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Alcohol use disorder (AUD) is a mental disorder that negatively affects personal health and burdens the global health system. Alcohol-attributed harms can also extend beyond the drinkers to other people in the society through increased road traffic accidents and more interpersonal violent behaviors. The effects of this disorder make it crucial to investigate predisposing mechanisms in order to identify at-risk individuals and further develop novel interventions. Although aberrant learning and dysfunctions in decision-making have been observed in individuals with AUD, it is not yet clear whether they predispose the development of risky drinking behaviors or result from repetitive alcohol use. To disentangle this, we studied the drinking behaviors of a community sample comprising participants who were 18–24, which is when the prevalence of alcohol use typically peaks. This thesis investigates whether two types of learning mechanisms—the balance between goal-directed and habitual control and the susceptibility to interference between Pavlovian cues and instrumental behaviors—are associated with the development of risky alcohol drinking behaviors. For Study 1, we assessed how goal-directed and habitual controls at 18 predispose alcohol use development over the course of 3 years. Goal-directed and habitual control, which are informed by model-based (MB) and model-free (MF) learning, were assessed with a two-step sequential decision-making task during functional magnetic resonance imaging. Three-year drinking trajectories were constructed based on the Alcohol Use Disorders Identification Test (AUDIT-C; assessed every 6 months) and a gram/drinking occasion measure (binge drinking score; assessed yearly). Latent growth curve models were applied to examine how the MB and MF controls were associated with the drinking trajectories. We found that MB control was negatively associated with the development of the binge drinking score trajectory. In contrast, MF reward prediction signals in the ventromedial prefrontal cortex and the ventral striatum (VS) were associated with a higher starting point and a steeper increase/less decrease in AUDIT-C, respectively. For Study 2, we investigated the cross-sectional association between the susceptibility to interference between Pavlovian cues and instrumental behaviors and risky (binge) drinking behaviors at age 18. During a Pavlovian-to-instrumental transfer (PIT) task, the participants were instructed to “collect good shells” and “leave bad shells” while the appetitive (monetary gain) or aversive (monetary loss) Pavlovian cues were presented in the background. The behavioral interference PIT effect was characterized by an increased error rate (ER) during incongruent trials (“collecting good shells” in the presence of an aversive Pavlovian cue or “leaving bad shells” during the presentation of an appetitive Pavlovian cue) in comparison to congruent ones. Overall, the individuals demonstrated a substantial behavioral PIT effect. Neural PIT correlates were found in the VS, dorsomedial, and lateral prefrontal cortices (dmPFC and lPFC, respectively). High-risk drinkers, in comparison to low-risk drinkers, exhibited a stronger behavioral PIT effect, decreased lPFC responses, and increased trend-level VS responses. Moreover, the effective connectivity from the VS to the lPFC during the incongruent trials was weaker for the high-risk drinkers, which indicates that the altered interplay between bottom-up and top-down neural responses may contribute to the poor interference control performance of this group. During Study 3, we further examined whether the susceptibility to Pavlovian cues during conflict trials was associated with the development of drinking behaviors over 6 years from ages 18 to 24. The drinking behaviors were again constructed based on the AUDIT-C and the binge drinking score. The PIT task was assessed at ages 18 and 21. Following Study 2, the increased ER in the incongruent condition compared with the congruent condition (along with the neural responses in the VS, lPFC, and dmPFC during the incongruent trials) were included in the latent growth curve models as predictors. A stronger VS response during a conflict at age 18 was associated with a higher starting point in both drinking trajectories but was negatively associated with the development of the binge drinking score trajectory. At age 21, high ER and enhanced neural responses in the dmPFC were associated with a risky AUDIT-C trajectory that started to emerge and develop until age 24. Through exploratory cluster analyses of the drinking trajectories, we identified two subgroups: the drinking behavior in the 'late riser' group escalated after age 21, whereas the drinking of 'early peakers' culminated at this age and then declined. The late risers displayed enhanced dmPFC responses and higher ER during conflict at age 21. Interestingly, this group also exhibited an increased ER from ages 18 to 21. Taken altogether, the unbalanced goal-directed to habitual control, informed by less MB and more MF control, appears to be a strong predisposing candidate mechanism that underlies the development of risky drinking behaviors during young adulthood. At age 18, the susceptibility to interference between Pavlovian cues and instrumental behaviors was associated with risky drinking behavior. The development of risky drinking behaviors over the 6 years was associated with the behavioral interference PIT effect at age 21 and its change from ages 18 to 21. Researchers could further explore the dynamics in PIT to predict risky drinking behaviors in the future.

