Varenicline is used to treat tobacco dependence. While varenicline decreases craving during a quit attempt, no studies have investigated its effect on cue-induced craving. Varenicline has also been shown to decrease alcohol consumption in animal and humans. This double-blind, randomized, placebo-controlled trial investigated the effect of varenicline on tobacco and alcohol cue-induced craving and alcohol consumption in dependent smokers/light drinkers. Tobacco and alcohol craving were assessed at baseline and after 2-weeks of drug administration using the QSU and ACQ. Significant decreases in cigarette and alcohol craving were observed between the pre- and post-drug session in the varenicline group on QSU Factor 1(87.5811.66 vs.70.5820.79, p=0.008) and ACQ Total (3.371.16 vs. 2.661.15, p=0.004) scores. This effect remained significant after correction for craving during neutral cues in the alcohol but not tobacco condition. No significant decreases in alcohol consumption were seen. These results suggest varenicline decreases overall craving, but not cue-induced craving specifically.

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L’objectif de ce travail de thèse était d’évaluer la faisabilité, l’acceptabilité et de fournir des résultats préliminaires du programme MBRP (Mindfulness Based relapse prevention) pour le traitement des addictions. Dans un premier lieu ce travail nous a permis de démontrer que ce programme représentait un type de prise en charge thérapeutique acceptable et faisable pour le traitement du trouble de l’usage de l’alcool. La participation au programme augmentait le niveau de pleine conscience et de flexibilité psychologique et réduisait le craving. Ensuite, nous avons pu identifier que la pratique à domicile, occupant une place centrale dans les traitements basés sur la pleine conscience, était facilitée par la motivation initiale des participants et de leur sentiment d’auto-efficacité quant à la capacité de mettre en place une pratique, à l’inverse, l’impression de « mal faire » ou l’absence d’effets immédiats de la pratique présentait un frein à la pratique autonome. Nous avons également pu rendre compte de l’intérêt de ce programme pour le traitement du trouble lié à la pratique de jeu d’argent et de hasard. A travers nos résultats descriptifs, nous avons pu montrer que la méditation de pleine conscience était un outil dont la majorité des patients joueurs se saisissaient volontiers pour gérer les envies de jeu et l’impulsivité. Nous avons trouvé que la participation au programme a permis de réduire la pratique de jeu, les symptômes de jeu, le craving, ainsi que les symptômes dépressifs et anxieux et augmenter le niveau de pleine conscience. Par ailleurs nous avons pu montrer à travers un cas clinique, que l’association de la pratique de pleine conscience et de training cognitif, pouvait représenter une prise en charge complémentaire et augmenter le contrôle de soi, chez une patiente résistante aux TCC classiques. Nous avons également montré que l’initiation à la pleine conscience chez des soignants travaillant dans le domaine de l’addictologie a été très bien accueillie, qu’en moyenne ils ont participés à 4 séances sur 5 et qu’ils ont tous mis en place une pratique autonome après l’initiation en groupe. Pour finir nous avons validé le Transdiagnostic Craving Trigger Questionnaire (TCTQ) visant à évaluer les déclencheurs de craving, dans une population présentant un trouble de l’usage de l’alcool. Nos analyses ont montré une solution à trois facteurs, les émotions désagréables, les émotions agréables et les déclencheurs externes et pensées associées aux consommations. Finalement ce travail de thèse nous a permis de conclure que le programme MBRP est un programme qui a tout son intérêt pour le traitement des addictions avec ou sans substances. Nous avons pu montrer qu’il agissait sur des processus sous-jacents de cette pathologie tels que les affectes dépressifs et l’anxiété, qu’il permettait de réduire le craving et qu’il mobilisait des ressources telles que la flexibilité psychologique. Nous avons l’objectif de conduire des travaux supplémentaires afin de pouvoir statuer sur son efficacité en comparaison à une condition contrôle. / The purpose of this work was to investigate feasibility, acceptability and preliminary outcomes of the MBRP (Mindfulness Based relapse prevention) program as a treatment of addictions. First, this work allowed us to establish that this program represented an acceptable and feasible therapeutic approach as a treatment for alcohol use disorders and that it increased the level of mindfulness and psychological flexibility and reduced craving. Secondly, we were able to identify that home practice, which is central to mindfulness-based treatments, was facilitated by the participants' initial motivation and their feeling of self-efficacy in terms of their ability to set up a practice, while the impression of "doing wrong" or the absence of immediate effects of the practice was a barrier to it. We have also been able to highlight the interest of this program as a treatment for gambling disorder. Through our descriptive results, we showed that mindfulness meditation was a tool that most gamblers readily used to manage craving and impulsive behavior. In addition, we found that participating in the program reduced gambling, gambling symptoms, craving, as well as depression and anxiety and increased mindfulness levels. In addition, we were able to show by examining a case report that the combination of the MBRP program and cognitive training could increase self-control in a patient who was resistant to conventional CBTs. We have also shown that the initiation to mindfulness among caregivers working in an addiction facility has been very well received. On average they participated in 4 out of 5 sessions and, all set up a personal home practice after the group initiation. Finally, we validated the Transdiagnostic Craving Trigger Questionnaire (TCTQ) to assess craving triggers in a population with an alcohol use disorder. Our analyses showed a three-factor solution, composed of unpleasant emotions, pleasant emotions and external triggers and associated thoughts. This thesis work allowed us to conclude that the MBRP program has a strong interest in the treatment of addictive disorders, with or without substances. We were able to show that it worked on underlying processes of this disorder, such as depression and anxiety, that it reduced craving and that it was a way of mobilizing resources, such as psychological flexibility. Our objective is to carry out further research which would allow us to state on its efficacy as compared to a control condition.

