Indiana University-Purdue University Indianapolis (IUPUI) / Drinking despite aversive consequences, or compulsive drinking, is a criterion of alcohol use disorder and can be modeled in rodents by adding bitter quinine into alcohol. Previous studies have shown the development of quinine-resistant ethanol (EtOH) drinking following a drinking history, but used animals that achieved relatively low blood alcohol levels. Selectively bred crossed High Alcohol Preferring (cHAP) mice average over 250 mg/dl during a two-bottle choice procedure. Compulsive drinking is hypothesized to be D1-receptor mediated via the dorsolateral striatum (DLS). We hypothesized that 2 weeks of free-choice EtOH would lead to quinine resistance and intra-DLS infusion of a D1-antagonist, SCH23390, would attenuate quinine-resistant alcohol drinking with no effect on non-conflicted EtOH drinking. Infusion of SCH23390 into the DMS would not affect quinine-resistant drinking. cHAP mice had guide cannulae placed in the DLS or DMS and had either two weeks (2W) of EtOH and water two-bottle choice or were EtOH naïve (0W). Mice were infused with either SCH23390 or saline immediately prior to one 10% EtOH and water test day and SCH23390 did not disturb alcohol drinking. The following day, we adulterated the EtOH with 0.32-g/L quinine (0.89 mM), and mice received the same microinjection. For animals cannulated in the DLS, 2W history group infused with saline drank more quinine-adulterated EtOH than the 0W saline mice. While SCH23390 infused 0W animals looked no different from saline treated mice, it attenuated quinine + EtOH intake in the 2W animals to the level of 0W animals. Interestingly, DMS-cannulated mice demonstrated similar behavior, with SCH23390 reducing EtOH + quinine consumption, while leaving EtOH consumption undisturbed. Quinine resistance following 2 weeks of free-choice EtOH consumption is attenuated by acute administration of a D1-antagonist in the DLS, suggesting that an alcohol history induces compulsivity and that dopamine contributes to this behavior. This is unique to compulsive drinking, as non-conflicted EtOH drinking was unaffected.

Compulsive eating behavior is a transdiagnostic construct that shares many behavioral, neurobiological, and theoretical features with compulsive drug use. The focus of this dissertation is to progress a framework for compulsive eating behavior, including identification of risk factors for its development and examination of functional neuroadaptations to brain reward systems in an animal model of compulsive eating. We first investigated impulsivity (impulsive choice and impulsive action) as a potential vulnerability factor for the development of binge and compulsive eating behavior. Impulsivity has been implicated in drug addiction as well as eating disorders and obesity, but its exact role in the conferment of risk for compulsive eating is unknown. To achieve this, we measured impulsive choice (i.e. delay discounting) and impulsive action (i.e. motor impulsivity) and subsequent binge-like eating. We observed no effects of impulsive choice behavior on binge-like eating of palatable food; however, impulsive action predicted higher binge-like eating, higher motivation for palatable food, and increased compulsive-eating behavior. Therefore, impulsive action, but not impulsive choice, predicted the development of binge- and compulsive-like eating behaviors. The second aim of this dissertation was to investigate functional neuroadaptations to brain reward pathways in rats with a history of palatable diet alternation, a model of compulsive eating. Overeating of palatable food, similar to exposure to drugs of abuse, is hypothesized to cause reward deficits via downregulation of mesolimbic dopamine systems. To investigate this, we measured sensitivity to d-Amphetamine using behavioral and neurochemical methods. To identify potential neuroadaptations to the dopamine and dopamine transporter (DAT) systems, we assessed baseline NAc-shell dopamine and DAT function in vivo. In rats with a history of palatable diet alternation, we observed deficits in the stimulating, reward-enhancing, and rewarding effects of d-Amphetamine, and impaired d-Amphetamine-induced dopamine efflux in the NAc-shell. Furthermore, dopamine and dopamine transporter systems were downregulated evidenced by decreased extracellular NAc-shell dopamine at baseline and decreased DAT function. These results contribute to an overall framework for compulsive eating behavior where initial impulsivity predisposes compulsive eating and compulsive eating results in the emergence of reward deficits. / 2021-06-14T00:00:00Z

