Cocaine's appetite for fat and the consequences on body weight.

For many individuals in treatment for cocaine dependence, weight gain is a substantial problem during recovery. This weight gain causes significant distress and seems to increase the risk of relapse. The mechanisms underlying cocaine's effects on weight remain elusive. It is widely assumed that this weight gain reflects a metabolic or behavioural compensatory response to the cessation of cocaine use. Here we challenge this assumption and outline potential mechanisms by which chronic cocaine use produces disturbances in the regulation of fat intake and storage, through its effects on the central and peripheral nervous systems, specifically the sympathetic nervous system. We hypothesize that the cocaine-induced alteration in fat regulation results in cocaine users developing a pronounced appetite for fatty food but keeps their fat mass low. This altered fat appetite subsequently leads to excessive weight gain when individuals enter treatment and stop using cocaine. Our aim is to shed light on the neurobiological mechanisms that may underlie the alterations in eating and fat regulation in cocaine-dependent individuals, to open up potential new avenues to support these individuals in recovery.LB is the recipient of a Wellcome Trust Vacation Scholarship and KDE is supported by the Medical Research Council (G1000018). The authors thank Hisham Ziauddeen for his comments on the manuscript and the Medical Research Council and the Wellcome Trust for their joint support of the Behavioural and Clinical Neuroscience Institute, which provided the infrastructure for this work.This is the author accepted manuscript. The final version is available from Informa Healthcare via http://dx.doi.org/10.3109/00952990.2014.96619

Using a drug-word Stroop task to differentiate recreational from dependent drug use.

Distinguishing dependent from recreational drug use can be a surprisingly difficult task, and the current means for identifying substance abuse can be inadequate or even misleading. In subjective self-reports, those who are most at risk may down play their consumption, not admitting to the full extent of their habit, and measures purely of quantity of use rarely capture the true nature of an individual's relationship to the drug, such as a psychological dependence on the substance. This trend is particularly true for heavy stimulant use, which is absent of the physical withdrawal symptoms that can help identify opiate or alcohol dependence. As such, a simple objective measure to help identify substance abuse, particularly in individuals who might not otherwise raise suspicion, would be a valuable tool in both clinical and experimental settings. We propose that the drug-word Stroop task, an objective assessment of attentional bias and distraction to salient drug-related stimuli, would be a valuable tool in helping to make these categorizations. This measure has been shown to correlate with drug craving, as well as to successfully distinguish dependent from recreational stimulant users and to help to predict outcomes in treatment-seeking individuals. Here, we survey prior literature on the drug-word Stroop task and provide a perspective on using the assessment as a potential diagnostic for drug use severity.Original research presented in this review was funded by a Medical Research Council (MRC) grant (G0701497), and conducted within the Behavioural and Clinical Neuroscience Institute (BCNI), which is jointly funded by an award from the MRC and Wellcome Trust (G00001354). DGS is supported by a studentship from the Cambridge Overseas Trust. KDE is supported by the MRC.This is the author accepted manuscript. The final version is available from Cambridge University Press via https://doi.org/10.1017/S109285291400013

Deficits in recognizing female facial expressions related to social network in cocaine-addicted men

Background: The ability to accurately recognise facial expressions of emotion is crucial for social functioning and maintaining healthy relationships. Recognising the emotional state of others allows us to respond to their needs and adjust our behaviour appropriately. Impairments in facial affect recognition have been reported in chronic cocaine users but little is known whether these contribute to their difficulties in social situations. Methods: We assessed face and facial emotional expression recognition in forty-five men with cocaine use disorder (CUD) and forty-four healthy control participants. Using standardised questionnaires, we also collected information on perceived social support, social provision and community integration. Results: Our results found that male cocaine users had greater difficulty in recognising female emotional facial expressions than male controls. This effect was not explained by demographic variables but it was associated with their social network; including social support, social provisions and community integration. Conclusion: Our findings suggest that men with CUD have greater difficulty in identifying emotional expression in female faces, which is linked with their social support networks. This may play an important role in misunderstanding non-verbal communications that contribute to destabilising friendship and family ties typically seen in drug addiction. Addressing deficits in recognising female emotional expressions may be an important piece of information for counselling and other interventions

Carrots and sticks fail to change behavior in cocaine addiction.

