L’innovation thérapeutique est limitée en psychiatrie. De nombreux médicaments sélectionnés sur la base de résultats encourageants dans les essais chez l’animal se révèlent décevants lors des essais cliniques. La validité limitée des modèles animaux, et leur utilisation pour tenter de mimer des pathologies définies de façon catégorielle sur la base de regroupement de symptômes de surface sans lien clair avec les processus cérébraux, les mécanismes biologiques ou la génétique, participent à ces difficultés. Une branche des neurosciences cognitives, l’étude de l’apprentissage par renforcement, associée à l’utilisation d’interventions pharmacologiques ciblées chez le sujet malade ou le sujet sain, représente une opportunité de mieux caractériser les processus cérébraux sous-tendant certaines dimensions cardinales des pathologies psychiatriques. Nous illustrons l’utilisation de l’étude de l’apprentissage par renforcement avec intervention pharmacologique dans deux études expérimentales. La première cherche à caractériser l’effet de l’aripiprazole, un antipsychotique atypique, chez des patients atteints du syndrome Gilles de la Tourette, en utilisant une tâche d’apprentissage contrefactuel, évaluant la capacité à apprendre non seulement des conséquences de ses actions, mais également des conséquences hypothétiques d’actions alternatives possibles. La seconde étude, randomisée contrôlée et en double aveugle, étudie l’effet de deux classes différentes d’antidépresseurs, l’escitalopram et l’agomélatine, chez le sujet sain. L’effet de leur administration est évalué à court terme (3 jours) et à long terme (8 semaines) dans deux tâches probabilistes de sélection de stimulus, l’une simple, l’autre avec renversements occasionnels. L’utilisation de cette approche pourrait participer à la définition d’endophénotypes et, en collaboration avec la recherche préclinique, aider à la création de nouveaux modèles animaux pour en améliorer la valeur prédictive. / Successful new drug development has declined in psychiatry in the last decades. This is in part the resut of a high failure rate in translating positive preclinical efficacy results to positive clinical trials. Limitations in the validity of animal models and shortcomings in the usefullnes of the current categorical diagnostic system. Cognitive neurosciences and particularly reinforcement learning and its computational analysis might provide biomarkers required to develop new ways of classifying mental disorders on the basis of both observable behaviour and neurobiological measues. Used in conjunction with pharmacological challenges, it may bring new insights into the physiopahtology and brain mechanisms underlying psychiatric disorders. It may also help design new animal models with imporved predictive validity for the develoment of medications relying on innovative mechanisms of action. We illustrate the use of reinforcement learning and pharmacological challenge in two experimental studies. In the first experiment, we administered a reinforcement learning task that involves both direct learning from obtained outcomes and indirect learning from forgone outcomes to two groups of Gilles de la Tourette patients, one receiving aripiprazole, one unmedicated and to a group of healty subjects. In the second experiment, we administered two probabilistic stimulus selection learning tasks (one simple, one with occasional reversals) to healthy subjects randomly and blindly allocated to either escitalopram, a typical serotonin reuptake inhibitor, agomelatine, an antidepressant with a different mechanism of action, or placebo. The experiment compard the effect of these two classes of antidepressants to placebo after both short term (3 days) and long term (8 weeks) treatment. These experiments bring insights into the understanding of the clinical condition studied, and the effects of the drugs tested. Implications of this approach for the translational approach to drug development is discussed.

Recent theoretical developments both within and outside the clinical literature have stressed the complex interactions between biological and environmental risk in relation to psychopathology development. They have also highlighted the importance of cognitive dimensions, especially those related to control perceptions, in the developmental path towards anxiety and mood disorders in children. Few studies have investigated these cognitive dimensions in relation to risk and protective factors. In light of these considerations, the present study evaluated structural models investigating the relationship of perceived control and competence to child temperamental risk, parent personal risk, family environmental risk and anxious and depressed feelings. It was hypothesised that temperamental, and psychological risk in relationship to family environment would be mediated by the cognitive dimensions of perceived control and competence. It was further hypothesised that family environment, would mediate the relationship between child temperamental risk and anxious and depressed feelings. A school sample of 293 New Zealand children aged between 8 and 11 and their parents was assessed using a cross-sectional design. Overall results indicated that in the face of temperamental and family adversity, feeling in control of emotions and social interactions and feeling socially competent afforded children protection from anxious or depressed feelings. In addition, a sensitive, accepting family environment was seen to protect a temperamentally vulnerable child from distressed feelings. In contrast, distress was more likely to occur when a temperamentally vulnerable child lived in a family characterised by parental psychological control and conflict than one characterised by less cohesion and parental rejection. Results also indicated that, in terms of cognitive features, perceptions of social competence were particularly important in protecting a child from having anxious or depressed feelings. These findings are discussed in relationship to Barlow's and other recent integrated aetiological theories of distress disorder. Findings are also considered in relation to implications for identification, intervention and prevention strategies for distressed children in both clinical and school populations. Further results, limitations and proposals for future research are also discussed.

