Tobacco Images Choice and Its Association with Craving and Dependence in People who Smoke Cigarettes.

INTRODUCTION: Increased salience of drug-related cues over non-drug reinforcers can drive drug use and contribute to tobacco use disorder (TUD). An important scientific and clinical goal is to effectively measure this elevated drug-seeking behavior in TUD. However, most TUD assessments rely on self-reported cravings and cigarette consumption, not providing an objective measure of the impact of drug-cues on biasing behavior towards drugs. The probabilistic image choice (PIC) task investigates the choice of viewing drug-related pictures as compared to other salient pictures (e.g., pleasant and unpleasant). This study aimed to develop and validate the PIC task for TUD and evaluate the associations between behavioral choice and tobacco craving, daily cigarette consumption, quit attempts and motivation to quit, and nicotine dependence (the Fagerström score). METHODS: We recruited 468 smokers and 121 nonsmokers using the Prolific online platform. Participants performed the PIC task twice (at a one-month interval) and completed other measures relevant to TUD. RESULTS: compared to nonsmokers, tobacco smokers selected to view significantly more tobacco images and less pleasant (non-drug reinforcer) images, a profile that remained stable at retest. Individual differences in choice of tobacco as compared to pleasant images on the PIC task were associated with craving but not with the other tobacco dependence measures, suggesting that the task may serve as a behavioral proxy measure of drug "wanting" rather than of cumulative nicotine exposure or physical dependence. CONCLUSIONS: these results suggest that the PIC task can be a valuable tool for objectively assessing craving-associated tobacco seeking in TUD. IMPLICATIONS SECTION: which should provide a brief description about what the study addsMost of the current measures of tobacco use disorder (TUD) rely on self-reports of consumption, dependence and craving and do not take into consideration the role of drug-related cues in driving tobacco seeking. This study shows that the probabilistic image choice (PIC) task provides an objective, reliable proxy measure of tobacco image seeking behavior in people who smoke cigarettes that is linked to craving (desire) for smoking but not to other measures of TUD. Therefore, the PIC task may be a useful complementary tool for the classification, diagnosis, and prognosis of TUD.

Tobacco Images Choice and Its Association with Craving and Dependence in Cigarette Smokers.

Introduction: Increased salience of drug-related cues over non-drug reinforcers can drive drug use and contribute to tobacco use disorder (TUD). An important scientific and clinical goal is to effectively measure this elevated drug-seeking behavior in TUD. However, most TUD assessments rely on self-reported cravings and cigarette consumption, not providing an objective measure of the impact of drug-cues on biasing behavior towards drugs. The probabilistic image choice (PIC) task investigates the choice of viewing drug-related pictures as compared to other salient pictures (e.g., pleasant and unpleasant). This study aimed to develop and validate the PIC task for TUD and evaluate the associations between behavioral choice and tobacco craving, daily cigarette consumption, quit attempts and motivation to quit, and nicotine dependence (the Fagerström score). Methods: We recruited 468 smokers and 121 nonsmokers using the Prolific online platform. Participants performed the PIC task twice (at a one-month interval) and completed other measures relevant to TUD. Results: compared to nonsmokers, tobacco smokers selected to view significantly more tobacco images and less pleasant (non-drug reinforcer) images, a profile that remained stable at retest. Individual differences in choice of tobacco as compared to pleasant images on the PIC task were associated with craving but not with the other tobacco dependence measures, suggesting that the task may serve as a behavioral proxy measure of drug "wanting" rather than of cumulative nicotine exposure or physical dependence. Conclusions: these results suggest that the PIC task can be a valuable tool for objectively assessing craving-associated tobacco seeking in TUD.

Effect of environmental enrichment on relapse rates in patients with severe alcohol use disorder: protocol for a randomised controlled trial.