Cocaine addiction is a major public health problem that is particularly difficult to treat. Without medically proven pharmacological treatments, interventions to change the maladaptive behavior of addicted individuals mainly rely on psychosocial approaches. Here we report on impairments in cocaine-addicted patients to act purposefully toward a given goal and on the influence of extended training on their behavior. When patients were rewarded for their behavior, prolonged training improved their response rate toward the goal but simultaneously rendered them insensitive to the consequences of their actions. By contrast, overtraining of avoidance behavior had no effect on patient performance. Our findings illustrate the ineffectiveness of punitive approaches and highlight the potential for interventions that focus on improving goal-directed behavior and implementing more desirable habits to replace habitual drug-taking.Sir Henry Wellcome Postdoctoral Fellowship (Grant ID: 101521/Z/12/Z)This is the author accepted manuscript. The final version is available from AAAS via http://dx.doi.org/10.1126/science.aaf370

Drug Use in Night Owls May Increase the Risk for Mental Health Problems.

Drugs of abuse are widely known to worsen mental health problems, but this relationship may not be a simple causational one. Whether or not a person is susceptible to the negative effects of drugs of abuse may not only be determined by their addictive properties, but also the users' chronotype, which determines their daily activity patterns. The present study investigates the relationship between chronotype, drug use and mental health problems in a cross-sectional community sample. Participants (n = 209) completed a selection of questionnaires online, including the Munich Chronotype Questionnaire, the Depression Anxiety Stress Scale, the Alcohol Use Disorder Identification Test, the Cannabis Use Disorder Identification Test and the Fagerström Test for Nicotine Dependence. We conducted multiple regression models to determine relationships between participants' chronotype and their reported mental health symptoms and then estimated mediation models to investigate the extent to which their drug consumption accounted for the identified associations. Chronotype was significantly associated with participants' overall mental health (β = 0.16, p = 0.022) and their anxiety levels (β = 0.18, p = 0.009) but not with levels of depression or stress. However, both relationships were fully mediated by participants' overall drug consumption. Thus, late chronotypes, so-called "night owls", not only use more drugs but consequently have an increased risk for developing anxiety and deteriorating mental health status. This group may be particularly vulnerable to the negative psychological effects of drugs. Our results point toward the importance of considering chronotype in designing preventative and therapeutic innovations, specifically for anxiety, which at present has been largely neglected.This work was financially supported by the Medical Research Council (MRC; MR/J012084/1) and the National Institute of Health Research (NIHR) Cambridge Biomedical Research Centre. The views expressed in this manuscript are those of the authors and not of the funder. KDE was supported by an Alexander von Humboldt Fellowship for senior researchers (Grant No. GBR 1202805 HFST-E). J.S. was partly supported by the NIHR Collaboration for Leadership in Applied Health Research and Care (CLAHRC) East of England and by the Charles University Research Development Schemes Programme P38. All authors declare to have no conflict of interest

Detecting Small Vessel Pathology in Cocaine Use Disorder

BackgroundCocaine use is associated with an increased risk of cerebrovascular accidents. Small vessel pathology has been linked to the risk of stroke in cocaine users, but can be challenging to detect on conventional magnetic resonance (MR) scans. Fluid-attenuated inversion recovery (FLAIR) scans permit better resolution of small vessel lesions.ObjectivesFLAIR scans are currently only acquired based on the subjective judgement of abnormalities on MR scans at face value. We sought to evaluate this practice and the added value of FLAIR scans for patients with cocaine use disorder (CUD), by comparing microbleeds detected by MR and FLAIR scans. We hypothesised that microbleeds are more pronounced in CUD patients, particularly so in participants who had been selected for a FLAIR scan by radiographers.MethodsSixty-four patients with CUD and 60 control participants underwent a brain scan. The MR of 20 CUD patients and 16 control participants showed indicators of cerebral infarction at face value and were followed up by a FLAIR scan. We determined the volume of microbleeds in both MR and FLAIR scans and examined associations with various risk factors.ResultsWhile MR lesion volumes were significantly increased in CUD patients, no significant differences in lesion volume were found in the subgroup of individuals who received a FLAIR.ConclusionThe current practice of subjectively evaluating MR scans as a basis for the follow-up FLAIR scans to detect vascular pathology may miss vulnerable individuals. Hence, FLAIR scans should be included as a routine part of research studies.</jats:sec