Elaborated Intrusion (EI) Theory posits that craving involves mental imagery in the same sensory modalities as the craved substance or activity. Visual imagery predominates, therefore craving should selectively interfere with performance on visual task, and conversely visual tasks should interfere with craving. This thesis reports tests of this prediction, both in the laboratory and real-world settings, to provide a basis for designing practical tasks for interfering with cravings in a natural environment. Contrary to predictions, experiments 1 and 2 showed no effect of craving on visual or verbal task performance. There were, however, effects of task performance on craving in experiment 2. Experiment 3 found that playing Tetris reduced craving relative to a no-task control (watching a load screen), but was no more effective than digit recall or counting in ones. Experiments 4 and 5 both compared the effects of visual pattern recall with digit recall, with contradictory results. Experiment 4 showed an effect of low load visual task on craving, but not verbal; whereas Experiment 5 found no impact of either task. Overall, the findings are consistent with the assumption that craving involves controlled cognitive processes, but do not clearly support or disprove the hypothesis that visual processes are key. Experiment 6 focussed on interfering with naturally occurring cravings in a laboratory setting. Playing the computer game Tetris reduced cravings compared to a no task control. The final study of this thesis examined cravings in a natural environment. Participants were lent an iPod with either a questionnaire-only task, or a task with the questionnaire and Tetris installed on it. They were prompted by SMS to complete the task at pseudo-random intervals across the day over the course of a week. Mixed effects regression and multilevel growth curve modelling showed that Tetris was effective at decreasing naturally occurring cravings in a natural environment but the binary measure used, did not find a reduction in indulgence rates, however other more sensitive measures may. In contrast to the literature reviewed, the findings from this thesis are more consistent with craving involving general cognitive effort rather than modality-specific processes. Games such as Tetris appear to have potential as take-home tasks in future research and to help people manage their cravings.

Environmental stimuli associated with drug use are related to drug craving and relapse. The mechanism of cue-induced craving is thought to involve the release of dopamine (DA) in brain regions associated with reward and habit formation. The aim of the study was to investigate the role of DA in cue-induced craving in tobacco-dependent smokers using Positron Emission Tomography (PET) and a picture cue paradigm. Tobacco-associated cues were capable of eliciting significantly greater subjective reports of craving relative to neutral cues in tobacco smokers (n=6) in a neuroimaging environment. Using this cue paradigm and [11C]-(+)-PHNO PET (n=6), a non-significant trend towards a greater decrease in binding potential, indicative of dopamine release, was shown in selected brain regions of interest. These findings are similar to findings in cocaine-dependent individuals and suggest the involvement of dopamine in the response to smoking-associated cues in tobacco-dependent individuals.