Orientador: Fernando Bastos / Banca: Álvaro Lorencini Junior / Banca: Jair Lopes Junior / Banca: Sérgio Mello Arruda / Banca: Luciana Maria Lunardi Campos / Resumo: A atuação dos professores de Ciências e Biologia na prevenção educacional do abuso de substâncias psicoativas (SPA) recorre necessariamente a um processo de aquisição de saberes relacionados com psicofarmacologia e toxicologia, disciplinas atualmente não disponibilizadas na formação inicial desses docentes. Estuda-se o papel desenhado para o sistema educacional no que se refere às metas de prevenção ao abuso de drogas pela nova estrutura legislativa e pelos recentes posicionamentos dos tribunais nos casos que envolvem esta problemática orientando-o fortemente a ser tratado sob a ótica da educação onde um dos atores principais é o professor. Incumbidos dessa especial responsabilidade, de elevada complexidade, se despreparados, esses professores serão obstatos de realizá-la com eficiência e eficácia. As questões respondidas nesta tese fixaram-se em elucidar os aspectos da necessidade e de como capacitar professores daquelas disciplinas para atuarem dentro das escolas como profissionais da prevenção ao uso abusivo de substâncias psicoativas (SPA). Concebeu-se um corpo de conhecimentos comportando os saberes científico e da educação para a saúde, cuidando-se que os docentes devam contemplar os aspectos emocional e racional que a abordagem do tema exige. A pesquisa de abordagem qualitativa foi aplicada junto a duas turmas de licenciandos concluintes do Curso de Ciências Biológicas da Faculdade de Ciência da UNESP-Bauru, durante dois semestres, aferindo-se os conhecimentos e concepções pré-existentes e os apropriados após a implementação da capacitação. A capacitação incluiu conhecimentos dos aspectos legais aplicáveis ao setor educacional e de Direito Penal, Processual Penal, práticos e relacionados com questões polêmicas passíveis de confrontação pelos docentes, em sala de aula. Estudou-se... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The performing of teachers of science and biology in the educational prevention of psychoactive substances (SPA) abuse necessarily uses a process of acquiring knowledge related to psychopharmacology, toxicoloy, subjects not currently available in the initial formation of teachers. This study reveals the role designed for the educational system with regard to the goals of prevention of drug abuse by the new legislative structure and the placement of the courts in recent cases involving this issue, advising it strongly to be treated from the perspective of education where one of the main actors is the teacher. Taking in consideration that this is a task of special responsibility and high complexity, if unprepared, these teachers will be hindered to do so with efficiency and effectiveness. The questions answered in this thesis were set up to elucidate the necessity's aspects to teacher's formations to work as professionals within the schools to prevent the abuse of psychoactive substances (SPA). It was conceive a knowledge's frame including scientific knowledge and health education, taking care to that teachers contemplate the emotional and rational aspects required by the subject approaching. The search of qualitative approach was applied among two classes of ending degree students of Biological Sciences, College of Sciences, UNESP-Bauru, for two semesters, checking up their knowledge and pre-existing conceptions and acquired after the implementation of training. The enable proceeding included applicable knowledge of legal aspects for the education, Criminal Law, Criminal Proceeding, and practical issues related to controversial subject of possible confrontation by teachers in the classroom. Was studied the Federal Act Nº 11343 of 8/23/2006, the current drug law. The formation's effectiveness was evaluated along the lines investigated in five state high schools... (Complete abstract click electronic access below) / Doutor

