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SCIENCE AND SOCIETY

Drug addiction: the neurobiology of behaviour gone awry
Nora D. Volkow and Ting-Kai Li
Abstract | Drug addiction manifests as a compulsive drive to take a drug despite serious adverse consequences. This aberrant behaviour has traditionally been viewed as bad ‘choices’ that are made voluntarily by the addict. However, recent studies have shown that repeated drug use leads to long-lasting changes in the brain that undermine voluntary control. This, combined with new knowledge of how environmental, genetic and developmental factors contribute to addiction, should bring about changes in our approach to the prevention and treatment of addiction.

Drugs, both legal (for example, alcohol and nicotine) and illegal (such as cocaine, methamphetamine, heroin and marijuana) are misused for various reasons, including for pleasurable effects, the alteration of mental state, to improve performance and, in certain instances, for self-medication of a mental disorder. Repeated drug use can result in addiction, which is manifested as an intense desire for the drug with an impaired ability to control the urges to take that drug, even at the expense of serious adverse consequences. To avoid confusion with physical dependence, the term ‘drug addiction’ is used here instead of ‘drug dependence’, which is the clinical term favoured by the Diagnostic and Statistical Manual of Mental Disorders (fourth edition; DSM-IV). Physical dependence results in withdrawal symptoms when drugs, such as alcohol and heroin, are discontinued, but the adaptations that are responsible for these effects are different from those that underlie addiction.

The aberrant behavioural manifestations that occur during addiction have been viewed by many as ‘choices’ of the addicted individual, but recent imaging studies have revealed an underlying disruption to brain regions that are important for the normal processes of motivation, reward and inhibitory control in addicted individuals1. This provides the basis for a different view: that drug addiction is a disease of the brain, and the associated abnormal behaviour is the result of dysfunction of brain tissue, just as cardiac insufficiency is a disease of the heart and abnormal blood circulation is the result of dysfunction of myocardial tissue2 (FIG. 1). Therefore, although initial drug experimentation and recreational use might be volitional, once addiction develops this control is markedly disrupted. Although imaging studies consistently show specific abnormalities in the brain function of addicted individuals, not all addicted individuals show these abnormalities. This highlights the need for further research to delineate other neurobiological processes that are involved in addiction. Chronic exposure to drugs of abuse is required for drug addiction, and its expression involves complex interactions between biological and environmental factors. This might explain why some individuals become addicted and others do not, and why attempts to understand addiction as a purely biological or a purely environmental disease have been largely unsuccessful. Recently, important discoveries have increased our knowledge of how drugs affect gene expression, protein

products and neuronal circuits3, and how these biological factors might affect human behaviour. This sets the stage for a better understanding of how different environmental factors interact with biological factors and contribute to patterns of behaviour that lead to addiction. Here, we summarize how new methodologies that allow us to study genes, molecular biology and the human brain are providing us with a greater understanding of drug addiction, and the implications of these findings for the prevention and treatment of addiction.
Addiction: a developmental disorder

Normal developmental processes might result in a higher risk of drug use at certain times in life than others. Experimentation often starts in adolescence, as does the process of addiction4 (FIG. 2). Normal adolescentspecific behaviours (such as risk-taking, novelty-seeking and response to peer pressure) increase the propensity to experiment with legal and illegal drugs5, which might reflect incomplete development of brain regions (for example, myelination of frontal lobe regions)6 that are involved in the processes of executive control and motivation. In addition, studies indicate that drug exposure during adolescence might result in different neuroadaptations from those that occur during adulthood. For example, in rodents, exposure to nicotine during the period that corresponds to adolescence, but not during adulthood, led to significant changes in nicotine receptors and an increased reinforcement value for nicotine later in life7. Future research might allow us to clarify whether this is the reason that adolescents seem to become addicted to nicotine after less nicotine exposure than adults8. Similarly, further studies might enable us to determine whether the increased neuroadaptations to alcohol that occur during adolescence, compared with those that occur during adulthood9 explain the greater vulnerability to alcoholism in individuals who start using alcohol early in life10.

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with the drug become salient. These previously neutral stimuli then increase dopamine by themselves and elicit the desire for the drug 21. This explains why the addicted person is at risk of relapsing when exposed to an environment where he/she has previously taken the drug. If natural reinforcers increase dopamine, why do they not lead to addiction? The difference might be due to qualitative and quantitative differences in the increases in dopamine induced by drugs, which are greater in magnitude (at least five- to tenfold) and duration than those induced by natural reinforcers13. In addition, whereas the dopamine increases produced by natural reinforcers in the NAc undergo habituation, those induced by drugs of abuse do not12. Non-decremental dopamine stimulation of the NAc from repeated drug use strengthens the motivational properties of the drug, which does not occur for natural reinforcers.
Neurobiology of drug addiction