Highly organised and differentiated neural circuits form and unite to link the cortex with the basal ganglia and thalamus to mediate movement, cognition and behaviour. Previous assertions that the basal ganglia primarily acted to filter cortical information to facilitate motor outputs only have since given way to an understanding of the basal ganglia as a relay and gating structure with functionally and structurally segregated inputs, functions and outputs. Thus, cortical – basal ganglia circuits can be segregated into three broadly separable functional domains mediating motor (primary and supplementary motor cortex (SMA) and putamen), cognitive (dorsolateral prefrontal cortex (dlPFC) and caudate), and limbic (ventromedial prefrontal cortex and ventral striatum (VS)) processes. In addition, cognitive and behavioural programs that pass through the cortical – basal ganglia circuitry can be subject to filtering by the subthalamic nucleus (STN), which receives direct projections from the cortex. This work first demonstrated the functional organisation of segregated intrinsic cortical – basal ganglia circuits in humans, alongside a detailed map of functional subzones within STN, a small and technically inaccessible midbrain structure. The behavioural relevance of the defined cortical – basal ganglia circuits was investigated by examining the cognitive constructs of impulsivity and compulsivity. Waiting impulsivity, a tendency towards rapid premature responses that has been associated with compulsive drug use, was associated with connectivity between limbic regions including subgenual anterior cingulate cortex, VS and STN. However, motor impulsivity, in the form of stopping ability, was associated with motoric regions including pre-SMA and STN. Compulsivity was captured as deficits in: reversal learning, implicating lateral orbitofrontal cortex; attentional shifting, implicating dlPFC; and habit learning, implicating SMA. Neural circuit changes were also examined in individuals with alcohol dependence and binge drinkers. Waiting impulsivity was elevated in both groups and the functional connectivity, microstructural integrity and anatomical connectivity of the neural circuit underlying waiting impulsivity were associated with problematic drinking behaviours in both groups. Together, this work establishes that discrete functional subzones of small subcortical regions can be differentiated in humans and that their behavioural correlates can be similarly mapped. The definition of intrinsic network architecture underlying a particular behaviour and the demonstration its disturbance in psychiatric groups will crucially inform the development of future diagnostic and therapeutic models.

Infusion of a dopamine D1-receptor antagonist into both the dorsolateral and dorsomedial striatum interfered with quinine-resistant alcohol drinking, but not unadulterated alcohol consumption. Dopamine in these two brain regions play a role in compulsive-like alcohol consumption.

Patients seeking help for hypersexual behavior often exhibit features of impulsivity, cognitive rigidity, poor judgment, deficits in emotion regulation, and excessive preoccupation with sex. Some of these characteristics are also common among patients presenting with neurological pathology associated with executive dysfunction. These observations led to the current investigation in which differences across scores on objective neuropsychological tests of executive functioning were explored in a group of hypersexual male patients (n = 30) compared with a non-hypersexual community sample (n = 30) of men. Using multivariate statistics, differences between the groups were examined yielding significant differences on measures of hypersexuality. However, the groups failed to exhibit significant differences across neuropsychological tests of executive functioning. These results contradict a previous finding of executive deficits among hypersexual men measured by self-report. These findings are discussed as they pertain to conceptualizations of hypersexual populations and possible implications for future research.

No description available.

No description available.