Made available in DSpace on 2015-05-14T13:00:17Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 848309 bytes, checksum: ccc0950ac2cd6a78a38eac3b62f6aa2c (MD5) Previous issue date: 2011-02-28 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Imidazolidine derivatives are synthetic products with many different therapeutic applications. Many imidazolidine derivatives have pharmacological properties at the level of the CNS, such as phenytoin, which is used in clinical practice as an anticonvulsant. However, this also works effectively in the treatment of neuropathic pain and it has been already used as anti-arrhythmic heart. The 3-phenyl-5-(4- ethyphenyl)-imidazolidine-2,4-dione (IM-3), recently synthesized from amino acid was selected for psychopharmacological studies. Based on the chemical and structural similarity, this study investigated the antinociceptive activity of IM-3 in animal models. The study has began with screening and behavioral pharmacology of the LD50 determination. In the screening results indicate a depressant activity on CNS and from the LD50 doses were chosen for subsequent tests with 50, 100 and 200 mg / kg intraperitoneally. In the next step, methodologies to evaluate the specific antinociceptive activity were used. The first was the writhing induced by acetic acid; afterwards, the formalin test and finally the hot plate test, which is specific for the central antinociceptive activity. In the three methodologies used, the IM-3 showed to be effective in the writhing test by acetic acid at a dose of 200 mg/kg which increased both the latency to the onset of writhing and reduced the number of writhing in the control group and in the formalin test at doses of 100 and 200 mg / kg decreased the time of the paw lick in the second phase of testing. Therefore, from these experimental data, it is possible to infer that the IM-3 has antinociceptive activity of the anti-inflammatory type. / Os derivados imidazolidínicos são produtos sintéticos com inúmeras diferentes aplicações terapêuticas. Muitos derivados imidazolidínicos apresentam propriedades farmacológicas em nível do SNC, por exemplo a fenitoína que é utilizada na prática clínica como anticonvulsivante, mas também atua no tratamento da dor neuropática e também já foi utilizada como antiarrítmico cardíaco. O 3-fenil-5-(4-etilfenil)- imidazolidina-2,4-diona (IM-3), sintetizado recentemente a partir de aminoácido foi selecionado para realização de estudos psicofarmacológicos. Baseado nessa semelhança químico-estrutural, o presente trabalho investigou a atividade antinociceptiva do IM-3 em modelos animais. O estudo teve início com a triagem farmacológica comportamental e determinação da DL50. Na triagem os resultados apontaram para uma atividade depressora no SNC e a partir da DL50, foram escolhidas as doses para testes subseqüentes de 50, 100 e 200 mg/kg por via intraperitoneal. Em seguida, metodologias para avaliar a atividade antinociceptiva específicas foram utilizadas. A primeira foi a das contorções abdominais induzidas pelo ácido acético; em seguida, o teste da formalina e por fim, o teste da placa quente, que é específico para atividade antinociceptiva central. Nas três metodologias usadas, o IM-3 apresentou-se efetivo no teste das contorções abdominais pelo ácido acético na dose de 200 mg/kg que aumentou tanto a latência para o aparecimento das contorções abdominais como reduziu o número de contorções abdominais em relação ao grupo controle e no teste da formalina nas doses de 100 e 200 mg/kg diminuiu o tempo de lambida da pata na segunda fase do teste. Portanto, a partir destes dados experimentais, é possível inferir que o IM-3 possui atividade antinociceptiva do tipo anti-inflamatória.

M.A. (Clinical Psychology) / The advances in psychopharmacology, as well as the establishment of various 'half-way houses' has changed the nature of psychiatric hospitals. Where once, the emphasis was on long-term, custodial care of patients, the, present emphasis is on short term care. Attempts are made to reintegrate patients into society as soon as possible. This approach has been partially successful. However, it appears that many patients, who were previously discharged as being ready to function and cope with everyday life, return to hospital, having decompensated after relatively short periods of time. The reasons for decompensation are manifold, and vary from individual to individual. It is the contention of this writer that one of the reasons for the limited success of treatment of some patients may lie in the nature of the interdisciplinary team approach to treatment currently operative in many psychiatric hospitals. Interdisciplinary teams are usually composed of psychiatrists, psychologists, social workers, occupational therapists and psychiatric nurses. The teams operate on the tacit assumption that no single approach holds the key to successful treatment of a patient...

The Reward Positivity (RewP) is a neurophysiological marker of reward sensitivity that has been found to be impacted in depression. However, there have been some mixed findings regarding the relationship between the RewP and depression, suggesting there are other factors which impact this relationship. The current study investigated how the demographic factors of sex, age, and socio-economic status might moderate the RewP-depression relationship, and examined if these effects generalize across three different inventories for symptoms of depression. 194 people were recruited by random digit dialing (55.2% male, mean age = 51.34 years, mean monthly income = $6625.95). They completed the SCID, HAM-D, and IDAS measures of depression, and an EEG session in which they did a random guessing task to elicit the RewP. We found that there was a trend-level interaction of a moderate effect size between symptoms of depression, age, and sex in predicting RewP amplitude. Further exploration of this interaction revealed that for females, there was an interactive effect between age and symptoms of depression, such that for younger females, increased symptoms of depression were associated with a blunted RewP, and lower symptoms of depression were associated with an enhanced RewP. These effects were specific to the SCID, but did not generalize to the HAM-D or IDAS. Moreover, there was no interactive effects between age and depression symptoms for males, nor did SES interact with depression and other demographic factors in predicting the RewP. This study provides evidence that demographic factors can impact the strength and nature of the relationships between the RewP and depression, and that future researchers might wish to over-sample younger females when investigating other moderating factors of the RewP in order to increase power.

