153 research outputs found

    Neural signatures of cognitive flexibility and reward sensitivity following nicotinic receptor stimulation in dependent smokers : a randomized trial

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    IMPORTANCE Withdrawal from nicotine is an important contributor to smoking relapse. Understanding how reward-based decision making is affected by abstinence and by pharmacotherapies such as nicotine replacement therapy and varenicline tartrate may aid cessation treatment. OBJECTIVE To independently assess the effects of nicotine dependence and stimulation of the nicotinic acetylcholine receptor on the ability to interpret valence information (reward sensitivity) and subsequently alter behavior as reward contingencies change (cognitive flexibility) in a probabilistic reversal learning task. DESIGN, SETTING, AND PARTICIPANTS Nicotine-dependent smokers and nonsmokers completed a probabilistic reversal learning task during acquisition of functional magnetic resonance imaging (fMRI) in a 2-drug, double-blind placebo-controlled crossover design conducted from January 21, 2009, to September 29, 2011. Smokers were abstinent from cigarette smoking for 12 hours for all sessions. In a fully Latin square fashion, participants in both groups underwent MRI twice while receiving varenicline and twice while receiving a placebo pill, wearing either a nicotine or a placebo patch. Imaging analysis was performed from June 15, 2015, to August 10, 2016. MAIN OUTCOME AND MEASURES A well-established computational model captured effects of smoking status and administration of nicotine and varenicline on probabilistic reversal learning choice behavior. Neural effects of smoking status, nicotine, and varenicline were tested for on MRI contrasts that captured reward sensitivity and cognitive flexibility. RESULTS The study included 24 nicotine-dependent smokers (12 women and 12 men; mean [SD] age, 35.8 [9.9] years) and 20 nonsmokers (10 women and 10 men; mean [SD] age, 30.4 [7.2] years). Computational modeling indicated that abstinent smokers were biased toward response shifting and that their decisions were less sensitive to the available evidence, suggesting increased impulsivity during withdrawal. These behavioral impairments were mitigated with nicotine and varenicline. Similarly, decreased mesocorticolimbic activity associated with cognitive flexibility in abstinent smokers was restored to the level of nonsmokers following stimulation of nicotinic acetylcholine receptors (familywise error-corrected P<.05). Conversely, neural signatures of decreased reward sensitivity in smokers (vs nonsmokers; familywise error-corrected P<.05) in the dorsal striatum and anterior cingulate cortex were not mitigated by nicotine or varenicline. CONCLUSIONS AND RELEVANCE There was a double dissociation between the effects of chronic nicotine dependence on neural representations of reward sensitivity and acute effects of stimulation of nicotinic acetylcholine receptors on behavioral and neural signatures of cognitive flexibility in smokers. These chronic and acute pharmacologic effects were observed in overlapping mesocorticolimbic regions, suggesting that available pharmacotherapies may alleviate deficits in the same circuitry for certain mental computations but not for others

    The Effect Of Abstinence From Smoking On Stress Reactivity

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    Subjective stress is a well-documented predictor of early smoking relapse, yet our understanding of stress and tobacco use is limited by the reliability of current available measures of stress. Functional magnetic reasoning imaging (fMRI) could provide a much-needed objective measure of stress reactivity. The goal of this dissertation is to contribute to the understanding of abstinence-induced changes in stress reactivity by examining neural, neuroendocrine (cortisol), and subjective measures of stress response during abstinence. In addition, this study investigated the influence of individual variation in nicotine metabolism rates on these measures of stress reactivity. Seventy-five treatment-seeking smokers underwent blood oxygen level dependent (BOLD) fMRI during the Montreal Imaging Stress Task (MIST) on two occasions: once during smoking satiety and once following biochemically confirmed 24-hour abstinence (order counter-balanced). The primary outcome measure was brain response during stress (vs. control) blocks of the MIST. Neural stress reactivity during abstinence (vs. satiety) was associated with significantly increased activation in the left inferior frontal gyrus (IFG), a brain region previously associated with inhibitory control. Greater abstinence-induced change in brain response to stress was associated with greater abstinence-induced change in subjective stress. However, there was no association with abstinence-induced change in cortisol response. In addition, higher rates of nicotine metabolism were associated with increased abstinence-induced change in self-reported stress, but not with brain or cortisol response. This study provides novel evidence that the brain response to stress is altered during the first 24 hours of a quit attempt compared to smoking satiety. These results underscore the importance of stress response during abstinence, and suggest that neuroimaging may provide a useful biomarker of stress response during the early smoking cessation, a period when smokers are most vulnerable to relapse

