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Compulsion is a cardinal symptom of drug addiction (severe substance use disorder). However, compulsion is observed in only a small proportion of individuals who repeatedly seek and use addictive substances. Here, we integrate accounts of the neuropharmacological mechanisms that underlie the transition to compulsion with overarching learning theories, to outline how compulsion develops in addiction. Importantly, we emphasize the conceptual distinctions between compulsive drug-seeking behaviour and compulsive drug-taking behaviour (that is, use). In the latter, an individual cannot stop using a drug despite major negative consequences, possibly reflecting an imbalance in frontostriatal circuits that encode reward and aversion. By contrast, an individual may compulsively seek drugs (that is, persist in seeking drugs despite the negative consequences of doing so) when the neural systems that underlie habitual behaviour dominate goal-directed behavioural systems, and when executive control over this maladaptive behaviour is diminished. This distinction between different aspects of addiction may help to identify its neural substrates and new treatment strategies.Compulsion is a key symptom of drug addiction. In this Review, Lüscher, Robbins and Everitt integrate the neural and psychological mechanisms that underlie the transition to compulsion within a learning theory framework, highlighting the distinctions between compulsive drug taking and compulsive drug seeking.

Key Points The motivation to eat, like the motivation to take addictive drugs, activates the forebrain dopamine systems. Excessive activation of this system strengthens the specific habits that precede the activation, sensitizing the animal's responsiveness to the specific conditions that elicit those habits. At the same time, overactivation of the dopamine system downregulates the dopamine receptors, leaving the subject less interested in other activities. The repeated intake of high-impact foods or addictive drugs thus makes food consumption or drug taking more habitual and decreases the importance of stimuli calling for alternatives. Repeated drug use erodes the function of brain networks necessary for self-regulation, thereby facilitating impulsive, inflexible and compulsive actions. The dopamine motive system, which integrates reinforcement and motivation, is influenced by obesogenic foods and addictive drugs. In this Review, Volkow and colleagues highlight how these stimuli sensitize the subject's motivation towards them while desensitizing the subject's motivation towards alternative reinforcers. Behaviours such as eating, copulating, defending oneself or taking addictive drugs begin with a motivation to initiate the behaviour. Both this motivational drive and the behaviours that follow are influenced by past and present experience with the reinforcing stimuli (such as drugs or energy-rich foods) that increase the likelihood and/or strength of the behavioural response (such as drug taking or overeating). At a cellular and circuit level, motivational drive is dependent on the concentration of extrasynaptic dopamine present in specific brain areas such as the striatum. Cues that predict a reinforcing stimulus also modulate extrasynaptic dopamine concentrations, energizing motivation. Repeated administration of the reinforcer (drugs, energy-rich foods) generates conditioned associations between the reinforcer and the predicting cues, which is accompanied by downregulated dopaminergic response to other incentives and downregulated capacity for top-down self-regulation, facilitating the emergence of impulsive and compulsive responses to food or drug cues. Thus, dopamine contributes to addiction and obesity through its differentiated roles in reinforcement, motivation and self-regulation, referred to here as the 'dopamine motive system', which, if compromised, can result in increased, habitual and inflexible responding. Thus, interventions to rebalance the dopamine motive system might have therapeutic potential for obesity and addiction.

Behaviors and disorders related to self-regulation, such as substance use, antisocial behavior and attention-deficit/hyperactivity disorder, are collectively referred to as externalizing and have shared genetic liability. We applied a multivariate approach that leverages genetic correlations among externalizing traits for genome-wide association analyses. By pooling data from ~1.5 million people, our approach is statistically more powerful than single-trait analyses and identifies more than 500 genetic loci. The loci were enriched for genes expressed in the brain and related to nervous system development. A polygenic score constructed from our results predicts a range of behavioral and medical outcomes that were not part of genome-wide analyses, including traits that until now lacked well-performing polygenic scores, such as opioid use disorder, suicide, HIV infections, criminal convictions and unemployment. Our findings are consistent with the idea that persistent difficulties in self-regulation can be conceptualized as a neurodevelopmental trait with complex and far-reaching social and health correlates. This paper identified >500 genetic loci associated with behaviors and disorders related to self-regulation, including addiction and child behavior problems. The resulting genetic risk scores predict several behavioral, medical and social outcomes.

In this Opinion article, Nutt and colleagues examine the history of and current evidence for the dopamine theory of addiction. They argue that dopamine's role in addiction is more complicated than the role that is put forward in this theory. For several decades, addiction has come to be viewed as a disorder of the dopamine neurotransmitter system; however, this view has not led to new treatments. In this Opinion article, we review the origins of the dopamine theory of addiction and discuss the ability of addictive drugs to elicit the release of dopamine in the human striatum. There is robust evidence that stimulants increase striatal dopamine levels and some evidence that alcohol may have such an effect, but little evidence, if any, that cannabis and opiates increase dopamine levels. Moreover, there is good evidence that striatal dopamine receptor availability and dopamine release are diminished in individuals with stimulant or alcohol dependence but not in individuals with opiate, nicotine or cannabis dependence. These observations have implications for understanding reward and treatment responses in various addictions.

