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Background: Alcohol and drug dependence are major health and economic burdens to society. One of the major challenges to reducing this burden will be to develop more effective and better tolerated medications that target alternative mechanisms in the brain. While the dopamine system has been well characterized for mediating the reward value of drugs, there is evidence that the endocrine system also conveys signals to the same neural systems using gut hormones., Summary: These gut hormones, produced in the stomach and intestine and that regulate food intake, have also been shown to control the use of other substances, such as alcohol and drugs of abuse. Examples of such hormones are ghrelin and glucagon-like peptide-1, which exert their effects on dopamine transmission in parts of the brain known to be involved in some of the core features of addiction, such as reward sensitivity., Key Messages: This raises the possibility that gut hormone systems may play a pivotal role in addictive disorders. This review will briefly outline emerging evidence that the ghrelin and glucagon-like peptide-1 hormones are contrasting mediators of alcohol and drug use and may present a promising alternative target for treatment intervention in addictive disorders., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: Cocaine use disorder is associated with cognitive deficits that reflect dysfunctional processing across neural systems. Because there are currently no approved medications, treatment centers provide behavioral interventions that have only short-term efficacy. This suggests that behavioral interventions are not sufficient by themselves to lead to the maintenance of abstinence in patients with cocaine use disorder. Self-control, which includes the regulation of attention, is critical for dealing with many daily challenges that would benefit from medication interventions that can ameliorate cognitive neural disturbances., Methods: To address this important clinical gap, we conducted a randomized, double-blind, placebo-controlled, crossover design study in patients with cocaine use disorder (n = 23) and healthy control participants (n = 28). We assessed the modulatory effects of acute atomoxetine (40 mg) on attention and conflict monitoring and their associated neural activation and connectivity correlates during performance on the Eriksen flanker task. The Eriksen flanker task examines basic attentional processing using congruent stimuli and the effects of conflict monitoring and response inhibition using incongruent stimuli, the latter of which necessitates the executive control of attention., Results: We found that atomoxetine improved task accuracy only in the cocaine group but modulated connectivity within distinct brain networks in both groups during congruent trials. During incongruent trials, the cocaine group showed increased task-related activation in the right inferior frontal and anterior cingulate gyri, as well as greater network connectivity than the control group across treatments., Conclusions: The findings of the current study support a modulatory effect of acute atomoxetine on attention and associated connectivity in cocaine use disorder., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Patients with stimulant use disorder (SUD) show impairments when making value-based choices that are associated with disruptions in neural processing across brain networks. Making optimal choices requires learning from outcomes to update knowledge and further optimise ongoing behaviour. The optimal functioning of neural systems that underpin the ability to make favourable choices is an essential component for life functioning, and successful recovery in patients with SUD. Therefore, we sought to investigate the neural processes that underpin value-based choices in SUD patients. We hypothesise that patients with SUD have reduced functional connectivity while making financial choices during a probabilistic reinforcement learning task., Methods: We investigated connectivity associated with loss and reward value-based choices and their outcomes in patients with SUD and healthy control participants during a pharmacological magnetic resonance imaging study. Participants received a single dose of a dopamine receptor agonist, pramipexole, and a dopamine receptor antagonist, amisulpride, in a randomised, double-blind, placebo-controlled, balanced, crossover design. Functional task-related connectivity was analysed taking a whole brain connectomics approach to identify networks that are differentially modulated by dopaminergic receptor functioning., Results: SUD patients showed widespread reductions in connectivity during both reward and loss value-based choices and outcomes, which were negatively correlated with the duration of stimulant drug use. Disturbances to functional brain connectivity in SUD patients during task performance were not modulated acutely by either amisulpride or pramipexole., Conclusions: Reductions in brain connectivity, particularly when making value-based choices and processing outcomes, may underlie learning impairments in SUD patients. Given that acute dopaminergic modulation did not improve brain connectivity impairments in SUD patients, it is likely that alternative treatments are needed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: Drug addiction is associated with blunted neural responses to nondrug rewards, such as money, but heightened responses to drug cues that predict drug-reward outcomes. This dissociation underscores the role of incentive context in the attribution of motivational salience, which may reflect a narrowing toward drug-related goals. This hypothesis, however, has scarcely been investigated., Methods: To address this important scientific gap, the current study performed an empirical assessment of differences in salience attribution by comparing patients with stimulant use disorder (SUD) (n = 41) with control participants (n = 48) on network connectivity related to anticipation and outcome processing using a modified monetary incentive delay task. We hypothesized increased task-related activation and connectivity to drug rewards in patients with SUD, and reduced task-related activation and connectivity to monetary rewards during incentive processing across brain networks., Results: In the presence of behavioral and regional brain activation similarities, we found that patients with SUD showed significantly less connectivity involving three separate distributed networks during monetary reward anticipation, and drug and monetary reward outcome processing. No group connectivity differences for drug reward anticipation were identified. Additional graph theory analyses revealed that patients with SUD had longer path lengths across these networks, all of which positively correlated with the duration of stimulant drug use., Conclusions: Specific disruptions in connectivity in networks related to the anticipation of nondrug reward together with more general dysconnectivity in the processing of rewarding outcomes suggest an insensitivity to consequences. These observations support the notion of a predominance of habitual control in patients with SUD., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Methamphetamine misuse, a surging cause of morbidity and mortality worldwide, identifies Methamphetamine Use Disorder (MUD) as a critical public health problem. Treatment for MUD typically is sought during early abstinence when patients are experiencing cognitive difficulties that may hamper their engagement in treatment and recovery. Cognitive difficulties, particularly those that involve executive functions, likely reflect disruptions in neural functioning involving multiple brain areas and circuits., Methods: To extend knowledge in this area, we compared individuals with MUD (MUD group, n = 30) in early abstinence (3-11 days abstinent) with a healthy control group (HC, n = 33) on brain activation and network connectivity and topology, using functional magnetic resonance imaging (fMRI) during performance on an N-back working memory task. The N-back task involves the maintenance and manipulation of information in short-term memory and engages multiple neural processes related to executive functioning. The task was administered at two working-memory difficulty loads (1-back and 2-back)., Results: Compared with the HC group, the MUD group had worse task performance but no differences in task-related brain activation. Network-based statistics analyses, however, revealed that the MUD group exhibited less functional network connectivity at both difficulty loads of the N-back task than the HC group. Additional graph theory analyses showed that path lengths were longer, and clustering was lower across these networks, which also exhibited disrupted small-world properties in the MUD group., Conclusion: These results suggest a decoupling in network dynamics that may underlie deficits in cognition during early abstinence in MUD patients., Competing Interests: Conflict of interest statement No authors have any relevant conflicts of interest to disclose., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Adolescence may be a period of increased vulnerability to the onset of drug misuse and addiction due to changes in developing brain networks that support cognitive and reward processing. Cannabis is a widely misused illicit drug in adolescence which can lead to dependence and alterations in reward-related neural functioning. Concerns exist that cannabis-related alterations in these reward networks in adolescence may sensitize behaviour towards all forms of reward that increase the risk of further drug use. Taking a functional connectomics approach, we compared an acutely abstinent adolescent cannabis-dependent (CAN) group with adolescent controls (CON) on global measures of network topology associated with anticipation on a monetary incentive delay task. In the presence of overall superior accuracy, the CAN group exhibited superior global connectivity (clustering coefficient, efficiency, characteristic path length) during monetary gain anticipation compared with the CON group. Additional analyses showed that the CAN group exhibited significantly greater connectivity strength during monetary gain anticipation across a subnetwork that included mesocorticolimbic nodes involving both interhemispheric and intrahemispheric connections. We discuss how these differences in reward-associated connectivity may allude to subtle functional alterations in network architecture in adolescent cannabis-dependence that could enhance the motivation for nondrug reward during acute abstinence., (© 2019 Society for the Study of Addiction.)