    Effects of gut hormones, glucagon-like peptide-1 and desacyl ghrelin, on eating behaviour in obesity and ex-smokers

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    Introduction: Unhealthy eating behaviour is more prevalent in obesity and contributes to weight regain after dieting. Smoking cessation weight gain, a common reason for relapse to cigarettes, also has adverse health consequences. Gut hormones, such as GLP-1 and desacyl ghrelin (DAG), reduce appetite and weight in obesity and Prader-Willi syndrome. GLP-1 and ghrelin signalling systems modulate central reward networks for food and nicotine in preclinical and human studies. However, the impact of GLP-1 and DAG on neurocircuitry involved in eating behaviour in obesity and ex-smokers remains unclear therefore further insight is needed to guide clinical use of gut hormones in prevention of weight gain during dieting and smoking cessation. Aims: Here, the effects of acute administration of GLP-1 analogue, Exenatide or DAG was explored in dieting adults with obesity, or in abstinent nicotine-dependence (double blind randomised placebo controlled cross-over design), on food cue responsivity using fMRI in reward-processing regions, food intake, food reward and appetite. Results: In dieting group with obesity, both Exenatide and DAG increased BOLD signal to high-energy (HE) food pictures in prefrontal cortex regions, implicated in inhibitory control. In contrast, in ex-smokers, both Exenatide and DAG decreased BOLD signal to HE food pictures in the mesolimbic reward-processing regions and prefrontal cortex, suggesting a reduction in anticipatory food reward with a concomitant decrease in executive control. With Exenatide, there was also a reduction in HE food appeal, food intake and appetite ratings in both groups. With DAG, there was no overall effect on HE food appeal, food intake or appetite ratings in both groups. Conclusion: These findings are in accord with the possibility that Exenatide and DAG could be used in prevention of smoking cessation weight gain. This experimental medicine study has provided pilot data for a larger clinical study to trial these gut hormones as potential therapies in smoking cessation.Open Acces

    BETA 2 NICOTINIC ACETYLCHOLINE RECEPTOR CONTRIBUTIONS TO ANXIETY-LIKE BEHAVIOR

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    Nicotine is a major psychoactive ingredient in tobacco that is thought to promote smoking behavior via nicotinic acetylcholine receptors (nAChRs) in the brain. Given reports that people smoke to relieve anxiety and that anxiety precipitates relapse, the overarching goal of this dissertation research is to assess beta 2 subunit containing nAChR (beta2*nAChR) contributions to anxiety-like behavior. Nicotine’s activity at beta2*nAChRs is concentration-dependent, with high concentrations facilitating activation followed by rapid desensitization and low concentrations preferentially desensitizing beta2*nAChRs; hence, activation or inhibition of beta2*nAChRs may support smoking behavior. Rodent studies reveal that nicotine affects anxiety-like behavior dose-dependently: low doses promote anxiolysis- and high doses support anxiogenic-like behavior. These pharmacological and genetic studies in mice test the hypothesis that nicotine administration promotes anxiolysis via inactivation of beta2*nAChRs and begin to identify which subunits, namely alpha 4 and alpha 6, work in concert with beta 2 to affect anxiety-like behavior. Low dose nicotine and inhibition of beta2*nAChRs supported anxiolysis-like behavior in a number of tasks with predictive validity for anxiolysis efficacy. These studies further suggest that activation of alpha6beta2*nAChRs is sufficient to produce anxiogenic-like behavior and that inhibition of alpha4beta2*nAChRs supports anxiolysis-like behavior. A secondary goal of these studies is to assess if beta2*nAChRs affect anxiety-like behavior during aging. Dysregulation of cholinergic tone can increase anxiety in the elderly, but little is known regarding beta2*nAChR contributions to anxiety in this population or where in the brain this may take place. These studies show that alpha4beta2*nAChR expression differentially affects anxiety-like behavior in adult and aged mice. With a focus on the lateral septum, a GABA-ergic limbic nucleus thought to regulate anxiety-like responses to external stimuli, a third goal of these studies is to elucidate the neuroanatomical and intracellular underpinnings of anxiety-like behavior that are affected by beta2*nAChR inhibition and expression. Previous studies demonstrate that exposure to stressors reduces phosphorylation of extracellular regulated kinase (ERK) in the lateral septum. In these studies, levels of pERK in the lateral septum were inversely associated with alpha4beta2*nAChR expression as well as anxiogenic-like behavior. In sum, these preclinical studies suggest that inhibition alpha4beta2*nAChRs may support cessation in those who smoke to relieve anxiety