Jogo Patológico é um transtorno psiquiátrico ao qual se reputa importante participação de fatores de personalidade. Jogo Patológico tem sido associado com dependências de substâncias e especula-se uma relação com Transtorno Obsessivo Compulsivo (TOC). Alguns propõem que seja visto como uma dependência não química, outros recusam esta designação argumentando que o termo dependência deveria ser reservado ao uso abusivo de substâncias psicoativas e que JP estaria mais próximo de transtornos do humor e ansiosos. Jogo patológico já foi classificado como comportamento compulsivo, como dependência e, atualmente, encontra-se entre os 'Transtornos do Controle dos Impulsos Não Classificados em Outro Local' no DSM-IV, e entre os 'Transtornos de Hábitos e Impulsos' na CID-10. A relativa juventude do Jogo Patológico, enquanto categoria diagnóstica operacionalmente definida, talvez explique a imprecisão em sua caracterização fenomenológica e clínica. Os objetivos desta tese foram comparar Jogo Patológico e TOC, quanto às características de curso clínico e comorbidade e comparar jogadores patológicos, portadores de TOC e controles normais quanto a traços de personalidade com enfoque específico em impulsividade e compulsividade. Foram selecionados 40 jogadores patológicos, 40 portadores de TOC e 40 controles normais, pareados por gênero, idade e nível educacional. Os instrumentos utilizados foram o SCAN (Schedules for Clinical Assessment in Neuropsychiatry), para investigação de curso e comorbidade; o Tridimensional Personality Questionnaire; a Barrat Impulsiveness Scale versão 11 e uma versão adaptada da Yale Brown Obsessive Compulsive Scale para investigação de compulsividade. Observou-se que os portadores de TOC apresentaram início mais precoce, curso mais insidioso e menor freqüência de períodos livres de sintomatologia. Jogo Patológico e TOC apresentaram elevada comorbidade com transtornos ansiosos e depressão, porém Jogo Patológico apresentou uma associação significativamente maior com alcoolismo e tabagismo, enquanto TOC apresentou maior freqüência de transtornos somatoformes. Jogadores pontuaram em média significativamente mais que portadores de TOC e controles normais nas medidas de impulsividade. Portadores de TOC pontuaram mais que jogadores e controles normais em compulsividade. Jogadores pontuaram mais que controles normais em compulsividade. Conclui-se que Jogo Patológico e TOC guardam alguma semelhança no tocante à elevada comorbidade com depressão e ansiedade. Contudo, o curso clínico do Jogo Patológico, marcado por exacerbações paroxísticas e períodos de abstinência, além da elevada comorbidade com alcoolismo e tabagismo, reforçam suas semelhanças com as dependências. Em relação à personalidade, o traço mais saliente dos jogadores foi a impulsividade, justificando sua classificação como um transtorno do impulso. / Pathological Gambling (PG) is a psychiatric disorder in which personality features are considered essential for its development. In addition, it has been associated to Substance Dependence and a relationship to Obsessive-Compulsive Disorder (OCD) has been proposed. Some authors conceptualize it as a non-chemical dependence; others refuse this concept, arguing that the term dependence should be used exclusively to the misuse of psychoactive substances, and that PG would be closer to anxiety and affective disorders. PG has been classified as a compulsive behavior, as a dependence, and presently it is classified among the Impulse Control Disorders Not Elsewhere Classified in the DSM-IV, and 'Habit and Impulse disorders' in the ICD-10. PG's relative youth as a diagnostic category may explain the inaccuracy of its phenomenology and clinical characterization. The objectives of this study were: to compare PG and OCD regarding clinical course and psychiatric comorbidity; to compare pathological gamblers, obsessive-compulsive patients, and normal controls regarding personality features, specifically focussing impulsivity and compulsivity. Forty pathological gamblers, 40 obsessive-compulsive patients, and 40 normal control volunteers, matched by gender, age, and educational level were included. They were assessed through the Schedules for Clinical Assessment in Neuropsychiatry for evaluation of course of illness and psychiatric comorbidity; the Tridimensional Personality Questionnaire; the Barratt Impulsiveness Scale version 11, and an adapted version of the Yale Brown Obsessive Compulsive Scale for investigation of compulsivity. It was observed that OCD patients were younger at illness onset, had a more insidious course of the illness, with less frequent symptom free periods. PG and OCD presented high comorbidity with anxiety and depressive disorders, but PG presented a higher association to alcoholism and tobacco dependence as compared to OCD, while OCD presented a higher association to somatoform disorders as compared to PG. Pathological gamblers scored significantly higher than OCD patients and normal controls on impulsivity measures. OCD patients scored higher than pathological gamblers and normal controls on impulsivity. Pathological gambler scored higher than normal controls on compulsivity. It was concluded that PG and OCD have similarities regarding their high comorbidity to depression and anxiety. Nevertheless, PG's clinical course, characterized by recurrent symptomatic periods and symptom free periods, in addition to the high comorbidity with alcoholism and tobacco dependence, reinforces its resemblance to the dependencies. Regarding personality, impulsivity was the most salient feature found among pathological gamblers, thus supporting PG's classification as an impulsive control disorder.