INTRODUCTION: Alcohol use disorder (AUD) ranks among the most prevalent psychiatric disorders worldwide. Despite current treatments, more than half of patients relapse within weeks after treatment. In animal models, exposure to environmental enrichment (EE) has been shown to be a promising approach to reduce relapse. However, controlled, multimodal EE is difficult to transpose to humans. To address this gap, this study aims at assessing the effectiveness of exposure to a newly designed EE protocol during AUD treatment in reducing relapse to alcohol use. Our EE will allow an enhancement of the standard intervention, and will combine several promising enrichment factors identified in the literature-physical activity, cognitive stimulation, mindfulness and virtual reality (VR). METHODS AND ANALYSIS: A randomised controlled trial involving 135 participants receiving treatment for severe AUD will be conducted. Patients will be randomised to an intervention enhancement group or a control group. The enhanced intervention will consist of six 40-min sessions of EE spread over 9 days. During the first 20 min of these sessions, patients will practise mindfulness in multisensory VR, in virtual environments designed to practise mindfulness and use it to regulate craving induced by virtual cues or stress. Then, participants will practise indoor cycling combined with cognitive training exercises. The control group will undergo standard management for AUD. The primary outcome is relapse assessed at 2 weeks after treatment, using a questionnaire and biological indicators. Relapse will be defined as drinking at least five drinks per occasion or drinking at least five times a week. It is predicted that the group receiving the EE intervention will have a lower relapse rate than the control group. The secondary outcomes are relapse at 1 month and 3 months after treatment, craving and drug-seeking behaviour, mindfulness skills acquisition and the effect of the intervention enhancement on the perceived richness of the daily environment, assessed by questionnaires and neuropsychological tasks. ETHICS AND DISSEMINATION: All participants have to give written informed consent to the investigator. This study is approved by the Ethics Committee Nord Ouest IV of Lille (reference number 2022-A01156-37). Results will be disseminated through presentations, peer-reviewed journals and seminar conferences. All information on ethical considerations and open science practices can be accessed at https://osf.io/b57uj/ TRIAL REGISTRATION NUMBER: NCT05577741.

Environmental enrichment-inspired pharmacological tools for the treatment of addiction.

Environmental enrichment (EE) has been shown to produce powerful beneficial effects in animal models of addiction. In particular, the ability of EE to promote abstinence and prevent relapse may allow for the identification of brain mechanisms responsible for the recovery from addiction. Indeed, the effects of EE on specific brain mechanisms could be mimicked by old or new molecules, which may become novel medications, called enviromimetics. Here, we review the best known enviromimetics for the treatment of addiction and suggest that, whereas these compounds may be relatively ineffective by themselves, they may be useful complements for existing therapeutic approaches to manage addiction which includes behavioural, environmental and pharmacological interventions.

Statins Reduce the Risks of Relapse to Addiction in Rats.

Statins are drugs that have been used for decades in humans for the treatment of hypercholesterolemia. More recently, several lines of evidence demonstrate that statins, in addition to their peripheral effects, produce a wide variety of effects in the brain and may be beneficial in neurological and psychiatric conditions. In this study, we allowed rats to self-administer cocaine for several weeks and, at the end of self-administration training, we treated them with low doses of statins daily for a 21-day period of abstinence. Chronic administration of brain-penetrating statins, simvastatin (1 mg/kg) and atorvastatin (1 mg/kg), reduced cocaine seeking compared with vehicle, whereas administration of pravastatin (2 mg/kg), a statin with low brain penetrability, did not. Importantly, the effects of brain-penetrating statins persisted even after discontinuation of the treatment and were specific for drug seeking because drug taking was not altered by simvastatin treatment. Finally, the effects of simvastatin were found to generalize to another drug of abuse such as nicotine, but not to food reward, and to reinstatement of cocaine seeking induced by stress. These results demonstrate that brain-penetrating statins can reduce risks of relapse to addiction. Given their well-known safety profile in humans, statins could be a novel effective treatment for relapse to cocaine and nicotine addiction and their use could be implemented in clinical settings without major health risks.

Chronic stimulation of the tone of endogenous anandamide reduces cue- and stress-induced relapse in rats.