Genetic and home chaos influences in early childhood have been independently associated with externalizing problems, characterized by inattentive, hyperactive, and aggressive behaviors. However, the Behavioral Genetics approach indicates that genetic and environmental influences, although independently effective, interact to produce behavior throughout development. Thus, this thesis uses two samples, the Early Growth and Development study (EGDS), n= 564, and the Avon Longitudinal Study of Parents and Children (ALSPAC), n= 8,952, and two genetically-sensitive approaches, a parent-child adoption approach and a polygenic scoring approach, to examine how genetic influences and home chaos interact in early childhood (age 3-4) to predict externalizing problems later in childhood (age 7). Results indicate that, although home chaos is correlated with later externalizing problems, the effect is reduced in the context of earlier externalizing, possibly suggesting that home chaos is most salient for concurrent, not later, externalizing problems. In addition, genetic influences were not predictive of externalizing problems in either study, nor was the interaction of home chaos and genetic influences. This pattern of results suggests that, although home chaos may be an important factor for concurrent externalizing problems, other factors, e.g., parenting style and prenatal risk, may be more salient than home chaos, especially in interaction with genetic effects. Further, failure to find genetic influence in this thesis suggest that accounting for the broad scope of genetic influences on complex traits like externalizing and the specific genetic risk for individual externalizing phenotypes is important in attempts to find genetic influence and interaction.

<p>Some individuals with alcohol use disorder (AUD) continue to drink because they have developed a habit in which they are not considering the consequences of their actions. Habitual actions persist despite changes in reward and are often studied using devaluation procedures. Stress hormones, such as corticotropin releasing factor (CRF), have been linked to AUD when examining binge-like drinking and withdrawal in rodents. Stress has been examined in the switch from goal-directed to habitual behavior, and CRF has often mimicked the effects of stress exposure. This study looked at the possible direct effects of CRF on habit expression in rats using an operant paradigm. Finding possible novel mechanisms of habit could create an avenue for future novel treatment options. Female and male Long Evans rats were trained on a variable interval schedule using sucrose as a reward. Rats then underwent devaluation procedures including both sensory-specific satiety and conditioned taste aversion (CTA) to test for habitual behaviors. Prior to an extinction session post-CTA, animals were treated with either 20 mg/kg R121919, a CRF1 receptor antagonist, or vehicle. A second extinction session was conducted where animals received the alternative treatment. Lever presses were recorded as a measure of goal-directed or habitual behavior. Sensory-specific satiety devaluation tests revealed that animals were not sensitive to devaluation. This was further supported by both post-CTA extinction sessions. R121919 had no effect on lever pressing in either devalued or valued groups. Further research is needed to explore how a CRF receptor antagonist may affect habit formation or the transition from goal-directed to habit behaviors. Future studies should also examine any possible interaction effects CRF may have with alcohol or stress on habitual behaviors.</p>

<div><div><div><p>Although marijuana and alcohol are two of the most commonly used drugs in the United States, relatively little is understood about how these drugs interact to effect drug use, cognitive behaviors, and neurophysiological changes. Specific drug use patterns such as simultaneous use may produce differential effects for consumption and other behaviors in addition to unique neurobiological changes compared to singular drug use. In order to better understand the effects of simultaneous alcohol and marijuana (SAM) use, we used the selectively bred crossed High Alcohol Preferring mice to examine consummatory, cognitive, and neurobiological changes following chronic alcohol and THC self-administration. We hypothesized that SAM mice would consume more drug than animals exposed to either substance alone. We used an operant behavioral flexibility paradigm to assess cognitive impairments believing that drug-exposed animals would show deficits relative to Control animals, with SAM mice being the most impaired of all drug conditions. Finally, we assessed CB1 receptor changes in the dorsal striatum, as this region is critical for behavioral flexibility (Bissonette & Powell, 2012; Ragozzino, 2007), CB1 receptors are the primary target of THC and these receptors are involved in numerous alcohol related behaviors (Maldonado et al., 2006; Pava & Woodward, 2012). Contrary to our hypothesis, SAM animals did not consume higher levels of drug compared to mice exposed to only THC or alcohol. Interestingly, female THC consumption was robust when THC was consumed alone but was reduced when simultaneous access to alcohol was available. Surprisingly, although we speculated that drug- exposed mice would be impaired compared to Control animals, and that SAM animals would likely be more compromised than THC and alcohol for Reversal Learning and Attentional Set-Shifting respectively, behavioral flexibility deficits were absent in our paradigm. Finally, alterations to dorsal striatal CB1 receptor expression were observed following a Short Abstinence period. Despite an absence of cognitive behavioral effects, this research contributes to furthering our understanding of co-drug use for consummatory and neurobiological changes, both of which are critically necessary given the evolving landscape surrounding simultaneous alcohol and recreational marijuana use.</p></div></div></div>