The prevalent spatial distribution of abnormalities reported in cognitive fMRI studies in addiction suggests there are extensive disruptions across whole brain networks. Studies using resting state have reported disruptions in network connectivity in addiction, but these studies have not revealed characteristics of network functioning during critical psychological processes that are disrupted in addiction populations. Analytic methods that can capture key features of whole brain networks during psychological processes may be more sensitive in revealing additional and widespread neural disturbances in addiction, that are the provisions for relapse risk, and targets for medication development. The current study compared a substance addiction (ADD; n = 83) group in extended abstinence with a control (CON; n = 68) group on functional MRI (voxel-wise activation) and global network (connectivity) measures related to reward anticipation on a monetary incentive delay task. In the absence of group differences on MID performance, the ADD group showed reduced activation predominantly across temporal and visual regions, but not across the striatum. The ADD group also showed disruptions in global network connectivity (lower clustering coefficient and higher characteristic path length), and significantly less connectivity across a sub-network comprising frontal, temporal, limbic and striatal nodes. These results show that an addiction group in extended abstinence exhibit localised disruptions in brain activation, but more extensive disturbances in functional connectivity across whole brain networks. We propose that measures of global network functioning may be more sensitive in highlighting latent and more widespread neural disruptions during critical psychological processes in addiction and other psychiatric disorders., (Copyright © 2020. Published by Elsevier Inc.)