Estudos reportando que a autoadministração repetida de drogas de abuso causa mudanças comportamentais, e na expressão de FosB, diferentes às causadas pela administração passiva repetida da mesma droga, em conjunto com estudos de discriminação de estímulos, têm sido chaves para compreender a dependência às drogas. Neste estudo se apresentam resultados de 3 experimentos que avaliaram diferenças gênicas e comportamentais entre a autoadministração de morfina e cocaína sob uma contingência operante, e a administração passiva destas drogas sob uma contingência Pavloviana, usando um modelo de administração de drogas acoplado e um protocolo de transferência operante-Pavloviana (PIT) seletiva em ratos. Os sujeitos foram distribuídos em três grupos: Administração por Contingência Operante (CO), Administração por Contingência Pavloviana (CP) e Controle (Ctr). No Experimento 1, cada sujeito do grupo CO foi exposto a sessões de autoadministração endovenosa de morfina. Depois, a expressão do gene FosB foi medida utilizando uma técnica imuno-histoquímicas em diferentes áreas do cérebro. No Experimento 2 os ratos foram expostos a um protocolo de PIT, treinando de forma inicial as contingências operante e Pavloviana separadamente, em associação a S1, utilizando infusões de morfina como reforçador. Em seguida foi treinado um encadeado de respostas (busca e administração) e finalmente, os sujeitos foram testados para avaliar o controle de estímulos que S1 adquiriu sobre as respostas de busca e administração. O Experimento 3 foi realizado utilizando os métodos dos primeiros dois experimentos, utilizando cocaína como reforçador. Em conjunto, os dados imunohistoquímicos e comportamentais sugerem que a maior expressão de FosB em subáreas envolvidas na dependência às drogas, em comparação entre os grupos CO e CP, está relacionada ao controle de estímulos estabelecido por S1 pelas diferentes contingências de aprendizagem. Ainda, os resultados apontam que estas áreas em que se encontrou uma expressão de FosB diferencial por diferentes contingências de administração de drogas coincidem com algumas das reportadas como envolvidas na PIT. Os resultados estão em concordância com estudos que reportam que a administração repetida de uma droga em contingências operantes ou pavlovianas alteram diferencialmente estruturas cerebrais envolvidas nos processos da dependência às drogas e apoiam a literatura que reporta que o estabelecimento de controle de estímulos que caracteriza a dependência se pode estabelecer por processos de aprendizagem na contingência operante e Pavloviana / Studies reporting that repeated drug self-administration produces behavioral changes, and in FosB expression, different from those produced by repeated passive administration of the same drug have been very important, together with stimulus control studies, have been the key to understand mechanisms underlying drug abuse. This study presents results from 3 experiments evaluating gene and behavioral differences between self-administration of morphine and cocaine under an operant contingency, and passive administration of these drugs under a Pavlovian contingency, using a yoked drug administration model and a selective Pavlovian to instrumental transfer (PIT) protocol in rats. Subjects were divided into three groups: Operant Contingency Administration (CO), Pavlovian Contingency Administration (CP) and Control (Ctr). In Experiment 1, each subject in the CO group was exposed to intravenous morphine self-administration sessions. Then, expression of FosB gene was measured using an immunohistochemical technique in different areas of the brain. In Experiment 2 rats were exposed to a PIT protocol, initially training the operant and Pavlovian contingencies separately in association with S1, using morphine infusions as a reinforcer. Then a chain of responses (seeking and taking) was trained and finally, subjects were tested to evaluate S1 stimulus control over search and administration responses. Experiment 3 was performed using the methods from the first two experiments, using cocaine as a reinforcer. Together, immunohistochemical and behavioral data interact and suggest that a higher expression on FosB expression in subareas involved in drug dependence, in comparison between CO and CP groups, is related to stimuli control established by S1 through the different learning contingencies. Moreover, results point out these same areas in which different FosB expression was found by different drug administration contingencies match some of those reported as being involved in PIT. Results are in agreement with studies reporting that repeated administration of a drug in operant or pavlovian contingencies differentially alter brain structures involved in drug dependence processes and support literature reporting the establishment of stimulus control characterizing addiction can be establish by learning processes in the operant and Pavlovian contingencies