L'impulsivité, un trait multidimensionnel, détermine la sévérité d'affections comportant des désordres compulsifs (syndrome de Gilles de la Tourette, maladie de Parkinson, troubles obsessionnels compulsifs), mais la nature de la relation impulsivité / compulsivité reste méconnue. L'intérêt du présent travail est d'identifier les substrats neurobiologiques de la balance impulsivité / compulsivité, dans une approche transnosographique, en s'aidant au plan préclinique, de manipulations causales et au plan clinique, d'une approche corrélationnelle. Ainsi, nous démontrons pour la première fois en dehors du champ de l'addiction, non seulement que l'impulsivité motrice, endophénotype de vulnérabilité à la compulsivité, prédit, sous l'influence de la transmission noradrénergique, la transition vers la compulsivité, mais aussi que (dans le modèle de la maladie de Parkinson) la dénervation de la voie nigrostriée et les traitements substitutifs dopaminergiques amplifient l'état impulsif. D'où l'interaction complexe entre le trait impulsif, les traitements et le processus dégénératif. Enfin, nous démontrons le bénéfice thérapeutique de la stimulation de la portion antérieure du pallidum interne dans les formes sévères de tics et suggérons dans un modèle préclinique d'une grande valeur heuristique, que le trait impulsif prédit l'efficacité de la stimulation du core du noyau accumbens. Nos résultats démontrent l'intérêt de mieux caractériser le trait impulsif des patients présentant des désordres compulsifs (syndrome de Gilles de la Tourette, maladie de Parkinson) et ouvrent ainsi de nouvelles perspectives thérapeutiques, tant pour la prévention de la transition de l'impulsivité à la compulsivité, que dans le traitement de ceux-ci. / Impulsivity, a multidimensional trait, determines the severity of compulsive disorders (Tourette's syndrome, Parkinson's disease, obsessive compulsive disorders), but the impulsive / compulsive relation remains unclear. The aim of this work is to identify the neurobiological substrates of impulsive / compulsive balance, using causal manipulations in rats and correlational studies in patients. The results demonstrate - for the first time beside the field of addiction - that, not only high impulsive trait is a transnosological endophenotype of increased vulnerability to develop compulsive disorders, but also that the transition from impulsivity toward compulsivity depends upon the noradrenergic transmission. Furthermore, we also show that, in a Parkinson's disease preclinical model, both the nigrostriatal denervation and dopaminergic treatments increase impulsive state, thereby indicating the contribution of a complex interaction between impulsive trait, medications and neurodegenerative process to the impulsive/compulsive balance. Finally, we show the therapeutic benefit of anterior globus pallidus interna in severe forms of tics and suggest in a preclinical model, with great heuristic value, that impulsive trait predicts the efficacy of nucleus accumbens core stimulation. Together, our results demonstrate the need to address the impulsive/compulsive balance in compulsive disorders and show promise for developing new pathophysiological-based therapeutic strategies that will treat both impulsivity and compulsivity.