The ICCAM platform study: An experimental medicine platform for evaluating new drugs for relapse prevention in addiction. Part B: fMRI description.

OBJECTIVES: We aimed to set up a robust multi-centre clinical fMRI and neuropsychological platform to investigate the neuropharmacology of brain processes relevant to addiction - reward, impulsivity and emotional reactivity. Here we provide an overview of the fMRI battery, carried out across three centres, characterizing neuronal response to the tasks, along with exploring inter-centre differences in healthy participants. EXPERIMENTAL DESIGN: Three fMRI tasks were used: monetary incentive delay to probe reward sensitivity, go/no-go to probe impulsivity and an evocative images task to probe emotional reactivity. A coordinate-based activation likelihood estimation (ALE) meta-analysis was carried out for the reward and impulsivity tasks to help establish region of interest (ROI) placement. A group of healthy participants was recruited from across three centres (total n=43) to investigate inter-centre differences. Principle observations: The pattern of response observed for each of the three tasks was consistent with previous studies using similar paradigms. At the whole brain level, significant differences were not observed between centres for any task. CONCLUSIONS: In developing this platform we successfully integrated neuroimaging data from three centres, adapted validated tasks and applied whole brain and ROI approaches to explore and demonstrate their consistency across centres.Medical Research Council (Grant ID: G1000018), GlaxoSmithKlineThis is the author accepted manuscript. The final version is available from SAGE Publications via http://dx.doi.org/10.1177/026988111666859

Impulsivity in abstinent alcohol and polydrug dependence: a multidimensional approach.

RATIONALE: Dependence on drugs and alcohol is associated with impaired impulse control, but deficits are rarely compared across individuals dependent on different substances using several measures within a single study. OBJECTIVES: We investigated impulsivity in abstinent substance-dependent individuals (AbD) using three complementary techniques: self-report, neuropsychological and neuroimaging. We hypothesised that AbDs would show increased impulsivity across modalities, and that this would depend on length of abstinence. METHODS: Data were collected from the ICCAM study: 57 control and 86 AbDs, comprising a group with a history of dependence on alcohol only (n = 27) and a group with history of dependence on multiple substances ("polydrug", n = 59). All participants completed self-report measures of impulsivity: Barratt Impulsiveness Scale, UPPS Impulsive Behaviour Scale, Behaviour Inhibition/Activation System and Obsessive-Compulsive Inventory. They also performed three behavioural tasks: Stop Signal, Intra-Extra Dimensional Set-Shift and Kirby Delay Discounting; and completed a Go/NoGo task during fMRI. RESULTS: AbDs scored significantly higher than controls on self-report measures, but alcohol and polydrug dependent groups did not differ significantly from each other. Polydrug participants had significantly higher discounting scores than both controls and alcohol participants. There were no group differences on the other behavioural measures or on the fMRI measure. CONCLUSIONS: The results suggest that the current set of self-report measures of impulsivity is more sensitive in abstinent individuals than the behavioural or fMRI measures of neuronal activity. This highlights the importance of developing behavioural measures to assess different, more relevant, aspects of impulsivity alongside corresponding cognitive challenges for fMRI.This article presents independent research funded by the Medical Research Council as part of their addiction initiative (grant number G1000018). GSK kindly funded the functional and structural MRI scans that took place at Imperial College. The research was carried out at the NIHR/Wellcome Trust Imperial Clinical Research Facility, the NIHR/Wellcome Trust Cambridge Research Facility and Clinical Trials Unit at Salford Royal NHS Foundation Trust, and is supported by the North West London, Eastern and Greater Manchester NIHR Clinical Research Networks.This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s00213-016-4245-