a Brain
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b Heart

Low Healthy heart Myocardial infarction

Figure 1 | Drug addiction as a disease of the brain. Images of the brain (a) in a healthy control and in an individual addicted to a drug, and parallel images of the heart (b) in a healthy control and in an individual with a myocardial infarction. The images were obtained with positron emission tomography (PET) and [18F]fluoro2-deoxyglucose (FDG–PET) to measure glucose metabolism, which is a sensitive indicator of damage to the tissue in the brain and the heart. Note the decreased glucose metabolism in the OFC (orbitofrontal cortex; arrow) of the addicted person and the decreased metabolism in the myocardial tissue (arrow) in the person with a myocardial infarct. Damage to the OFC will result in improper inhibitory control and compulsive behaviour, and damage to the myocardium will result in improper blood circulation. Although abnormalities in the OFC are some of the most consistent findings in imaging studies of addicted individuals (including alcoholics), they are not detected in all addicted individuals. This implies that disruption of this frontal region is not the only mechanism that underlies the addictive process. Heart images courtesy of H. Schelbert, University of California at Los Angeles.

Neurobiology of drugs of abuse

Many neurotransmitters, including GABA (γ-aminobutyric acid), glutamate, acetylcholine, dopamine, serotonin and endogenous opioid peptides, have been implicated in the effects of the various types of drugs of abuse. Of these, dopamine has been consistently associated with the reinforcing effects of most drugs of abuse. Drugs of abuse increase extracellular dopamine concentrations in limbic regions, including the nucleus accumbens (NAc)11,12. Specifically, it seems that the reinforcing effects of drugs of abuse are due to their ability to surpass the magnitude and duration of the fast dopamine increases that occur in the NAc when triggered by natural reinforcers such as food and sex13. Drugs such as cocaine, amphetamine, methamphetamine and ecstasy increase dopamine by inhibiting dopamine reuptake or promoting dopamine release through their effects on dopamine transporters14. Other drugs, such as nicotine, alcohol, opiates and marijuana, work indirectly by stimulating neurons (GABA-mediated or glutamatergic) that modulate dopamine cell

firing through their effects on nicotine, GABA, mu opiate or cannabinoid CB1 receptors, respectively15. It seems that increases in dopamine are not directly related to reward per se, as was previously believed, but rather to the prediction of reward16 and for salience17. Salience refers to stimuli or environmental changes that are arousing or that elicit an attentional– behavioural switch18. Salience, which, in addition to reward, applies to aversive, new and unexpected stimuli, affects the motivation to seek the anticipated reward and facilitates conditioned learning19,20. This provides a different perspective about drugs, as it implies that drug-induced increases in dopamine will inherently motivate further procurement of more drug (regardless of whether or not the effects of the drug are consciously perceived to be pleasurable). Indeed, some addicted individuals report that they seek the drug even though its effects are no longer pleasurable. Drug-induced increases in dopamine will also facilitate conditioned learning, so previously neutral stimuli that are associated

Addiction probably results from neurobiological changes that are associated with chronic and intermittent supraphysiological perturbations in the dopamine system, which occur in the same circuits that affect biologically important functions1. We and others have postulated that adaptations in these dopaminergic circuits make the addicted individual more responsive to the supraphysiological increases in dopamine that are produced by drugs of abuse and less sensitive to the physiological increases in dopamine produced by natural reinforcers22. Recent advances in both molecular biology and imaging have increased our insight into how these neural adaptations occur. At a cellular level, drugs have been reported to alter the expression of certain transcription factors (nuclear proteins that bind to regulatory regions of genes, thereby regulating their transcription into mRNA), as well as a wide variety of proteins involved in neurotransmission in brain regions that are regulated by dopamine17. The long-lasting changes that occur in the transcription factors δFosB and cAMP responsive element binding protein (CREB) after chronic drug administration are of particular interest because they modulate the synthesis of proteins that are involved in synaptic plasticity3. Indeed, chronic drug exposure alters the morphology of neurons in dopamine-regulated circuits. For example, in rodents, chronic cocaine or amphetamine administration increases neuronal dendritic branching and spine density in the NAc and prefrontal cortex — an adaptation that is thought to participate

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dopamine release in the NAc25. The adaptations in this pathway seem to be involved in the relapse that occurs after drug withdrawal in animals previously trained to self-administer a drug when they are again exposed to the drug, a drug stimulus or stress25. At the circuit level, there is clear evidence that adaptations in the mesocortical circuit (including the OFC and CG) cause compulsive drug administration and poor inhibitory control, and they probably participate in relapse. However, adaptations also seem to occur in the mesolimbic circuit (including the NAc, amygdala and hippocampus), which probably cause the enhanced saliency value of the drug and drug stimuli, and the decreased sensitivity to natural reinforcers26. Furthermore, adaptations have also been reported in the nigrostriatal circuit (including the dorsal striatum), which might underlie habits that are linked to the rituals of drug consumption27.
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Figure 2 | Age at which marijuana use is first initiated. Data from the National Survey of Drug Use and Health57.

