Indiana University-Purdue University Indianapolis (IUPUI) / Sensitization to the locomotor stimulant effects of alcohol (ethanol) is thought to be a heritable risk factor for the development of alcoholism that reflects progressive increases in the positive motivational effects of this substance. However, very little is known about the genetic influences involved in this phenomenon or the extent to which ethanol’s positive motivational effects are altered in parallel to its development. The first goal of this work was to determine the heritability of ethanol-induced locomotor sensitization in mice using short-term behavioral selection. Genetically heterogeneous C57BL/6J (B6) x DBA/2J (D2) F2 mice were generated from B6D2F1 progenitors, phenotyped for the expression of locomotor sensitization, and bred for high (HLS) and low (LLS) expression of this behavior. A secondary goal was to characterize possible line differences in ethanol’s positive motivational effects using a conditioned place preference assay. There were large and significant differences in locomotor sensitization between HLS and LLS lines by the fourth generation. Twenty-two percent of the observed line difference(s) were attributable to genes (h2=.22). However, there were no significant differences in conditioned place preference between lines despite significant line differences in ethanol-stimulated locomotion following repeated exposures. The results of this work have several implications. First, that changes in ethanol sensitivity following repeated exposures are in part genetically regulated highlights the relevance of studies aimed at determining how genes regulate susceptibility to ethanol-induced behavioral and neural adaptations. Additionally, the lack of line differences in ethanol-induced CPP, and the observation that CPP and ethanol sensitization are dissociable, suggests that 1) different genes regulate these two behaviors and 2) the utility of locomotor sensitization as a model of alterations in ethanol’s positive motivational effects is, at best, still unclear. Together these studies provide evidence that genes are capable of regulating alterations in ethanol-induced locomotor behavior but provide little support for ethanol-induced locomotor sensitization as a model for increases in ethanol’s positive subjective effects in mice.

This thesis is an interdisciplinary project in experimental social psychology, psychopharmacology, neuroscience, and neuroethics. The role of emotion in higher order psychological processes – social and moral judgments – was investigated. Specifically the role of noradrenergic mediated emotional arousal was researched. Behavioural studies demonstrated that acute beta adrenergic blockade with propranolol led to a reduction in negative implicit racial associations and also a modification of moral decision making. These findings suggest that basic affective processes might be causally relevant for higher order evaluations. However, enhancement with the noradrenergic potentiating agent reboxetine did not show effects opposite to those of propranolol on racial attitudes or moral judgments, which might indicate that emotional arousal, specific to beta-adrenoceptors might be involved in the effects of propranolol. Further a pharmacological fMRI study demonstrated that the activation pattern in brain regions commonly associated with intergroup bias -- such as the amygdala, insula, dorsolateral prefrontal cortex, and fusiform gyrus -- was affected by propranolol, and that the effect in the amygdala was correlated with implicit racial bias. Taken together the research suggests that automatic emotional arousal plays a role in higher order psychological processes, such as moral and social judgments, which aids the understanding of the underlying neurobiology of such processes. Finally, the ethical implications – such as the prospect of pharmacological moral enhancement – are discussed. The findings also suggest that the moral and social effects of already widely used psychotropic medications should be subject to further empirical and ethical investigation.