Computational modelling reveals contrasting effects on reinforcement learning and cognitive flexibility in stimulant use disorder and obsessive-compulsive disorder: remediating effects of dopaminergic D2/3 receptor agents

Abstract: Rationale: Disorders of compulsivity such as stimulant use disorder (SUD) and obsessive-compulsive disorder (OCD) are characterised by deficits in behavioural flexibility, some of which have been captured using probabilistic reversal learning (PRL) paradigms. Objectives: This study used computational modelling to characterise the reinforcement learning processes underlying patterns of PRL behaviour observed in SUD and OCD and to show how the dopamine D2/3 receptor agonist pramipexole and the D2/3 antagonist amisulpride affected these responses. Methods: We applied a hierarchical Bayesian method to PRL data across three groups: individuals with SUD, OCD, and healthy controls. Participants completed three sessions where they received placebo, pramipexole, and amisulpride, in a double-blind placebo-controlled, randomised design. We compared seven models using a bridge sampling estimate of the marginal likelihood. Results: Stimulus-bound perseveration, a measure of the degree to which participants responded to the same stimulus as before irrespective of outcome, was significantly increased in SUD, but decreased in OCD, compared to controls (on placebo). Individuals with SUD also exhibited reduced reward-driven learning, whilst both the SUD and OCD groups showed increased learning from punishment (nonreward). Pramipexole and amisulpride had similar effects on the control and OCD groups; both increased punishment-driven learning. These D2/3-modulating drugs affected the SUD group differently, remediating reward-driven learning and reducing aspects of perseverative behaviour, amongst other effects. Conclusions: We provide a parsimonious computational account of how perseverative tendencies and reward- and punishment-driven learning differentially contribute to PRL in SUD and OCD. D2/3 agents modulated these processes and remediated deficits in SUD in particular, which may inform therapeutic effects

Goal-Directed and Habitual Control in Smokers.

INTRODUCTION: Harmful behavior such as smoking may reflect a disturbance in the balance of goal-directed and habitual control. Animal models suggest that habitual control develops after prolonged substance use. In this study, we investigated whether smokers (N = 49) differ from controls (N = 46) in the regulation of goal-directed and habitual behavior. It was also investigated whether individual differences in nicotine dependence levels were associated with habitual responding. METHODS: We used two different multistage instrumental learning tasks that consist of an instrumental learning phase, subsequent outcome devaluation, and a testing phase to measure the balance between goal-directed and habitual responding. The testing phases of these tasks occurred after either appetitive versus avoidance instrumental learning. The appetitive versus aversive instrumental learning stages in the two different tasks modeled positive versus negative reinforcement, respectively. RESULTS: Smokers and nonsmoking controls did not differ on habitual versus goal-directed control in either task. Individual differences in nicotine dependence within the group of smokers, however, were positively associated with habitual responding after appetitive instrumental learning. This effect seems to be due to impaired stimulus-outcome learning, thereby hampering goal-directed task performance and tipping the balance to habitual responding. CONCLUSIONS: The current finding highlights the importance of individual differences within smokers. For future research, neuroimaging studies are suggested to further unravel the nature of the imbalance between goal-directed versus habitual control in severely dependent smokers by directly measuring activity in the corresponding brain systems. IMPLICATIONS: Goal-directed versus habitual behavior in substance use and addiction is highly debated. This study investigated goal-directed versus habitual control in smokers. The findings suggest that smokers do not differ from controls in goal-directed versus habitual control. Individual differences in nicotine dependence within smokers, however, were positively associated with habitual responding after appetitive instrumental learning. This effect seems to be due to impaired stimulus-outcome learning, thereby hampering goal-directed task performance and tipping the balance to habitual responding. These findings add to the ongoing debate on habitual versus goal-directed control in addiction and emphasize the importance of individual differences within smokers