<b>Study 1:</b><div><b>Background:</b> Insomnia may be a risk factor for cardiovascular disease in HIV (HIV-CVD); however, mechanisms have yet to be elucidated. <b>Methods:</b> We examined cross-sectional associations of insomnia symptoms with biological mechanisms of HIV-CVD (immune activation, systemic inflammation, and coagulation) among 1,542 people living with HIV from the Veterans Aging Cohort Study (VACS) Biomarker Cohort. Past-month insomnia symptoms were assessed by the item, “Difficulty falling or staying asleep?,” with the following response options: “I do not have this symptom” or “I have this symptom and…” “it doesn’t bother me,” “it bothers me a little,” “it bothers me,” “it bothers me a lot.” Circulating levels of the monocyte activation marker soluble CD14 (sCD14), inflammatory marker interleukin-6 (IL-6), and coagulation marker D-dimer were determined from blood specimens. Demographic- and fully-adjusted (CVD risk factors, potential confounders, HIV-related factors) regression models were constructed, with log-transformed biomarker variables as the outcomes. We present the exponentiated regression coefficient (exp[b]) and its 95% confidence interval (<i>CI</i>). <b>Results:</b> For sCD14 and D-dimer, we observed no significant associations. For IL-6, veterans in the “bothers a lot” group had 15% higher IL-6 than veterans in the “I do not have this symptom” group in the demographic-adjusted model (exp[b]=1.15, 95%<i>CI</i>=1.02-1.29, <i>p</i>=.03). This association was nonsignificant in the fully-adjusted model (exp[b]=1.07, 95%<i>CI</i>=0.95-1.19, <i>p</i>=.25). <b>Conclusion:</b> We observed little evidence of relationships between insomnia symptoms and markers of biological mechanisms of HIV-CVD. Other mechanisms may be responsible for the insomnia-CVD relationship in HIV; however, future studies with comprehensive assessments of insomnia symptoms are warranted.</div><div><p><b>Study 2:</b></p><p><b>Background:</b> While insomnia has been identified as a potential risk factor for cardiovascular disease in HIV (HIV-CVD), research on the underlying pathophysiological mechanisms is scarce. <b>Methods:</b> We examined associations between 0-to-12-week changes in sleep disturbance and the concurrent 0-to-12-week changes and the subsequent 12-to-24-week changes in markers of systemic inflammation, coagulation, and endothelial dysfunction among people living with HIV (<i>n</i> = 33-38) enrolled in a depression clinical trial. Sleep disturbance was measured using the Pittsburgh Sleep Quality Index. Inflammatory markers interleukin-6 (IL-6) and C-reactive protein (CRP) and coagulation marker D-dimer were determined from blood specimens; endothelial dysfunction marker brachial flow-mediated dilation (FMD) was determined by ultrasound. 0-to-12-week variables were calculated as 12-week visit minus baseline, and 12-to-24-week variables were calculated as 24-week minus 12-week. We constructed multivariate linear regression models for each outcome adjusting for age, sex, race/ethnicity, Framingham risk score, and baseline depressive symptoms. <b>Results:</b> We did not observe statistically significant associations between 0-to-12-week changes in sleep disturbance and 0-to-12-week or 12-to-24-week changes in IL-6, CRP, D-dimer, or FMD. However, we did observe potentially meaningful associations, likely undetected due to low power. For 0-to-12-weeks, every 1-standard deviation (<i>SD</i>) increase, or worsening, in the sleep disturbance change score was associated with a 0.41 pg/mL and 80 ng/mL decease in IL-6 and D-dimer, respectively. For 12-to-24-weeks, every 1-<i>SD</i> increase in sleep disturbance change score was associated with a 0.63 mg/L, 111 ng/mL, and 0.82% increase in CRP, D-dimer, and FMD, respectively. <b>Conclusion:</b> We observed potentially meaningful, though not statistically significant, associations between changes in sleep disturbance and changes in biological mechanisms underlying HIV-CVD over time. Some associations were in the expected direction, but others were not. Additional studies are needed that utilize larger samples and validated, comprehensive assessments of insomnia.</p></div>