Made available in DSpace on 2016-04-28T20:39:41Z (GMT). No. of bitstreams: 1 Fernando Alberto Taddei Cembranelli.pdf: 700138 bytes, checksum: cde5b176f87208c871a26b3489796b4c (MD5) Previous issue date: 2008-02-15 / Conselho Nacional de Desenvolvimento Científico e Tecnológico / The practice of psychoanalysis holds some challenges nowadays. One of them refers to the coexistence with medical treatments in a general way and, over all, with the psychopharmacological treatments, which had grown in the last years exponentially. The treatment of dual situation by psychoanalysis and conventional medicine becomes each day more common. This work represents an attempt to consider the possible clinical effects of this practice on the analytical situation. The research considers two premises: 1. The specific social cultural context that favors the dual situation strongly is that one which is dominated by the concern about the risks that surround the healthy and the body, inside the risk-society . 2. The more current psychopathological pictures are the psychosomatic manifestations, the addictions and the cases that an exceeding adaptation is observed (normopathy). The work tries to show that there are some non accidental resonances between the cultural environment and the clinic. The two initial chapters examine the social cultural context above critically, through concept analysis, values and specific mechanisms that produce it; this allows pointing out psychoanalysis, whiling therapeutic experience, away from the horizon of adaptation and equalization that reaches the individual, which cognitivism is one of its representatives. At this point some researches about psychoanalytical analysis of the contemporary culture are helpful guides. In the second part of the research, some clinical narratives are presented and argued in order to show what happens between analyst and patient in these situations. Two types of effects are detached: a weakness of transference, and a partial invalidation of the analyst s abilities, for instance, the decrease of the function of continent, as described by Wilfred Bion. Under this perspective, a conclusion that a risk logic appears is developed, which may affect the analytical experience and its results in a negative way / O exercício da clínica psicanalítica na atualidade comporta vários desafios. Um deles refere-se à coexistência com os tratamentos médicos, de maneira geral, e, sobretudo, com os tratamentos psicofarmacológicos, que cresceram exponencialmente nos últimos anos. O que aqui se denomina situações dúplices de tratamento, pela psicanálise e pela medicina, torna-se a cada dia uma realidade mais comum e incontornável. Este trabalho representa uma tentativa de considerar os possíveis efeitos clínicos desta realidade sobre a situação analítica. A pesquisa parte de dois pressupostos: 1. O contexto sócio-cultural específico que favorece fortemente as situações dúplices é aquele dominado pela preocupação com os riscos que cercam a saúde e o corpo, no interior da chamada sociedade do risco . 2. Os quadros psicopatológicos mais freqüentes nestas situações são as manifestações psicossomáticas, as adições e os casos em que se nota uma sobre-adaptação á realidade externa, as normopatias. Procura-se mostrar que, não por acaso, há várias ressonâncias entre os planos da cultura e da clínica. Os dois capítulos iniciais examinam criticamente o contexto sócio-cultural referido, por meio da análise dos conceitos, valores e certos mecanismos que o engendram; isso permite situar a psicanálise, enquanto experiência terapêutica, como distinta do horizonte de adaptação e normatização que se abre para o indivíduo contemporâneo, e do qual o cognitivismo seria um dos representantes. Nesse ponto, servem de guia alguns estudos de autores que fazem uma interpretação psicanalítica da cultura contemporânea. Na segunda parte da dissertação, algumas narrativas clínicas são apresentadas e discutidas com o objetivo de mapear o que se passa na relação entre o analista e o paciente, nestas situações. Dois tipos de efeitos são destacados: um enfraquecimento da transferência, e uma invalidação parcial das capacidades do analista, entre as quais, a capacidade de oferecer continência, nos termos descritos por Wilfred Bion. À luz desse entendimento, desenvolve-se a noção-síntese de uma lógica do risco , algo que pode vir interferir negativamente com a experiência analítica e seus resultados

Tension-Type Headache (TH) is highly prevalent and associated with significant personal and social cost. The causes of TH are unclear, precluding optimal treatment or prevention at present. Stress is a well-documented correlate and trigger of TH activity, however the causal significance has not been experimentally demonstrated to date. Similarly, the mechanisms by which stress contributes to TH, if in fact it does, are not clearly understood. Findings of increased pain sensitivity in TH sufferers suggests TH pathophysiology may involve dysfunction in peripheral and/or central nervous system processing of pain. Studies on animals and healthy humans demonstrate that stress can increase pain sensitivity by affecting peripheral and central pain mechanisms proposed as dysfunctional in TH. It has therefore been proposed that stress may contribute to TH through aggravating already increased pain sensitivity in TH sufferers. However, this hypothesis has not been adequately examined in TH sufferers to date. Addressing the above issues, the present project conducted seven studies examining relationships between stress, pain sensitivity, and headache activity in TH sufferers. The aim was to test the hypothesis that stress contributes to TH by aggravating already increased pain sensitivity in TH sufferers. Studies 1 and 2 demonstrated increased general arousal and complex temporal relationships between general arousal and headache activity in the natural environment in Episodic TH (ETH) sufferers. In Study 3, experimentally induced stress of brief duration increased pressure pain sensitivity at the head in Chronic TH (CTH) sufferers more than in healthy controls. Study 4 found CTH sufferers to have increased levels of daily stress, increased pericranial muscle tenderness, and reduced pain thresholds, which were inter-related. Both daily stress and pain sensitivity were predictive of prospective daily headache activity. In Study 5, an experimental model demonstrated that stress-induced headache was associated with stress-induced increase in pericranial muscle tenderness and reduction in pressure pain thresholds at head and hand. Additionally, induced stress reduced pain tolerance and increased pain intensity ratings to cold pressor more in TH sufferers than in healthy controls (Study 7). Finally, TH sufferers were found to have abnormal temporal summation of pressure pain and impaired noxious inhibition of temporal summation compared to healthy controls, however neither temporal summation nor noxious inhibition of temporal summation were affected by induced stress (Study 6). Together, the results support the hypotheses: 1) Stress contributes to both ETH and CTH, and 2) Stress contributes to CTH through aggravating already increased pain sensitivity in CTH sufferers. Impaired pain inhibition and increased wind-up may be underlying abnormalities contributing to increased pain sensitivity in CTH sufferers.