Die These fasst die ersten Untersuchungen zum Pawlowsch`-Instrumentellen Transfer in alkoholabhängigen (AA) Patienten zusammen. Es ist bekannt, dass kontextuelle Umgebungsreize Verhalten beeinflussen. Tier- und Humanstudien haben gezeigt, dass positive Pawlowsche Reize instrumentelles Antwortverhalten verstärken und negative Pawlowsche Reize dieses reduzieren (PIT-Effekt). Bei Abhängigkeit wird angenommen, dass dieser Mechanismus relevant für Rückfall ist, da z.B. drogenassoziierte Reize bei Patienten im Vergleich zu Kontrollen erhöhtes Verlagen und funktionelle Aktivität in Belohnungsarealen auslösen. In Tier- und Humanstudien wurden stärkere PIT-Effekte vor allem mit funktioneller Aktivierung im Nucleus Accumbens (NAcc) beobachtet. Weiterhin zeigten sich bei Probanden mit stärkerem PIT-Effekt und bei AA Patienten erhöhte Impulsivitätswerte. Die PIT-Aufgabe besteht aus 3 Hauptteilen: i) Instrumentelle Konditionierung, ii) Pawlowsche Konditionierung, iii) Transfer mit Pawlowschen oder alkoholassoziierten Kontextstimuli. Impulsives Auswahlverhalten wurde durch die delay discounting Aufgabe erhoben. Es zeigten sich signifikant stärkere PIT-Effekte mit Pawlowschen Kontextreizen in AA Patienten im Vergleich zu Kontrollen mit funktioneller Aktivierung im NAcc, die zur Rückfallvorhersage beitrug. Der Transfer mit alkoholassoziierten Kontextreizen bewirkte eine signifikante Reduktion des instrumentellen Antwortverhaltens mit neuronalem Korrelat im NAcc nur bei abstinenten Patienten. Impulsives Auswahlverhalten und PIT hingen nur bei Patienten positiv zusammen. Die Studien lassen darauf schließen, dass PIT ein für Rückfall wichtiger Mechanismus ist mit funktionellem Korrelat im NAcc, der sich für motivationale Prozesse als auch als Salienzsignal relevant gezeigt hat. Die Subgruppe von hoch impulsiven Patienten ist im Besonderen durch Kontextreize im instrumentellen Antwortverhalten beeinflussbar, daher sollte ihr besondere Aufmerksamkeit bei Interventionen zukommen. / This thesis summarizes the first Pavlovian-to-instrumental transfer (PIT) studies in alcohol-dependent (AD) patients. Contextual stimuli are known to influence our behavior. Animal and human studies showed that positive Pavlovian stimuli enhance and negative Pavlovian stimuli reduce instrumental behavior (PIT effect). This mechanism might be relevant for relapse risk, as drug-associated stimuli have shown to enhance e.g. craving and functional activation in reward-related brain areas in patients compared to controls. In animal and human studies enhanced PIT effects were associated with activation particularly in the nucleus accumbens (NAcc). Moreover, control subjects with stronger PIT effects and AD patients were more impulsive on different facets of impulsivity. The PIT task consists of three main parts: i) instrumental conditioning, ii) Pavlovian conditioning, iii) transfer with Pavlovian background stimuli and instrumental task in the foreground (nondrug-related PIT: Pavlovian contextual cues; drug-related PIT: alcohol-related contextual cues). Choice impulsivity was measured by delay discounting task. We observed significantly enhanced nondrug-related PIT effects in AD patients compared to controls with a functional activation in the NAcc being predictive for relapse. Regarding drug-related PIT effects, we observed significantly reduced instrumental behavior during alcohol-related backgrounds with neural correlates in the NAcc in abstainers only. Choice impulsivity was positively related to PIT in AD patients only. Our data suggest that PIT is a mechanism contributing to relapse in AD patients with functional correlations within the NAcc, which based on our data is involved in motivation and attribution of salience. The subgroup of high impulsive patients is particularly susceptible for PIT effects, thus should be main target for intervention programs.