    Role of Prefrontal Cortex Dopamine and Noradrenaline Circuitry in Addiction

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    Understanding the mechanisms of drug dependence has been the goal of a large number of neuroscientists, pharmacologists and clinicians who carried out research with the hope of individuating and proposing an efficacious therapy for this disorder (Sofuoglu, 2010; Kalivas and Volkow, 2011). Unfortunately, although huge efforts, drug dependence is still a relevant health, social and economical problem (Popova et al., 2012; Hiscock et al., 2011; Shorter and Kosten, 2011). Treatments for drug abuse are for the most part ineffective because the molecular and cellular mechanisms through which drugs of abuse alter neuronal circuitry are still unexplained and above all, because drugs of abuse determine a global alteration of cerebral functions that govern behaviour through decision formation, making therefore unfocused the identification of a pharmacological target (Volkow et al., 2011; Schultz 2011). One of the first strategies pursued in drug dependence therapy was directed to removal of pleasure associated with drug taking, but the compliance with the treatment has been always limited, although it could improve when it was supported by psychology based motivational therapy as in alcohol dependence (Krampe and Ehrenreich, 2010; Simkin and Grenoble, 2010). On the other hand it is not infrequent that heavy smokers or heavy drinkers stop suddenly dependence just because their will overcome year-long habits. Decision making is a process based on the interaction between prefrontal cortex (PFC) and subcortical regions involved in reward and motivation, therefore it is likely that failure in self-regulatory behavior, that is common in addicted subjects, could be dependent upon the alteration of interactions between the prefrontal cortex and subcortical regions (Heatherton and Wagner, 2011). In this chapter we will review the role of PFC in addiction with particular attention to dopamine and norepinephrine transmission

    MOLECULAR AND CELLULAR MECHANISMS UNDERLYING COGNITIVE NEUROADAPTATION IN ADDICTION: AN IN VIVO-VITRO INTEGRATIVE APPROACH