Drug addiction is a worldwide societal problem and public health burden, and results from recreational drug use that develops into a complex brain disorder. The opioid system, one of the first discovered neuropeptide systems in the history of neuroscience, is central to addiction. Recently, opioid receptors have been propelled back on stage by the rising opioid epidemics, revolutions in G protein-coupled receptor research and fascinating developments in basic neuroscience. This Review discusses rapidly advancing research into the role of opioid receptors in addiction, and addresses the key questions of whether we can kill pain without addiction using mu-opioid-receptor-targeting opiates, how mu- and kappa-opioid receptors operate within the neurocircuitry of addiction and whether we can bridge human and animal opioid research in the field of drug abuse.

Craving is a core feature of substance use disorders. It is a strong predictor of substance use and relapse and is linked to overeating, gambling, and other maladaptive behaviors. Craving is measured via self-report, which is limited by introspective access and sociocultural contexts. Neurobiological markers of craving are both needed and lacking, and it remains unclear whether craving for drugs and food involve similar mechanisms. Across three functional magnetic resonance imaging studies ( n  = 99), we used machine learning to identify a cross-validated neuromarker that predicts self-reported intensity of cue-induced drug and food craving ( P  < 0.0002). This pattern, which we term the Neurobiological Craving Signature (NCS), includes ventromedial prefrontal and cingulate cortices, ventral striatum, temporal/parietal association areas, mediodorsal thalamus and cerebellum. Importantly, NCS responses to drug versus food cues discriminate drug users versus non-users with 82% accuracy. The NCS is also modulated by a self-regulation strategy. Transfer between separate neuromarkers for drug and food craving suggests shared neurobiological mechanisms. Future studies can assess the discriminant and convergent validity of the NCS and test whether it responds to clinical interventions and predicts long-term clinical outcomes. Craving—the urge to use a drug or to eat—is a core feature of substance use disorders. Koban et al. present an fMRI-based and machine-learning-based neuromarker that predicts the intensity of drug and food craving and separates drug users from non-users.

Key Points Major depression encompasses heterogeneous disorders in humans that are associated with abnormalities in reward-related brain structures such as the nucleus accumbens, prefrontal cortex, amygdala and hippocampus. Changes in the activity and functional connectivity of these sites leads to abnormalities in the perception and interpretation of reward valence, in the motivation for rewards, and in subsequent decision-making. Recent drug development efforts and other new treatment approaches such as deep brain stimulation offer the potential to more effectively treat depression. However, the field still faces major difficulties. The heterogeneity of depression symptoms suggests that its aetiology is diverse, there are still no known or accepted biomarkers to diagnose major depression — let alone its many subtypes — and promising new treatments have yet to gain approval by the US Food and Drug Administration (FDA). Increasing evidence indicates that precipitating factors such as chronic stress induce changes in the functional connectivity within the brain's reward regions, and that such changes mediate reward-related depression-like behavioural symptoms in animal models, including social avoidance and anhedonia. The molecular and cellular bases of these behavioural abnormalities include changes in glutamatergic and GABAergic synaptic plasticity, dopamine neuron excitability, epigenetic and transcriptional mechanisms, and neurotrophic factors. The nucleus accumbens is central in processing and responding to rewarding and aversive stimuli. It has been extensively implicated in reward-related behavioural abnormalities that characterize depression and associated syndromes. Chronic exposure to stress alters gene expression patterns in and the morphology (and ultimately the functional activity and connectivity) of nucleus accumbens neurons — neuroadaptations that contribute importantly to depression-like behaviours. Advanced experimental tools, such as inducible mutations in mice, virus-mediated gene transfer and optogenetics, have made it possible for the first time to directly delineate the role of specific proteins acting within specific cell types within reward-related brain structures in mediating depression-like behavioural abnormalities in animal models. For example, medium spiny neurons (MSNs) that predominantly express D1 dopamine receptors have a very different effect on reward from MSNs that predominantly express D2 dopamine receptors. It will be important for future studies to examine the molecular and cellular underpinnings of depression-like behaviours in females. Depression is twice as likely to occur in women than in men, but animal studies have mostly been conducted in males. There is evidence that females use different cognitive strategies, exhibit increased stress sensitivity and show variations in reward-related behaviours throughout the oestrus cycle that may render them more sensitive to the deleterious effects of stress. Recent evidence suggests that mood disorders are associated with altered reward function. Russo and Nestler review studies that have shown alterations in the brain reward circuitry in patients with, and animal models of, depression, and discuss the cellular and molecular underpinnings of these alterations. Mood disorders are common and debilitating conditions characterized in part by profound deficits in reward-related behavioural domains. A recent literature has identified important structural and functional alterations within the brain's reward circuitry — particularly in the ventral tegmental area–nucleus accumbens pathway — that are associated with symptoms such as anhedonia and aberrant reward-associated perception and memory. This Review synthesizes recent data from human and rodent studies from which emerges a circuit-level framework for understanding reward deficits in depression. We also discuss some of the molecular and cellular underpinnings of this framework, ranging from adaptations in glutamatergic synapses and neurotrophic factors to transcriptional and epigenetic mechanisms.