La prescription médicamenteuse est l’un des principaux outils thérapeutiques utilisé par le médecin. Si la médecine somatique décline sa clinique selon l’enchaînement symptômes- diagnostic-traitement, la psychiatrie se démarque d’une telle linéarité. En effet, bien qu’elle se soit calquée sur le modèle médical depuis la découverte des psychotropes en 1952, elle relève d’une clinique spécifique : en psychiatrie, d’une part le symptôme constitue une adresse à l’Autre, il contient donc une dimension relationnelle essentielle, d’autre part, le soin psychique implique une participation active du sujet, toute thérapie étant aussi auto-thérapie. La neuropharmacologie, en plein essor depuis 1952, propose un schéma thérapeutique se voulant plus scientifique car de plus en plus éloigné de la psychopathologie clinique. Le psychiatre est alors convoqué en tant que technicien de la prescription de psychotropes, le médicament se suffisant à lui-même d’un point de vue thérapeutique. Face à une telle évolution de la psychiatrie, comment préserver un abord clinique ?Notre pratique esquisse la possibilité de dégager l’acte de prescrire d’une technicité exclusive. En effet, sous certaines conditions, la prescription de psychotropes constitue un acte psychothérapeutique à part entière. Pour cheminer dans notre réflexion, nous sommes passés par le paradigme du pharmakon afin de complexifier la question du prescrire. La clinique suggère une possible alliance entre parole et médicament. Prescrire dans la parole, au-delà de la molécule, consiste à qualifier la substance par la parole, de façon à ce qu’elle devienne un médicament spécifique de la rencontre clinique. La molécule, guidée par la magie des mots, sera plus efficace. L’acte de prescrire se conçoit donc comme une création à deux, à réinventer à chaque nouvelle rencontre, le moment de la prescription relevant d’un cheminement intime du côté du clinicien. Ainsi, loin de s’exclure mutuellement, psychothérapie analytique et pharmacothérapie ont tout intérêt à croiser leurs regards sur la question du prescrire. Penser conjointement effet pharmacologique et relation clinique permet au clinicien de s’engager dans une authentique rencontre humaine avec le patient. La psychopathologie s’ouvrira, peut-être, sur de nouvelles perspectives thérapeutiques. / Prescribing medication is one of the main therapeutic tools used by physicians. If somatic medicine clinically acts according to a 'symptom-diagnosis-treatment' model, psychiatry does not follow this linear pathway. Although it has copied the medical model since the discoveryof psychoactive drugs in 1952, it possesses a specific clinical approach. First of all, in psychiatric care, the symptom is an address to the Other, it contains an essential social dimension. Moreover, it implies the subject's active participation, each therapy also being a self-therapy. Neuropharmacology, in full expansion since 1952, has taken a therapeutic scheme aiming at more scientificity by moving away from clinical psychopathology. Hence psychiatrists are seen as technicians of psychoactive drugs prescription, drugs being considered as self sufficient therapeuticaly. With regard to this evolution in psychiatric care, how can a clinical approach be maintained ? In practice, the act of prescribing can free itself from being exclusively technical. Prescribing psychoactive drugs can indeed, under certain conditions, be a true psychotherapeutic act. To guide us through this reflection, we used the pharmakon paradigm to make the issue of prescribing more complex. Clinical practice suggests a possible alliance between patients'words and medication. Beyond molecular action, prescribing through talking qualifies the substance by words, so it becomes a clinical-interaction-specific drug. The molecule, guided by the magic of words, will be more efficient. The act of prescribing is thus conceived as a creation made possible by two people, that must be reinvented at each encounter. The moment for prescribing is rather the fruit of the clinician intimate decision process. Thus, far from excluding each other, analytical therapy and pharmacotherapy would gain much from sharing their views on the issue of prescribing. Integrating both the pharmacological effect and the clinical interaction would allow clinicians to engage in an authentic human encounter with patients. Psychopathology may then open up to new therapeutic perspectives.