BACKGROUND: The endogenous cannabinoid system plays an important role in motivation, stress, and drug abuse. Pharmacologically, the endocannabinoid system can be stimulated by either agonists of CB1 receptors or inhibition of metabolic degradation of endogenous cannabinoids and consequent increases in their brain levels. METHODS: Here, we investigated whether chronic administration during a period of withdrawal of the fatty acid amide hydrolase inhibitor URB597, which increases anandamide levels, would decrease the risks of relapse to cocaine seeking. Rats were allowed to self-administer cocaine and then they underwent forced withdrawal for 28 days, during which they were treated with URB597 or vehicle. One day after the last injection, we investigated cocaine seeking in one 6h extinction session and relapse triggered by re-exposure to drug-associated cues or a pharmacological stressor. RESULTS: We found that administration of URB597 significantly decreases cocaine-seeking behavior and cue- and stress-induced relapse. CONCLUSION: These results suggest that stimulation of the endocannabinoid system could be helpful to prevent relapse to cocaine addiction.

Effects of environmental enrichment on the incubation of cocaine craving.

Recent studies have demonstrated that exposure to environmental enrichment (EE) during withdrawal periods reduces the risks of relapse to drug-seeking behavior. In this study, we investigated whether EE could prevent the development of time-dependent increases in cocaine-seeking behavior (incubation of craving). In addition, we investigated whether EE could eliminate already developed incubation and whether the effects of EE would last when enrichment is discontinued. For this, we allowed rats to self-administer cocaine for 10 daily 6 h sessions and measured cocaine-seeking 1, 30 and 60 days after the last self-administration session. In between these tests, rats were kept in forced abstinence and housed either in EE or standard environments (SE). Between day 30 and 60 of withdrawal, half of the rats in each group were maintained in their original environmental condition and the other half was switched to the other environmental condition. We found that exposure to EE prevents development of incubation of cocaine craving and eliminates already developed incubation. In addition, contrary to our expectations, when EE was discontinued, its positive effects on incubation of craving disappeared. These results indicate that EE can reduce cocaine seeking but only temporarily and questions the hypothesis that EE can permanently eliminate the neural consequences of exposure to drugs of abuse. Therefore, stimulating environments could have positive effects on the treatment of cocaine addiction only if they are maintained for long periods of abstinence that encompass the time-frame during which addicts are most vulnerable to relapse.

Loss of environmental enrichment increases vulnerability to cocaine addiction.

Life experiences, especially during critical periods of maturation, such as adolescence, can dramatically affect vulnerability to diseases at adulthood. Early exposure to positive environmental conditions such as environmental enrichment (EE) has been shown to reduce the occurrence and the intensity of neurological and psychiatric disorders including drug addiction. However, whether or not exposure to EE during early stages of life would protect from addiction when, at adulthood, individuals may find themselves in non-enriched conditions has not been investigated. Here we show that switching mice from EE to non-enriched standard environments not only results in the loss of the preventive effects of EE but also increases the rewarding effects of cocaine. This enhanced vulnerability is associated with emotional distress and with increased levels in the mRNA levels of corticotropin releasing factor (CRF) in the bed nucleus of the stria terminalis (BNST), as well as with increases in CREB phosphorylation in the BNST and in the shell of the nucleus accumbens. The increased sensitivity to the rewarding effects of cocaine is completely blocked by the CRF antagonist antalarmin, confirming a major role of the CRF system in the negative consequences of this environmental switch. These results indicate that positive life conditions during early stages of life, if they are not maintained at adulthood, may have negative emotional consequences and increase the risks to develop drug addiction.

Environmental enrichment does not reduce the rewarding and neurotoxic effects of methamphetamine.

Abuse of amphetamine analogues, such as methamphetamine (METH), represents an important health problem because of their powerful addictive and neurotoxic effects. Abuse of METH induces dopamine neuron terminals loss and cell death in the striatum similar to what is found in other neurodegenerative processes. Exposing mice and rats to enriched environments (EE) has been shown to produce significant protective effects against drug-induced reward as well as against neurodegenerative processes. Here, we investigated whether exposure to EE could reduce the METH-induced reward and neurotoxicity. For this, we reared mice for 2 months during early stages of life in standard environments or EE and then, at adulthood, we tested the ability of METH to induce conditioned place preference and neurotoxicity. We found that, contrary to what we found with other drugs such as cocaine and heroin, EE was unable to reduce the rewarding effects of METH. In addition, contrary to what we found with other toxins such as MPTP, EE did not diminish the striatal neurotoxicity induced by METH (4 x 10 mg/kg) as measured by dopamine content, tyrosine hydroxylase protein levels and apoptosis. Our results demonstrate that the rewarding and neurotoxic effects of METH are not reduced by EE and highlight the great risks associated with the increased popularity of this drug amongst the young population.