Addiction treatment has not been appreciably improved by neuroscientific research. One problem is that mechanistic studies using rodent models do not incorporate volitional social factors, which play a critical role in human addiction. Here, using rats, we introduce an operant model of choice between drugs and social interaction. Independent of sex, drug class, drug dose, training conditions, abstinence duration, social housing, or addiction score in Diagnostic & Statistical Manual IV-based and intermittent access models, operant social reward prevented drug self-administration. This protection was lessened by delay or punishment of the social reward but neither measure was correlated with the addiction score. Social-choice-induced abstinence also prevented incubation of methamphetamine craving. This protective effect was associated with activation of central amygdala PKCδ-expressing inhibitory neurons and inhibition of anterior insular cortex activity. These findings highlight the need for incorporating social factors into neuroscience-based addiction research and support the wider implantation of socially based addiction treatments.

Research on the neural substrates of drug addiction has yet to be translated into a treatment of addiction. Heilig et al . propose that finding neural links between social factors, such as exclusion, and drug addiction would help to make addiction neuroscience research more clinically relevant. Research on the neural substrates of drug reward, withdrawal and relapse has yet to be translated into significant advances in the treatment of addiction. One potential reason is that this research has not captured a common feature of human addiction: progressive social exclusion and marginalization. We propose that research aimed at understanding the neural mechanisms that link these processes to drug seeking and drug taking would help to make addiction neuroscience research more clinically relevant.

Key Points Vulnerability to relapse that persists even after prolonged abstinence is a major problem in treating cocaine addiction. Mechanisms underlying this persistent vulnerability can be studied using rodent models of cue-induced cocaine craving during abstinence from cocaine self-administration. Cue-induced cocaine craving in rodents progressively intensifies (incubates) over the first month of abstinence and remains high for months. Incubation of craving also occurs in human drug users. Incubation of cocaine craving depends on an evolving series of neuroadaptations in the reward circuitry. Early adaptations in the ventral tegmental area and perhaps also the amygdala lead to more persistent changes in the nucleus accumbens, medial prefrontal cortex and central nucleus of the amygdala that increase the reactivity of neurons in these regions to cocaine cues and are ultimately required for the expression of incubated craving. Increased reactivity of these regions of the rodent brain to cocaine cues presented during abstinence is important because neuroimaging studies in human cocaine users have found that heightened cue reactivity in related brain regions is associated with addiction severity and risk of relapse. The relationship between cocaine craving and synaptic transmission has been most thoroughly studied in the nucleus accumbens, where abstinence is associated with changes in AMPA receptor subunit composition and silent synapse-based remodelling. Strengthening of excitatory synapses on nucleus accumbens neurons is particularly important for the maintenance of incubated craving after prolonged abstinence. Dopamine transmission is altered during abstinence owing to plasticity within the ventral tegmental area and changes in dopamine receptor expression in dopaminergic projection areas, but many questions remain about the role of dopamine transmission in modulating synaptic plasticity and behaviour during abstinence. Potential therapeutic strategies to prolong abstinence, identified through rodent studies, include the use of agonists of metabotropic glutamate receptor 2 (mGluR2) and/or mGluR3, mGluR1 positive allosteric modulators, serotonin (5-HT) receptor ligands (including 5-HT 1B receptor agonists, 5-HT 2C receptor agonists and 5-HT 2A receptor antagonists), D3 dopamine receptor antagonists, environmental enrichment and interventions to normalize sleep patterns. One of the greatest challenges in treating addiction is preventing relapse during abstinence. In this Review, Marina Wolf discusses rodent models of cocaine craving that reveal the synaptic plasticity that occurs in reward-related brain regions during the abstinence phase. Although it is challenging for individuals with cocaine addiction to achieve abstinence, the greatest difficulty is avoiding relapse to drug taking, which is often triggered by cues associated with prior cocaine use. This vulnerability to relapse persists for long periods (months to years) after abstinence is achieved. Here, I discuss rodent studies of cue-induced cocaine craving during abstinence, with a focus on neuronal plasticity in the reward circuitry that maintains high levels of craving. Such work has the potential to identify new therapeutic targets and to further our understanding of experience-dependent plasticity in the adult brain under normal circumstances and in the context of addiction.