Pesquisas com drogas de abuso têm mostrado consistentemente que a apresentação de estímulos ambientais associados ao uso destas substâncias pode induzir comportamentos de busca e autoadministração das mesmas. Existe a hipótese de que o controle que estímulos ambientais adquirem sobre comportamentos de autoadministração e busca por drogas de abuso poderia ser influenciado tanto pela forma de administração da droga, autoadministração (administração ativa) ou heteroadministração (administração passiva), quanto pela contingência (operante ou respondente) em que a droga foi associada com tais estímulos. Foram formados trios compostos por um sujeito de cada grupo (CONT, ACOP e VEÍC) e realizados dois experimentos. Inicialmente os sujeitos de cada trio foram acoplados por meio de caixas experimentais separadas e expostos a tentativas discretas de apresentação dos estímulos luminosos, S1 e S2, simultaneamente. Como consequência do girar a roda operante na presença de S1 por um integrante do grupo CONT, este recebia uma infusão endovenosa de morfina (0,75 mg/kg), e simultaneamente os animais acoplados no trio recebiam uma infusão de morfina na mesma dose (grupo ACOP) ou de veículo (grupo VEÍC). Posteriormente, os sujeitos de todos os grupos foram treinados a pressionar uma barra por infusões endovenosas de morfina, sem contingência discriminativa programada alguma. Para esta fase, no experimento 1, S2 esteve presente durante as sessões experimentais, porém no experimento 2, nenhum S foi apresentado. Finalmente, os estímulos S1 e S2 foram apresentados em tentativas discretas, em condições de extinção. Os resultados mostram que, durante a extinção, o desempenho dos animais do grupo CONT, mas não os dos grupos ACOP e VEÍC, foi condizente com o treino recebido inicialmente (com 80% ou mais de respostas na barra em presença de S1), indicando que foi estabelecido controle discriminativo sobre a autoadministração de morfina no treino sob a contingência operante, mas não sob a respondente. Estes resultados sugerem que comportamentos de autoadministração e busca por drogas de abuso são influenciados tanto pela forma de administração da droga, quanto pelo tipo de contingência em que uma droga é associada com estímulos ambientais / Drug abuse research has consistently shown that presentation of a drug associated with environmental stimuli can induce drug-seeking and drug-administration behaviors. It has been hypothesized that stimuli control over drug-seeking and self-administration behaviors could be influenced by drug administrations nature, self-administration (active administration) or hetero-administration (passive administration), and also influenced by the drug-stimuli association contingency (operant or respondent). Animals were exposed to right jugular vein catheterization procedure. Groups Contingent (C), Yoked (Y) and Toked Saline (YS) were formed randomly after recovery. Yoked triads were formed with one subject from each group and two experiments were executed. Initially a discriminative training (light stimuli S1 and S2 discrete trials) was presented to triads. Each time C S group member turned an instrumental wheel in presence of S1, simultaneously, an intravenous morphine infusion (0.75 mg/kg) were administrated to that subject and yoked Y group member, as well as an intravenous saline infusion was administrated to yoked YS group member, in every triad. Afterward all subjects were individually trained to lever-press for an intravenous morphine infusion with no discrimination contingency programed. In this phase, S2 was presented through sessions in Experiment 1, while in Experiment 2 no S were presented. After achieving response stability, subjects were exposed to extinction sessions. Stimuli S1 and S2 discrete trials were presented but no consequences were programed for bar-press responses. Results show that only C groups performance was consistent with the previously received discriminative training (80% or more of bar-press responses in S1 presence) during extinction sessions, indicating that an operant training, but not a respondent training, successfully established morphine self-administration discriminative control. These results suggest that self-administration behaviors are in fact influenced by drugs administration nature and also by the drug-stimuli association contingency