Identifying key neural substrates in addiction disorders for targeted drug development remains a major challenge for clinical neuroscience. One emerging target is the opioid system, where substance-dependent populations demonstrate prefrontal opioid dysregulation that predicts impulsivity and relapse. This may suggest that disturbances to the prefrontal opioid system could confer a risk for relapse in addiction due to weakened 'top-down' control over impulsive behaviour. Naltrexone is currently licensed for alcohol dependence and is also used clinically for impulse control disorders. Using a go/no-go (GNG) task, we examined the effects of acute naltrexone on the neural correlates of successful motor impulse control in abstinent alcoholics (AUD), abstinent polysubstance-dependent (poly-SUD) individuals and controls during a randomised double blind placebo controlled fMRI study. In the absence of any differences on GNG task performance, the AUD group showed a significantly greater BOLD response compared to the control group in lateral and medial prefrontal regions during both placebo and naltrexone treatments; effects that were positively correlated with alcohol abstinence. There was also a dissociation in the positive modulating effects of naltrexone in the orbitofrontal cortex (OFC) and anterior insula cortex (AIC) of the AUD and poly-SUD groups respectively. Self-reported trait impulsivity in the poly-SUD group also predicted the effect of naltrexone in the AIC. These results suggest that acute naltrexone differentially amplifies neural responses within two distinct regions of a salience network during successful motor impulse control in abstinent AUD and poly-SUD groups, which are predicted by trait impulsivity in the poly-SUD group., (© 2018 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

This corrects the article DOI: 10.1038/npp.2016.60.

Addiction to cigarettes presents with considerable health risks and induces high costs on healthcare resources. While the majority of cigarette smokers endorse the desire to quit, only a small percentage of quit attempts lead to full abstinence. Failure to achieve abstinence may arise from maladaptive reactivity in fronto-striatal regions that track positive and negative valence outcomes, thus biasing the choice to smoke in the presence of alternative, non-drug reinforcement. Alternatively, long-term nicotine abstinence may reveal neural substrates of adaptive valence outcome processing that promote and maintain smoking cessation. The present study set out to examine the neural correlates of operant response outcomes in current smokers, ex-smokers and matched controls using a monetary incentive delay task during functional MRI. Here we report that compared to controls, both current smokers and ex-smokers showed significantly less activation change in the left amygdala during positive response outcomes, and in the anterior cingulate cortex, during both positive and negative response outcomes. Ex-smokers, however, demonstrated significantly greater activation change compared to smokers and controls in the right amygdala during negative response outcomes. Activation change in the anterior cingulate cortex and middle frontal gyrus of smokers was significantly negatively correlated with nicotine dependence and cigarette pack-years. These results suggest a pattern of shared and divergent reactivity in current smokers and ex-smokers within corticolimbic regions that track both positive and negative operant response outcomes. Exaggerated adaptive processing in ex-smokers may promote long-term smoking cessation through amplified negative valence outcome monitoring., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Despite an increased understanding of nicotine addiction, there is a scarcity of research comparing the neural correlates of non-drug reward between smokers and ex-smokers. Long-term changes in reward-related brain functioning for non-drug incentives may elucidate patterns of functioning that potentially contribute to ongoing smoking behaviour in current smokers. Similarly, examining the effects of previous chronic nicotine exposure during a period of extended abstinence may reveal whether there are neural correlates responsible for non-drug reward processing that are different from current smokers. The current study, therefore, sets out to examine the neural correlates of reward and loss anticipation, and their respective outcomes, in smokers, ex-smokers and matched controls using a monetary incentive delay task during functional magnetic resonance imaging. Here, we report that in the absence of any significant behavioural group differences, both smokers and ex-smokers showed a significantly greater activation change in the lateral orbitofrontal/anterior insular cortex compared with smokers when anticipating both potential monetary gains and losses. We further report that ex-smokers showed a significantly greater activation change in the ventral putamen compared with both controls and smokers and in the caudate compared with controls during the anticipation of potential monetary losses only. The results suggest that smoking may sensitize striato-orbitofrontal circuitry subserving motivational processes for loss avoidance and reward gain in nicotine addiction., (© 2016 Society for the Study of Addiction.)