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    Il fumo di tabacco \ue8 la principale causa di morte prevenibile nel mondo industrializzato. L\u2019effetto farmacologico della nicotina gioca un ruolo fondamentale nella dipendenza da fumo di tabacco. La nicotina ha propriet\ue0 di rinforzo positivo e negativo, e induce condizionamento operante (comportamento motivato al consumo di nicotina) durante la fase di acquisizione della dipendenza. Vari studi pre-clinici e clinici hanno dimostrato l\u2019importanza di alcuni fattori non farmacologici, come gli stimoli ambientali, nel mantenimento della dipendenza da nicotina e nell\u2019induzione della ricaduta. Questi stimoli inizialmente neutri, ripetutamente associati alla nicotina (es. accendino) assumono un nuovo valore condizionato alla nicotina (CS) attraverso il condizionamento Pavloviano, ed acquisiscono la capacit\ue0 di indurre \u201ccraving\u201d (voglia di fumare) in assenza della droga. Considerata l\u2019importanza delle associazioni CS-nicotina consolidate nella memoria del fumatore nel fenomeno della ricaduta, \ue8 stato proposto che trattamenti atti a distruggere le memorie formate ed associate alla nicotina potrebbero agire da pro-astinenti e anti-ricaduta nel trattamento della dipendenza da fumo di tabacco. Dopo una fase di apprendimento le memorie sono immagazzinate tramite un processo chiamato consolidamento. Il condizionamento operante (anche detto strumentale) e il condizionamento pavloviano portano alla formazione di diversi tipi di memorie associate alla droga e responsabili della ricaduta dopo lunga astinenza. Evidenze provenienti da studi sull\u2019animale e sull\u2019uomo dimostrano che le memorie, una volta richiamate/riattivate, tornano in uno stato labile durante il quale possono venire aggiornate e reimmagazzinate oppure distrutte. Il richiamo delle memorie dunque le destabilizza ed innesca un fenomeno detto di riconsolidamento necessario affinch\ue8 la memoria venga mantenuta. Vi \ue8 una certa evidenza che le memorie pavloviane possano subire riattivazione e riconsolidamento ed \ue8 stato proposto che trattamenti che intervengono per distruggere il riconsolidamento di queste memorie possono rendersi utili nella inibizione delle memorie associate alla paura e anche delle memorie associate alle droghe. La distruzione delle memorie associate alle droghe \ue8 stato proposto come potenziale trattamento per prevenire la ricaduta al consumo di droga indotta dai CS nei tossicodipendenti. Molti studi condotti nell\u2019animale da laboratorio hanno dimostrato che il riconsolidamento delle memorie associate alle droghe pu\uf2 essere prevenuto attraverso la somministrazione di farmaci amnesici, che agiscono a specifici livelli molecolari (es., sistema adrenergico e glutamatergico), prima o dopo la loro riattivazione. Ad oggi non \ue8 ancora chiaro se tutte le memorie, o solo alcune, possono essere riattivate e riconsolidate. Ad esempio la possibilit\ue0 che la memoria strumentale possa essere riattivata e riconsolidata o distrutta \ue8 ancora molto discussa ed esperimenti comportamentali volti a studiare la pura memoria strumentale potrebbero chiarire questa questione. Lo scopo di questo lavoro di tesi era di studiare se fosse possibile distruggere le memorie pavloviane e strumentali associate alla nicotina somministrando propranololo, antagonista del recettore \u3b2-adrenergico, o MK-801, antagonista del recettore N-methyl-d-aspartato (NMDARs). Inoltre abbiamo verificato la possibilit\ue0 di utilizzare la tecnica dell\u2019immunoistochimica per determinare il livello di espressione di Zif268, un marker molecolare specificamente coinvolto nel riconsolidamento della memoria, dopo la riattivazione di memorie pavloviane associate alla nicotina nel ratto. E\u2019 stato utilizzato il modello di laboratorio della autosomministrazione di nicotina, basato sul paradigma del condizionamento operante e pavloviano, alla nicotina e ai CS associati alla nicotina. Abbiamo condotto due studi nei quali il trattamento farmacologico (propranololo o MK-801) veniva somministrato prima o dopo la riattivazione delle memorie pavloviane o strumentali associate alla nicotina. Abbiamo quindi testato l\u2019effetto del trattamento farmacologico sulla ricaduta al comportamento di ricerca di nicotina. La riattivazione della memoria pavloviana \ue8 consistita nella presentazione dei CS in assenza della nicotina. La riattivazione della memoria strumentale \ue8 consistita nel permettere all\u2019animale di premere la leva precedentemente associata all\u2019infusione di nicotina, senza che la nicotina venisse somministrata. Abbiamo inoltre effettuato un esperimento di immunoistochimica su fettine di cervello di ratto per determinare l\u2019espressione di Zif268 in amigdala basolaterale, regione maggiormente coinvolta nel risonsolidamento della memoria, dopo la presentazione dei CS associati alla nicotina. I risultati hanno dimostrato che