Pesquisas com drogas de abuso têm mostrado consistentemente que a apresentação de estímulos ambientais associados ao uso destas substâncias pode induzir comportamentos de busca e autoadministração das mesmas. Existe a hipótese de que o controle que estímulos ambientais adquirem sobre comportamentos de autoadministração e busca por drogas de abuso poderia ser influenciado tanto pela forma de administração da droga, autoadministração (administração ativa) ou heteroadministração (administração passiva), quanto pela contingência (operante ou respondente) em que a droga foi associada com tais estímulos. Foram formados trios compostos por um sujeito de cada grupo (CONT, ACOP e VEÍC) e realizados dois experimentos. Inicialmente os sujeitos de cada trio foram acoplados por meio de caixas experimentais separadas e expostos a tentativas discretas de apresentação dos estímulos luminosos, S1 e S2, simultaneamente. Como consequência do girar a roda operante na presença de S1 por um integrante do grupo CONT, este recebia uma infusão endovenosa de morfina (0,75 mg/kg), e simultaneamente os animais acoplados no trio recebiam uma infusão de morfina na mesma dose (grupo ACOP) ou de veículo (grupo VEÍC). Posteriormente, os sujeitos de todos os grupos foram treinados a pressionar uma barra por infusões endovenosas de morfina, sem contingência discriminativa programada alguma. Para esta fase, no experimento 1, S2 esteve presente durante as sessões experimentais, porém no experimento 2, nenhum S foi apresentado. Finalmente, os estímulos S1 e S2 foram apresentados em tentativas discretas, em condições de extinção. Os resultados mostram que, durante a extinção, o desempenho dos animais do grupo CONT, mas não os dos grupos ACOP e VEÍC, foi condizente com o treino recebido inicialmente (com 80% ou mais de respostas na barra em presença de S1), indicando que foi estabelecido controle discriminativo sobre a autoadministração de morfina no treino sob a contingência operante, mas não sob a respondente. Estes resultados sugerem que comportamentos de autoadministração e busca por drogas de abuso são influenciados tanto pela forma de administração da droga, quanto pelo tipo de contingência em que uma droga é associada com estímulos ambientais / Drug abuse research has consistently shown that presentation of a drug associated with environmental stimuli can induce drug-seeking and drug-administration behaviors. It has been hypothesized that stimuli control over drug-seeking and self-administration behaviors could be influenced by drug administrations nature, self-administration (active administration) or hetero-administration (passive administration), and also influenced by the drug-stimuli association contingency (operant or respondent). Animals were exposed to right jugular vein catheterization procedure. Groups Contingent (C), Yoked (Y) and Toked Saline (YS) were formed randomly after recovery. Yoked triads were formed with one subject from each group and two experiments were executed. Initially a discriminative training (light stimuli S1 and S2 discrete trials) was presented to triads. Each time C S group member turned an instrumental wheel in presence of S1, simultaneously, an intravenous morphine infusion (0.75 mg/kg) were administrated to that subject and yoked Y group member, as well as an intravenous saline infusion was administrated to yoked YS group member, in every triad. Afterward all subjects were individually trained to lever-press for an intravenous morphine infusion with no discrimination contingency programed. In this phase, S2 was presented through sessions in Experiment 1, while in Experiment 2 no S were presented. After achieving response stability, subjects were exposed to extinction sessions. Stimuli S1 and S2 discrete trials were presented but no consequences were programed for bar-press responses. Results show that only C groups performance was consistent with the previously received discriminative training (80% or more of bar-press responses in S1 presence) during extinction sessions, indicating that an operant training, but not a respondent training, successfully established morphine self-administration discriminative control. These results suggest that self-administration behaviors are in fact influenced by drugs administration nature and also by the drug-stimuli association contingency

Dysfunktionale Lernvorgänge (wie z.B. Pawlowsche Konditionierung) können bei Patienten mit Alkoholabhängigkeit das Rückfallrisiko erhöhen, was innerhalb der vorliegenden Arbeit mittels drei Studien untersucht wurde.

