, the barriers, facilitators, and interventions impacting on systematic review uptake were identified. The evidence from these three systematic reviews, using diverse methodologies, was then combined to identify the interventions that overcame specific obstacles and built on highlighted facilitators in order to improve the uptake of evidence from systematic reviews. Juxtaposing barriers and facilitators alongside effectiveness studies in this final, mixed-methods systematic review allowed a number of interventions to be recommended. The synthesis also allowed strategies to be highlighted that required further development. Interventions with a statistically significant effect such as educational visits, summaries of systematic reviews, and targeted messaging, addressed a wide range of the identified barriers and facilitators. These interventions were recommended. Promising uptake strategies requiring further development were also identified. Furthermore, large gaps in the evidence base regarding systematic review utilization were highlighted. Fewer of the facilitators identified as part of this project, such as the medico-legal protection provided by systematic reviews, appear to have been built on in order to increase review uptake. Finally, all the preceding evidence was drawn on in order to develop a proposal focused on improving the uptake of evidence from systematic reviews and meta-analyses. This doctoral project offers a menu or range of evidence-based factors that can be considered by organisations and researchers when planning strategies aimed at increasing the uptake of pre-appraised, synthesized evidence.