Jogo Patológico é um transtorno psiquiátrico ao qual se reputa importante participação de fatores de personalidade. Jogo Patológico tem sido associado com dependências de substâncias e especula-se uma relação com Transtorno Obsessivo Compulsivo (TOC). Alguns propõem que seja visto como uma dependência não química, outros recusam esta designação argumentando que o termo dependência deveria ser reservado ao uso abusivo de substâncias psicoativas e que JP estaria mais próximo de transtornos do humor e ansiosos. Jogo patológico já foi classificado como comportamento compulsivo, como dependência e, atualmente, encontra-se entre os 'Transtornos do Controle dos Impulsos Não Classificados em Outro Local' no DSM-IV, e entre os 'Transtornos de Hábitos e Impulsos' na CID-10. A relativa juventude do Jogo Patológico, enquanto categoria diagnóstica operacionalmente definida, talvez explique a imprecisão em sua caracterização fenomenológica e clínica. Os objetivos desta tese foram comparar Jogo Patológico e TOC, quanto às características de curso clínico e comorbidade e comparar jogadores patológicos, portadores de TOC e controles normais quanto a traços de personalidade com enfoque específico em impulsividade e compulsividade. Foram selecionados 40 jogadores patológicos, 40 portadores de TOC e 40 controles normais, pareados por gênero, idade e nível educacional. Os instrumentos utilizados foram o SCAN (Schedules for Clinical Assessment in Neuropsychiatry), para investigação de curso e comorbidade; o Tridimensional Personality Questionnaire; a Barrat Impulsiveness Scale versão 11 e uma versão adaptada da Yale Brown Obsessive Compulsive Scale para investigação de compulsividade. Observou-se que os portadores de TOC apresentaram início mais precoce, curso mais insidioso e menor freqüência de períodos livres de sintomatologia. Jogo Patológico e TOC apresentaram elevada comorbidade com transtornos ansiosos e depressão, porém Jogo Patológico apresentou uma associação significativamente maior com alcoolismo e tabagismo, enquanto TOC apresentou maior freqüência de transtornos somatoformes. Jogadores pontuaram em média significativamente mais que portadores de TOC e controles normais nas medidas de impulsividade. Portadores de TOC pontuaram mais que jogadores e controles normais em compulsividade. Jogadores pontuaram mais que controles normais em compulsividade. Conclui-se que Jogo Patológico e TOC guardam alguma semelhança no tocante à elevada comorbidade com depressão e ansiedade. Contudo, o curso clínico do Jogo Patológico, marcado por exacerbações paroxísticas e períodos de abstinência, além da elevada comorbidade com alcoolismo e tabagismo, reforçam suas semelhanças com as dependências. Em relação à personalidade, o traço mais saliente dos jogadores foi a impulsividade, justificando sua classificação como um transtorno do impulso. / Pathological Gambling (PG) is a psychiatric disorder in which personality features are considered essential for its development. In addition, it has been associated to Substance Dependence and a relationship to Obsessive-Compulsive Disorder (OCD) has been proposed. Some authors conceptualize it as a non-chemical dependence; others refuse this concept, arguing that the term dependence should be used exclusively to the misuse of psychoactive substances, and that PG would be closer to anxiety and affective disorders. PG has been classified as a compulsive behavior, as a dependence, and presently it is classified among the Impulse Control Disorders Not Elsewhere Classified in the DSM-IV, and 'Habit and Impulse disorders' in the ICD-10. PG's relative youth as a diagnostic category may explain the inaccuracy of its phenomenology and clinical characterization. The objectives of this study were: to compare PG and OCD regarding clinical course and psychiatric comorbidity; to compare pathological gamblers, obsessive-compulsive patients, and normal controls regarding personality features, specifically focussing impulsivity and compulsivity. Forty pathological gamblers, 40 obsessive-compulsive patients, and 40 normal control volunteers, matched by gender, age, and educational level were included. They were assessed through the Schedules for Clinical Assessment in Neuropsychiatry for evaluation of course of illness and psychiatric comorbidity; the Tridimensional Personality Questionnaire; the Barratt Impulsiveness Scale version 11, and an adapted version of the Yale Brown Obsessive Compulsive Scale for investigation of compulsivity. It was observed that OCD patients were younger at illness onset, had a more insidious course of the illness, with less frequent symptom free periods. PG and OCD presented high comorbidity with anxiety and depressive disorders, but PG presented a higher association to alcoholism and tobacco dependence as compared to OCD, while OCD presented a higher association to somatoform disorders as compared to PG. Pathological gamblers scored significantly higher than OCD patients and normal controls on impulsivity measures. OCD patients scored higher than pathological gamblers and normal controls on impulsivity. Pathological gambler scored higher than normal controls on compulsivity. It was concluded that PG and OCD have similarities regarding their high comorbidity to depression and anxiety. Nevertheless, PG's clinical course, characterized by recurrent symptomatic periods and symptom free periods, in addition to the high comorbidity with alcoholism and tobacco dependence, reinforces its resemblance to the dependencies. Regarding personality, impulsivity was the most salient feature found among pathological gamblers, thus supporting PG's classification as an impulsive control disorder.