Background: Pavlovian processes are thought to play an important role in the development, maintenance and relapse of alcohol dependence, possibly by influencing and usurping ongoing thought and behavior. The influence of pavlovian stimuli on ongoing behavior is paradigmatically measured by pavlovian-to-instrumental transfer (PIT) tasks. These involve multiple stages and are complex. Whether increased PIT is involved in human alcohol dependence is uncertain. We therefore aimed to establish and validate a modified PIT paradigm that would be robust, consistent and tolerated by healthy controls as well as by patients suffering from alcohol dependence, and to explore whether alcohol dependence is associated with enhanced PIT. Methods: Thirty-two recently detoxified alcohol-dependent patients and 32 age- and gender-matched healthy controls performed a PIT task with instrumental go/no-go approach behaviors. The task involved both pavlovian stimuli associated with monetary rewards and losses, and images of drinks. Results: Both patients and healthy controls showed a robust and temporally stable PIT effect. Strengths of PIT effects to drug-related and monetary conditioned stimuli were highly correlated. Patients more frequently showed a PIT effect, and the effect was stronger in response to aversively conditioned CSs (conditioned suppression), but there was no group difference in response to appetitive CSs. Conclusion: The implementation of PIT has favorably robust properties in chronic alcohol-dependent patients and in healthy controls. It shows internal consistency between monetary and drug-related cues. The findings support an association of alcohol dependence with an increased propensity towards PIT.

Introduction: The emergence of Pavlovian-to-instrumental transfer (PIT) research in the human neurobehavioral domain has been met with increased interest over the past two decades. A variety of PIT tasks were developed during this time; while successful in demonstrating transfer phenomena, existing tasks have limitations that should be addressed. Herein, we introduce two PIT paradigms designed to assess outcome-specific and general PIT within the context of addiction. - Materials and Methods: The single-lever PIT task, based on an established paradigm, replaced button presses with joystick motion to better assess avoidance behavior. The full transfer task uses alcohol and nonalcohol rewards associated with Pavlovian cues and instrumental responses, along with other gustatory and monetary rewards. We constructed mixed-effects models with the addition of other statistical analyses as needed to interpret various behavioral measures.- Results: Single-lever PIT: both versions were successful in eliciting a PIT effect (joystick: p < 0.001, ηp² = 0.36, button-box: p < 0.001, ηp ² = 0.30). Full transfer task: it was determined that the alcohol and nonalcoholic reward cues selectively primed their respective reward-associated responses (gustatory version: p < 0.001, r = 0.59, and monetary version: p < 0.001, r = 0.84). The appetitive/aversive cues resulted in a general transfer effect (gustatory: p < 0.001, ηp² = 0.09, and monetary: p < 0.001, ηp ² = 0.17). - Discussion/Conclusion: Single-lever PIT: PIT was observed in both task versions. We posit that the use of a joystick is more advantageous for the analysis of avoidance behavior. It evenly distributes movement between approach and avoid trials, which is relevant to analyzing fMRI data. Full transfer task: While gustatory conditioning has been used in the past to elicit transfer effects, we present the first paradigm that successfully elicits both specific and general transfers in humans with gustatory alcohol rewards.

Pavlovian cues can influence ongoing instrumental behaviour via Pavlovian-toinstrumental transfer (PIT) processes. While appetitive Pavlovian cues tend to promote instrumental approach, they are detrimental when avoidance behaviour is required, and vice versa for aversive cues. We recently reported that susceptibility to interference between Pavlovian and instrumental control assessed via a PIT task was associated with risky alcohol use at age 18. We now investigated whether such susceptibility also predicts drinking trajectories until age 24, based on AUDIT (Alcohol Use Disorders Identification Test) consumption and binge drinking (gramme alcohol/drinking occasion) scores. The interference PIT effect, assessed at ages 18 and 21 during fMRI, was characterized by increased error rates (ER) and enhanced neural responses in the ventral striatum (VS), the lateral and dorsomedial prefrontal cortices (dmPFC) during conflict, that is, when an instrumental approach was required in the presence of an aversive Pavlovian cue or vice versa. We found that a stronger VS response during conflict at age 18 was associated with a higher starting point of both drinking trajectories but predicted a decrease in binge drinking. At age 21, high ER and enhanced neural responses in the dmPFC were associated with increasing AUDIT-C scores over the next 3 years until age 24. Overall, susceptibility to interference between Pavlovian and instrumental control might be viewed as a predisposing mechanism towards hazardous alcohol use during young adulthood, and the identified high-risk group may profit from targeted interventions.