Naltrexone, an opioid receptor antagonist, is commonly used as a relapse prevention medication in alcohol and opiate addiction, but its efficacy and the mechanisms underpinning its clinical usefulness are not well characterized. In the current study, we examined the effects of 50-mg naltrexone compared with placebo on neural network changes associated with substance dependence in 21 alcohol and 36 poly-drug-dependent individuals compared with 36 healthy volunteers. Graph theoretic and network-based statistical analysis of resting-state functional magnetic resonance imaging (MRI) data revealed that alcohol-dependent subjects had reduced functional connectivity of a dispersed network compared with both poly-drug-dependent and healthy subjects. Higher local efficiency was observed in both patient groups, indicating clustered and segregated network topology and information processing. Naltrexone normalized heightened local efficiency of the neural network in alcohol-dependent individuals, to the same levels as healthy volunteers. Naltrexone failed to have an effect on the local efficiency in abstinent poly-substance-dependent individuals. Across groups, local efficiency was associated with substance, but no alcohol exposure implicating local efficiency as a potential premorbid risk factor in alcohol use disorders that can be ameliorated by naltrexone. These findings suggest one possible mechanism for the clinical effects of naltrexone, namely, the amelioration of disrupted network topology., (© 2017 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

There is a concerted research effort to investigate brain mechanisms underlying addiction processes that may predicate the development of new compounds for treating addiction. One target is the brain's opioid system, because of its role in the reinforcing effects of substances of abuse. Substance-dependent populations have increased numbers of the mu opioid receptor (MOR) in fronto-striatal regions that predict drug relapse, and demonstrate disturbances in these regions during the processing of non-drug rewards. Naltrexone is currently licensed for alcohol and opiate dependence, and may remediate such disturbances through the blockade of MORs in fronto-striatal reward circuitry. Therefore, we examined the potential acute modulating effects of naltrexone on the anticipation of, and instrumental responding for, non-drug rewards in long-term abstinent alcoholics, alcoholic poly substance-dependent individuals and controls using a monetary incentive delay (MID) task during a randomized double blind placebo controlled functional MRI study. We report that the alcoholic poly substance-dependent group exhibited slower and less accurate instrumental responding compared to alcoholics and controls that was less evident after acute naltrexone treatment. However, naltrexone treatment was unable to remediate disturbances within fronto-striatal regions during reward anticipation and 'missed' rewards in either substance-dependent group. While we have not been able to identify the underlying neural mechanisms for improvement observed with naltrexone in the alcoholic poly-substance dependent group, we can confirm that both substance-dependent groups exhibit substantial neural deficits during an MID task, despite being in long-term abstinence., (© 2016 Society for the Study of Addiction.)

Evidence suggests that disturbances in neurobiological mechanisms of reward and inhibitory control maintain addiction and provoke relapse during abstinence. Abnormalities within the dopamine system may contribute to these disturbances and pharmacologically targeting the D3 dopamine receptor (DRD3) is therefore of significant clinical interest. We used functional magnetic resonance imaging to investigate the acute effects of the DRD3 antagonist GSK598809 on anticipatory reward processing, using the monetary incentive delay task (MIDT), and response inhibition using the Go/No-Go task (GNGT). A double-blind, placebo-controlled, crossover design approach was used in abstinent alcohol dependent, abstinent poly-drug dependent and healthy control volunteers. For the MIDT, there was evidence of blunted ventral striatal response to reward in the poly-drug-dependent group under placebo. GSK598809 normalized ventral striatal reward response and enhanced response in the DRD3-rich regions of the ventral pallidum and substantia nigra. Exploratory investigations suggested that the effects of GSK598809 were mainly driven by those with primary dependence on alcohol but not on opiates. Taken together, these findings suggest that GSK598809 may remediate reward deficits in substance dependence. For the GNGT, enhanced response in the inferior frontal cortex of the poly-drug group was found. However, there were no effects of GSK598809 on the neural network underlying response inhibition nor were there any behavioral drug effects on response inhibition. GSK598809 modulated the neural network underlying reward anticipation but not response inhibition, suggesting that DRD3 antagonists may restore reward deficits in addiction.

Background and Aims: Addiction is associated with severe economic and social consequences and personal tragedies, the scientific exploration of which draws upon investigations at the molecular, cellular and systems levels with a wide variety of technologies. Magnetic resonance imaging (MRI) has been key to mapping effects observed at the microscopic and mesoscopic scales. The range of measurements from this apparatus has opened new avenues linking neurobiology to behaviour. This review considers the role of MRI in addiction research, and what future technological improvements might offer., Methods: A hermeneutic strategy supplemented by an expansive, systematic search of PubMed, Scopus and Web of Science databases, covering from database inception to October 2015, with a conjunction of search terms relevant to addiction and MRI. Formal meta-analyses were prioritized., Results: Results from methods that probe brain structure and function suggest frontostriatal circuitry disturbances within specific cognitive domains, some of which predict drug relapse and treatment response. New methods of processing imaging data are opening opportunities for understanding the role of cerebral vasculature, a global view of brain communication and the complex topology of the cortical surface and drug action. Future technological advances include increases in MRI field strength, with concomitant improvements in image quality., Conclusions: The magnetic resonance imaging literature provides a limited but convergent picture of the neurobiology of addiction as global changes to brain structure and functional disturbances to frontostriatal circuitry, accompanied by changes in anterior white matter., (© 2016 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