abstract: Serotonin 1B receptors (5-HT1BRs) are a novel target for developing pharmacological therapies to reduce psychostimulant craving. 5-HT1BRs are expressed in the mesolimbic pathway projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), which is involved in reward and motivation. 5-HT1BR agonists modulate both cocaine- and methamphetamine-seeking behaviors in rat models of psychostimulant craving. In this dissertation, I tested the central hypothesis that 5-HT1BRs regulate cocaine and methamphetamine stimulant and rewarding effects in mice. I injected mice daily with cocaine for 20 days and then tested them 20 days after their last injection. The results showed that the 5-HT1BR agonist CP94253 attenuated sensitization of cocaine-induced locomotion and cocaine-seeking behavior, measured as a decrease in the ability of a cocaine priming injection to reinstate extinguished cocaine-conditioned place preference (CPP). Subsequent experiments showed that CP94253 given prior to conditioning sessions had no effect on acquisition of methamphetamine-CPP, a measure of drug reward; however, CP94253 given prior to testing attenuated expression of methamphetamine-CPP, a measure of drug seeking. To examine brain regions and cell types involved in CP94253 attenuation of methamphetamine-seeking, I examined changes in the immediate early gene product, Fos, which is a marker of brain activity involving gene transcription changes. Mice expressing methamphetamine-CPP showed elevated Fos expression in the VTA and basolateral amygdala (BlA), and reduced Fos in the central nucleus of the amygdala (CeA). In mice showing CP94253-induced attenuation of methamphetamine-CPP expression, Fos was increased in the VTA, NAc shell and core, and the dorsal medial caudate-putamen. CP94253 also reversed the methamphetamine-conditioned decrease in Fos expression in the CeA and the increase in the BlA. In drug-naïve, non-conditioned control mice, CP94253 only increased Fos in the CeA, suggesting that the increases observed in methamphetamine-conditioned mice were due to conditioning rather than an unconditioned effect of CP94253 on Fos expression. In conclusion, 5-HT1BR stimulation attenuates both cocaine and methamphetamine seeking in mice, and that the latter effect may involve normalizing activity in the amygdala and increasing activity in the mesolimbic pathway. These findings further support the potential efficacy of 5-HT1BR agonists as pharmacological interventions for psychostimulant craving in humans. / Dissertation/Thesis / Doctoral Dissertation Neuroscience 2018

Environmental stimuli associated with drug use are related to drug craving and relapse. The mechanism of cue-induced craving is thought to involve the release of dopamine (DA) in brain regions associated with reward and habit formation. The aim of the study was to investigate the role of DA in cue-induced craving in tobacco-dependent smokers using Positron Emission Tomography (PET) and a picture cue paradigm. Tobacco-associated cues were capable of eliciting significantly greater subjective reports of craving relative to neutral cues in tobacco smokers (n=6) in a neuroimaging environment. Using this cue paradigm and [11C]-(+)-PHNO PET (n=6), a non-significant trend towards a greater decrease in binding potential, indicative of dopamine release, was shown in selected brain regions of interest. These findings are similar to findings in cocaine-dependent individuals and suggest the involvement of dopamine in the response to smoking-associated cues in tobacco-dependent individuals.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20796号 / 医博第4296号 / 新制||医||1025(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 中山 健夫, 教授 富樫 かおり, 教授 鈴木 実 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Alcohol consumption is prevalent on college campuses. There are a number of theories that seek to explain the link between alcohol use and mood. The affective-processing model posits that negative affect may interact with subconscious cognitive factors, such as attention bias (AB), to promote drug-seeking behavior. In contrast, the incentive-sensitization model suggests positive mood may drive drug seeking behavior, and this drive may be moderated by cognitive factors (e.g., AB). The current study hypothesized that both positive and negative mood would be associated with drug craving in the moment. It was further hypothesized that AB would moderate mood-craving associations. Participants (n = 69) from a Midwestern University carried a mobile device for 15 days and provided ratings of momentary mood (positive mood, anxiety, anger, and sadness), craving, and attention bias. Across assessments, all four moods were positively associated with momentary craving (p < .05). There were significant interactions of Anxiety x AB, Anger x AB, and Positive Mood x AB; all of which varied by gender. For men, Anxiety (B = .15, p = .004) and Positive Mood (B = .22, p < .001) were more robustly associated with momentary craving when their AB was +1SD above their own mean. For women, Anger (B = .14, p = .001) was more robustly associated with momentary craving when their AB was +1SD above their own mean. These results indicate differential effects of AB on mood by gender. Theoretical models of mood x cognition interactions may have more nuanced effects based on one's gender. This suggests that different forms of mood may trigger drug seeking behavior for men and women, offering important gender differences in relapse risk.

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