Prevention and treatment of drug addiction by environmental enrichment.

Environmental enrichment (EE) has been shown to have powerful beneficial effects on a variety of physiological and pathological processes. Accumulating evidence indicates that EE can mimic positive life experiences and prevent the development of drug addiction. More recently, EE has also been shown to eliminate already developed addiction-related behaviors and to reduce the risks of relapse. These preventive and "curative" effects of EE are associated with dramatic plastic changes in several brain areas such as the hippocampus, the frontal cortex and the striatum. EE alters neurotransmitter systems, produces changes in gene expression and transcription factors, induces chromatin rearrangement, and stimulates hippocampal neurogenesis. Here we review the existent literature on behavioral, neurochemical, cellular and molecular effects of EE and we discuss different possible ways in which EE-induced neuroadaptations result in decreased vulnerability to addiction and relapse. We propose a unified theoretical framework in which EE is seen as a functional opposite of stress. On the one hand, the antistress effects of EE would reduce the reinforcing effects of drugs and their ability to induce long-lasting neuroplastic changes and, thus, they would prevent the development of drug addiction. On the other hand, permanent or transient restoration of the normal, pre-drug functioning of the stress system would facilitate resisting prepotent desire to take drug and it would decrease the risks of relapse. This theoretical framework highlights the importance of stress in each phase of drug addiction and strongly suggests that life conditions of abstinent addicts should be considered as part of their treatment.

Environmental enrichment reduces cocaine seeking and reinstatement induced by cues and stress but not by cocaine.

Whereas earlier studies have focused on the preventive effects of enriched environments (EE) in drug addiction, in a recent study we suggested that EE can also have 'curative' effects. In fact, we found that cocaine addiction-related behaviors can be eliminated by housing cocaine-treated mice in EE during periods of forced abstinence. However, those results were obtained with two simple models of addiction, conditioned place preference (CPP), and behavioral sensitization. In this study, we used intravenous drug self-administration procedures in rats to further investigate the beneficial effects of EE on cocaine addiction in a reinstatement model of relapse. Singly housed rats learned to self-administer cocaine during 10 consecutive daily sessions (0.6 mg/injection, 6 h/day). They were then housed three per cage in either standard environments (SE) or EE and were kept abstinent in the animal facility until testing for extinction and reinstatement. We found that 30 days of EE significantly and consistently reduced cocaine seeking during a 6-h extinction session. In addition, EE significantly reduced cue- and stress-induced reinstatement. Surprisingly, given our earlier results in mice with CPP, EE did not reduce cocaine-induced reinstatement regardless of the level of exposure to cocaine and the duration of the period of abstinence and exposure to EE. Altogether, these results support the hypothesis that EE can reduce cocaine-induced craving and highlight the importance of positive life conditions in facilitating abstinence and preventing relapse to cocaine addiction.

Reversal of cocaine addiction by environmental enrichment.

Environmental conditions can dramatically influence the behavioral and neurochemical effects of drugs of abuse. For example, stress increases the reinforcing effects of drugs and plays an important role in determining the vulnerability to develop drug addiction. On the other hand, positive conditions, such as environmental enrichment, can reduce the reinforcing effects of psychostimulants and may provide protection against the development of drug addiction. However, whether environmental enrichment can be used to "treat" drug addiction has not been investigated. In this study, we first exposed mice to drugs and induced addiction-related behaviors and only afterward exposed them to enriched environments. We found that 30 days of environmental enrichment completely eliminates behavioral sensitization and conditioned place preference to cocaine. In addition, housing mice in enriched environments after the development of conditioned place preference prevents cocaine-induced reinstatement of conditioned place preference and reduces activation of the brain circuitry involved in cocaine-induced reinstatement. Altogether, these results demonstrate that environmental enrichment can eliminate already established addiction-related behaviors in mice and suggest that environmental stimulation may be a fundamental factor in facilitating abstinence and preventing relapse to cocaine addiction.