The A118G single-nucleotide polymorphism (SNP rs1799971) in the μ-opioid receptor gene, OPRM1, has been much studied in relation to alcohol use disorders. The reported effects of allelic variation at this SNP on alcohol-related behaviors, and on opioid receptor antagonist treatments, have been inconsistent. We investigated the pharmacogenetic interaction between A118G variation and the effects of two μ-opioid receptor antagonists in a clinical lab setting. Fifty-six overweight and moderate-heavy drinkers were prospectively stratified by genotype (29 AA homozygotes, 27 carriers of at least 1 G allele) in a double-blind placebo-controlled, three-period crossover design with naltrexone (NTX; 25 mg OD for 2 days, then 50 mg OD for 3 days) and GSK1521498 (10 mg OD for 5 days). The primary end point was regional brain activation by the contrast between alcohol and neutral tastes measured using functional magnetic resonance imaging (fMRI). Secondary end points included other fMRI contrasts, subjective responses to intravenous alcohol challenge, and food intake. GSK1521498 (but not NTX) significantly attenuated fMRI activation by appetitive tastes in the midbrain and amygdala. GSK1521498 (and NTX to a lesser extent) significantly affected self-reported responses to alcohol infusion. Both drugs reduced food intake. Across all end points, there was less robust evidence for significant effects of OPRM1 allelic variation, or for pharmacogenetic interactions between genotype and drug treatment. These results do not support strong modulatory effects of OPRM1 genetic variation on opioid receptor antagonist attenuation of alcohol- and food-related behaviors. However, they do support further investigation of GSK1521498 as a potential therapeutic for alcohol use and eating disorders.

Individuals who abuse methamphetamine (MA) perform at levels below those of healthy controls on tests that require cognitive control. As cognitive control deficits may influence the success of treatment for addiction, we sought to help clarify the neural correlates of this deficit. MA-dependent (n=10, abstinent 4-7 days) and control subjects (n=18) performed a color-word Stroop task, which requires cognitive control, during functional MRI (fMRI). The task included a condition in which participants were required to respond to one stimulus dimension while ignoring another conflicting dimension, and another condition without conflict. We compared the groups on performance and neural activation in the two conditions. MA-dependent subjects made more errors and responded more slowly than controls. Controlling for response times in the incongruent condition, voxel-wise mixed effects analyses (whole-brain corrected) demonstrated that MA-dependent subjects had less activation than control subjects in the right inferior frontal gyrus, supplementary motor cortex/anterior cingulate gyrus and the anterior insular cortex during the incongruent condition only. MA-dependent subjects did not exhibit greater activation in any brain region in either of the Stroop conditions. These preliminary findings suggest that hypofunction in cortical areas that are important for executive function underlies cognitive control deficits associated with MA dependence., (2011 Elsevier Ireland Ltd. All rights reserved.)

Prior research suggests that abrupt initiation of abstinence from cigarette smoking reduces neural cognitive efficiency. When cognitive efficiency is high, processing speed and accuracy are maximized with minimal allocation of cognitive resources. The study presented here tested the effects of resumption of smoking on cognitive response conflict after overnight abstinence from smoking, hypothesizing that smoking would enhance cognitive efficiency. Twenty paid research volunteers who were chronic cigarette smokers abstained from smoking overnight (>12 h) before undergoing fMRI while performing a color-word Stroop task during two separate test sessions: one that did not include smoking before testing and another one that did. Statistical analyses were performed by modeling the Stroop effect (incongruent >congruent) BOLD response within a collection of a priori regions of interest that have consistently been associated with cognitive control. Behavioral assessment alone did not reveal any significant differences in the Stroop effect between the two sessions. BOLD activations, however, indicated that in the right anterior cingulate cortex (ACC), smokers had significantly less task-related activity following smoking (p<0.02). In contrast, the right middle frontal gyrus exhibited significantly greater activity after smoking as compared to the no-smoking session (p<0.003). Exaggerated neural activity in the ACC during nicotine withdrawal may reflect a compensatory mechanism by which cognitive control networks expend excessive energy to support selective attention processes. Resumption of smoking may enhance cognitive control in smokers, involving a reduction in ACC response conflict activity together with improvement in conflict resolution involving the dorsolateral prefrontal cortex.