Purpose: The Internet has provided an unprecedented opportunity for psychotropic medication consumers, a traditionally silenced group in clinical trial research, to have voice by contributing to the construction of drug knowledge in an immediate, direct manner. Currently, there are no systematic appraisals of the potential of online consumer drug reviews to contribute to drug knowledge. The purpose of this research was to explore the content of drug information on various websites representing themselves as consumer- and expert-constructed, and as a practical consideration, to examine how each source may help and hinder treatment decision-making. Methodology: A mixed-methods research strategy utilizing a grounded theory approach was used to analyze drug information on 5 exemplar websites (3 consumer- and 2 expert-constructed) for 2 popularly prescribed psychotropic drugs (escitalopram and quetiapine). A stratified simple random sample was used to select 1,080 consumer reviews from the websites (N=7,114) through February 2009. Text was coded using QDA Miner 3.2 software by Provalis Research. A combination of frequency tables, descriptive excerpts from text, and chi-square tests for association were used throughout analyses. Findings: The most frequently mentioned effects by consumers taking either drug were related to psychological/behavioral symptoms and sleep. Consumers reported many of the same effects as found on expert health sites, but provided more descriptive language and situational examples. Expert labels of less serious on certain effects were not congruent with the sometimes tremendous burden described by consumers. Consumers mentioned more than double the themes mentioned in expert text, and demonstrated a diversity and range of discourses around those themes. Conclusions: Drug effects from each source were complete relative to the information provided in the other, but each also offered distinct advantages. Expert health sites provided concise summaries of medications’ effects, while consumer reviews had the added advantage of concrete descriptions and greater context. In short, consumer reviews better prepared potential consumers for what it’s like to take psychotropic drugs. Both sources of information benefit clinicians and consumers in making informed treatment-related decisions. Social work practitioners are encouraged to thoughtfully utilize online consumer drug reviews as a legitimate additional source for assisting clients in learning about treatment options.

There is a significant body of literature stating that caffeine is the most widely consumed drug in the world, yet its effects on operant behavior are little understood. Some of the current research on caffeine suggests that it may play a role in altering motivational states related to transitions between previous and upcoming work requirements. The purpose of the current study was to examine the effects of caffeine on postreinforcement pausing during transitions between small and large fixed ratio rudiments. Eight rats were exposed to five doses of caffeine and and a two-component multiple schedule. We found that caffeine does systematically alter the length of pausing during transitions between fixed ratio requirements, however the magnitude of the effect may be dependent on the baseline rate of responding.

Dietary intervention remains a popular, albeit challenging, approach for combating obesity. In recent years, dietary interventions that increase consumption of medium-chain triglycerides (MCT) instead of long-chain triglycerides (LCT) have gained attention. Pre-clinical research has demonstrated that rats fed a high-fat diet (HFD) induce adiposity, but a dietary shift from LCT to MCT suppresses this effect. To date, the extent to which this effect operates via suppressed hyperphagia is not fully understood. In the present study, we sought to determine how consuming a HFD composed of different fat types affects energy intake, adiposity, and hippocampal brain-derived neurotropic factor (BDNF) levels. Rats were assigned to one of four diet groups – rat chow (CHOW), LCT-enriched HFD (LCT-HFD), MCT-enriched HFD (MCT-HFD), or coconut oil-enriched HFD (COCO-HFD), which composes a mixture of LCT and MCT. In Experiment 1, all animals were given <i>ad libitum</i> access to their assigned diet, whereas in Experiments 2 and 3, HFD-subjects were pair-fed to CHOW to prohibit hyperphagia. In Experiments 1 and 2, subjects were aged 20-24 weeks, whereas in Experiment 3, subjects were aged 10-11 weeks. Across experiments, we found that the effect of MCT consumption on suppressing HFD-induced adiposity is causally related to suppressed HFD-induced hyperphagia. Additionally, we failed to detect an effect of HFD consumption on hippocampal BDNF. Therefore, our findings did not support or oppose the hypothesis that MCT consumption attenuates HFD-induced BDNF deficiency. Future studies should focus on determining the causal relationship between MCT consumption, energy expenditure, and HFD-induced adiposity.