il propranololo somministrato dopo la riattivazione della memoria pavloviana associata alla nicotina (30 CS) non \ue8 stato in grado di prevenire la ricaduta al comportamento di ricerca di nicotina. Un\u2019ipotesi plausibile potrebbe essere che la memoria strumentale ancora presente non possa essere riattivata e riconsolidata, e quindi non possa essere nemmeno distrutta. Per verificare questa ipotesi abbiamo testato l\u2019effetto dell\u2019MK-801, dimostrato essere pi\uf9 efficace nella distruzione del riconsolidamento di diversi tipi di memoria, somministrato 30 minuti prima della riattivazione della memoria strumentale. I risultati hanno dimostrato che la somministrazione di MK-801 prima della riattivazione non previene la ricaduta al comportamento di ricerca di nicotina. Questi dati suggeriscono una prevenzione della destabilizzazione della memoria strumentale, che la blocca in una fase stabile, piuttosto che una distruzione del riconsolidamento. Un altro studio in cui MK-801 \ue8 stato somministrato dopo che la destabilizzazione della memoria strumentale ha avuto luogo (es., somministrato dopo la sessione di riattivazione) ha dimostrato che MK-801 \ue8 stato in grado di prevenire la ricaduta al comportamento di ricerca di nicotina. Infine l\u2019immunoistochimica ha consentito di individuare un aumento del livello di espresione di Zif268 in amigdala basolaterale nei ratti sottoposti a riattivazione della memoria pavloviana associata alla nicotina. Questi dati confermano la validit\ue0 della tecnica nella determinazione dell\u2019espressione di markers molecolari specificamente coinvolti nel riconsolidamento della memoria. In conclusione, i nostri dati suggeriscono che: i) propranololo non distrugge il riconsolidamento della memoria pavloviana associata alla nicotina nelle nostre condizioni, ii) MK-801 somministrato prima della riattivazione potrebbe prevenire la destabilizzazione della memoria strumentale associata alla nicotina ma non ne distrugge il riconsolidatemnto nelle nostre condizioni, iii) MK-801 somministrato dopo la riattivazione della memoria strumentale associata alla nicotina ne distrugge il riconsolidamento nelle nostre condizioni, iiii) l\u2019immunoistochimica \ue8 una tecnica adatta ad investigare l\u2019espressione di markers molecolari specifiamente coinvolti nel riconsolidamento della memoria come Zif268, e potr\ue0 dunque essere utilizzata per dimostrare direttamente il riconsolidamento della memoria e suppoortare i risultati degli esperimenti comportamentali. Questi dati suggeriscono che la memoria strumentale potrebbe essere responsabile della mancanza di effetto di alcuni trattamenti farmacologici anti-ricaduta e che comunque questo tipo di memoria pu\uf2 essere distrutta se contrastata opportunamente. Lo sviluppo di nuovi farmaci capaci di agire a livello dei diversi meccanismi molecolari che sottostanno ai differenti tipi di memorie associate alle droghe potrebbere consentire una terapia coadiuvante alle attuali terapie anti-fumo e anti-ricaduta in grado di garantire una astinenza a lungo termine agli ex fumatori.Tobacco use through cigarette smoking is the leading preventable cause of death in the developed world. The pharmacological effect of nicotine plays a crucial role in tobacco addiction. Nicotine is positively and negatively reinforcing and leads to the development of \u201coperant conditioning\u201d (motivated behaviour to nicotine consumption) in smokers during the acquisition phase of addiction. Several preclinical and clinical studies have also underlined the importance of non-pharmacological factors, such as environmental stimuli, in maintaining smoking behaviour and promoting relapse. Initially neutral stimuli that are repeatedly paired with a reinforcing drug (e.g. lighter) acquire a new conditioned value (conditioned stimuli, CS) through \u201cPavlovian conditioning\u201d and become able to elicit craving even in the absence of the drug. Given the importance of the learned association between stimuli and nicotine in the phenomenon of relapse to nicotine-seeking behaviour, it has been proposed that treatment that disrupts the nicotine-associated memories could act as a pro-abstinent and anti-relapse therapy. After learning experience, memories are stored by a process called consolidation. Operant conditioning (also called instrumental learning) and Pavlovian conditioning lead to different drug-related memories formation (instrumental memories and Pavlovian memories) responsible for the relapse even after prolonged abstinence. However converging evidence from animal and human studies have revealed that memories may return to a vulnerable phase during which they can be updated, maintained and even disrupted. The retrieval of a memory indeed may destabilize the consolidated memory that requires a new process to be maintained. This hypothetical process is called reconsolidation. There is strong evidence that Pavlovian fear memories