<p>There has been a rapid shift in food environment of Western cultures that has increased consumption of diets high in fat and sugar, which have imparted negative effects on metabolic and neurocognitive health. There is also building evidence that the adverse effects of Western diet</p> <p>(WD) are different in males and females, such that males are impacted more at an earlier age and females are impacted later in life. The underlying biological mechanisms linking WD and neurocognitive health are often associated with energy dysregulation or neuroinflammation. WD</p> <p>disrupts glucose homeostasis and causes low grade inflammation in the body, and these can impact</p> <p>the brain by disrupting the blood-brain barrier (BBB). The BBB is the microvasculature found throughout the entire brain that tightly regulates what compounds get into the brain to ensure optimal neuronal function. WD disrupts the BBB, however, the effects of WD on BBB integrity</p> <p>in females and younger individuals remain largely unknown. Based on the metabolic and behavioral effects of WD, we hypothesized that the effects are age- and sex- specific. To test this, we gave male and female rats access to a WD for 8-10 weeks starting in juvenile period (post-natal</p> <p>day 21) or in adulthood (post-natal day 75), then measured body weight, behavior, glucose tolerance, the density of two different markers of BBB integrity. We also measured density of resident immune cells (microglia) to assess the relationship between inflammation and BBB integrity. First, we focused on the impact of hyperglycemia on the BBB since elevated glucose alters glucose transporter 1 (GLUT1). We found sex- and age- specific decreases in GLUT1 density in the prefrontal cortex and hippocampus—two brain regions commonly associated with neurocognitive impairments associated with WD. Correlational comparisons between WD and chow (CH) animals also found that the typically relationship between glucose tolerance and</p> <p>GLUT1 in the PFC and hippocampus were overall disrupted in WD animals. Second, we measured the leakage of albumin, a blood protein, since WD depletes the tight junctions that would typically prevent albumin from entering the brain and triggering a neuroinflammatory response. We did not find an increase in albumin density in WD animals, however, we found a main effect of age which</p> <p>offers insight to differential susceptibilities to BBB leakage. Third, we focused on inflammation and found that WD did not impact microglia density in our experiments, nor did it correlate with GLUT1, albumin, or behavior. Collectively, our findings support the hypothesis that the impact of</p> <p>WD on the BBB is sex- and age- specific, suggest that WD does not increase leakage of compounds such as albumin, and highlights the nuanced relationships between WD, metabolic disruption, behavioral deficits, and neuroinflammation.  </p>

Catechol-O-methyltransferase (COMT) metabolises catechol-containing compounds, including dopamine. The aim of this thesis was to investigate whether COMT is involved in hippocampal function. This thesis also explored the role of functional polymorphisms within the COMT gene in the pathogenesis of schizophrenia and schizophrenia-related phenotypes. First, as part of a study investigating the role of COMT in schizophrenia, human hippocampal COMT mRNA levels were shown to be neither altered in schizophrenia or bipolar disease, nor affected by COMT genotype. Hence, functional COMT polymorphisms do not appear to operate by altering gross COMT mRNA expression. Importantly, this study showed that COMT is expressed in the human hippocampus. Second, the role of COMT in hippocampal neurochemistry was explored by studying the effect of pharmacological COMT inhibition on catecholamines and metabolites in rat hippocampal homogenates, and extracellularly, using microdialysis. Both demonstrated that COMT modulates hippocampal dopamine metabolism. Thus, hippocampal COMT is of functional significance with respect to dopamine. Third, the effect of COMT inhibition on hippocampus-dependent behaviour was investigated. The results suggested a memory-enhancing effect of pharmacological COMT inhibition on hippocampus-dependent associative and non-associative forms of short-term memory in rats. In contrast, acute COMT inhibition appeared to have no effect on behavioural correlates of ventral hippocampal function i.e. anxiety-like behaviour. In summary, the expression of COMT mRNA in the human hippocampus, as well as the effect of COMT inhibition on rat hippocampal neurochemistry and hippocampus-dependent behaviour provide evidence for a functional role of COMT in the hippocampus. Moreover, changes in COMT activity alter hippocampal dopamine metabolism, which could be a potential mechanism for the role of COMT in hippocampus-dependent short-term memory.