undergo reconsolidation and it was proposed that interventions to disrupt reconsolidation may help for specific and selective inhibition of fear related memories and, similarly, appetitive memories (i.e., for drug addiction). The disruption of drug-related memories reconsolidation has been proposed as a potential therapeutic target to prevent the CS-induced relapse in ex drug-addicts. Several animal studies have shown that the reconsolidation of some drug-related memories can be disrupted by the administration of an amnestic drug contingently upon retrieval of the memory acting at specific molecular levels (i.e. adrenergic and glutamatergic systems). However it is not known if all memories or only certain kind of memories could be retrieved and reconsolidated or disrupted. To date reconsolidation of instrumental memories is still under discussion and behavioural experiments targeting the pure instrumental memory reconsolidation disruption are needed to clarify this issue. The main objective of the present thesis was to study if it is possible to disrupt Pavlovian and instrumental nicotine-related memories reconsolidation by \u3b2-adrenergic receptor antagonist propranolol, or N-methyl-d-aspartate receptors (NMDARs) antagonist MK-801 respectively. We also verified the feasibility and reliability of Zif268 (a specific marker of memory reconsolidation) expression assessment by immunohistochemistry after retrieval of Palovian memory in rodents. The experimental approach used to address this issue was the laboratory model of nicotine self-administration in rats, based on the paradigms of operant and Pavlovian conditioning to nicotine and nicotine-associated cues. We performed two studies in which the pharmacological treatment (propranolol or MK-801) was associated to retrieval of Pavlovian or instrumental nicotine-related memories. We therefore assessed the effect of these pharmacological treatments on relapse to nicotine seeking behaviour. Retrieval of Pavlovian memories consists in presenting the CS in the absence of US. Retrieval of instrumental memories consists in allowing the animal to press the lever previously paired to nicotine reinforcement, without nicotine infusion. We also performed an immunohistochemistry assay in which the Zif268 level of expression was determined in basolateral amygdala (the most important region involved in memory reconsolidation) after nicotine CS presentation. Results showed that propranolol given after retrieval of Pavlovian memories (30 CS presentations) did not reduce the relapse to nicotine seeking behaviour compared to control groups that received vehicle injection in both retrieved or no-retrieved groups. It could be possible that instrumental memories, still present, do not undergo reconsolidation and could not be disrupted. To address this issue we tested the effect of MK-801, known to be more effective against instrumental memory than propranolol, given 30 minutes before the retrieval of instrumental memories. Results showed that pre-retrieval MK-801 injection did not prevent the relapse to nicotine-seeking behaviour when compared to control groups. This effect suggests a potential role of MK-801 in inhibition of the memory destabilization process instead of reconsolidation disruption. Further experiments in which MK-801 was given after memory destabilization was engaged (i.e. given after memory retrieval) showed that MK-801 prevented the relapse to nicotine-seeking behaviour. Finally immunohistochemistry showed an increased level of Zif268 expression in basolateral amygdala after retrieval of Pavlovian nicotine-related memories. These data confirm the validity and feasibility of immunohistochemistry to assess the expression of molecular markers correlating reconsolidation such as Zif268 after memory retrieval. In conclusion, our findings suggest that: i) propranolol did not disrupt Pavlovian memory reconsolidation in our conditions, ii) MK-801 given prior to retrieval session could prevent instrumental memory destabilization, but did not disrupt memory reconsolidation in our conditions, iii) MK-801 given after retrieval session disrupted memory reconsolidation in our conditions, iiii) immunohistochemistry is a feasible technique to investigate the expression of molecular markers correlating reconsolidation such as Zif268, thus it can be used to support our future behavioural studies. These data suggest that instrumental memory could be responsible for the lack of effect of some anti-relapse pharmacological treatments and that this kind of memory can be disrupted. New and specific pharmacological intervention, acting at specific molecular mechanisms that underlies reconsolidation of different kind of memories (i.e. Pavlovian but also instrumental memories), could be used as a potential co-adjuvant to current therapeutic interventions for smoking cessation and abstinence maintenance
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