in the enhanced incentive motivational value of the drug (a process that results in increased ‘wanting’ in contrast to just ‘liking’ the drug) in the addicted person23. At the neurotransmitter level, addictionrelated adaptations have been documented not only for dopamine, but also for glutamate, GABA, opiates, serotonin and various neuropeptides. These changes contribute to the abnormal function of brain circuits. For example, in individuals who are addicted to cocaine, imaging studies have documented that disrupted dopamine activity in the brain (shown by reductions in dopamine D2 receptors) is associated with abnormal activity in the orbitofrontal cortex (OFC) and in the anterior cingulate gyrus (CG) — brain regions that are involved in salience attribution and inhibitory control24 (FIG. 3). Abnormal function of these cortical regions has been particularly revealing in furthering our understanding of addiction , as their disruption is linked to compulsive behaviour (OFC) and disinhibition24 (CG). Therefore, the abnormalities in these frontal regions could underlie the compulsive nature of drug administration in addicted individuals and their inability to control their urges to take the drug when they are exposed to it. In addition, animal studies have shown that drug-related adaptations in these frontal regions result in enhanced activity in the glutamatergic pathway that regulates

Genetic factors. It is estimated that 40–60% of the vulnerability to addiction is attributable to genetic factors28. In animal studies, several genes have been identified that are involved in drug responses, and their experimental modifications markedly affect drug selfadministration29. In humans, several chromosomal regions have been linked to drug abuse, but only a few specific genes have been identified with polymorphisms (alleles) that either predispose to or protect from drug addiction28. Some of these polymorphisms interfere with drug metabolism. For example, specific alleles for the genes that encode alcohol dehydrogenases ADH1B and ALDH2 (enzymes involved in the metabolism of alcohol) are reportedly protective against alcoholism30. Similarly, polymorphisms in the gene that encodes cytochrome P-450 2A6 (an enzyme that is involved in nicotine metabolism) are reportedly protective against nicotine addiction31. Furthermore, genetic polymorphisms in the cytochrome P-450 2D6 gene (an enzyme that is involved in conversion of codeine to morphine) seem to provide a degree of protection against codeine abuse 32. Some polymorphisms in receptor genes that mediate drug effects have also been associated with a higher risk of addiction. For example, there is an association between alcoholism and the genes for the GABA type A (GABAA) receptors GABRG3 (REF. 33) and GABRA2 (REF. 34). D2-receptor polymorphisms have been linked to a higher vulnerability to drug addiction, although some studies have failed to replicate this finding28. Replication of many of the genetic findings in substance abuse and addiction is still pending.

Environmental factors. Environmental factors that have been consistently associated with the propensity to self-administer drugs include low socio-economic class, poor parental support and drug availability. Stress might be a common feature in a wide variety of environmental factors that increase the risk for drug abuse. The mechanisms responsible for stress-induced increases in vulnerability to drug use and to relapse in people who are addicted are not yet well understood, but there is evidence that the stress-responsive neuropeptide corticotropin-releasing factor is involved through its effects in the amygdala and the pituitary–adrenal axis35. Imaging techniques now allow us to investigate how environmental factors affect the brain and how these, in turn, affect the behavioural responses to drugs of abuse. For example, in non-human primates, social status affects D2-receptor expression in the brain, which in turn affects the propensity for cocaine self-administration36. Animals that achieve a dominant status in the group show increased numbers of D2 receptors and are reluctant to administer cocaine, whereas animals that are subordinate have lower D2-receptor numbers and readily administer cocaine. As animal studies have shown that increasing D2 receptors in NAc markedly decreases drug consumption (which has been shown for alcohol37), this could provide a mechanism by which a social stressor could modify the propensity to self-administer drugs. Co-morbidity with mental illness. The risk for substance abuse and addiction in individuals with mental illness is significantly higher than for the general population. The high co-morbidity probably reflects, in part, overlapping environmental, genetic and neurobiological factors that influence drug abuse and mental illness38. It is likely that different neurobiological factors are involved in co-morbidity depending on the temporal course of its development (that is, mental illness followed by drug abuse or vice versa). In some instances, the mental illness and addiction seem to cooccur independently39, but in others there might be a sequential dependency. It has been proposed that co-morbidity might be due to the use of the abused drugs to selfmedicate the mental illness in cases in which the onset of mental illness is followed by abuse of some types of drug. But, when drug abuse is followed by mental illness, the chronic exposure could lead to neurobiological changes, which might explain the increased risk of mental illness38. For example, the high

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Figure 3 | Dopamine D2 receptors and glucose metabolism in addiction. a,b | Positron emission tomography (PET) images showing dopamine D2 receptors and brain glucose metabolism in the OFC (orbitofrontal cortex) in controls and in individuals who abuse cocaine. Note that the individuals abusing cocaine have reductions in D2 receptors and in OFC metabolism. c | Correlation between measures of D2 receptors and brain glucose metabolism in the OFC and anterior cingulate gyrus (CG). The lower the D2receptor expression, the lower the metabolism in the OFC and CG. Decreased activity in the OFC, a brain region that is implicated in salience attribution and whose disruption results in compulsive behaviour, could underlie the compulsive drug administration that occurs in addiction. Decreased activity in the CG, a brain region that is involved in inhibitory control, could underlie the inability to restrain from taking the drug when the addicted person is exposed to them58.

lives when they are more likely to take risks, interventions that educate them about the harmful effects of drugs with age-appropriate messages can decrease the rate of drug use44,45. However, not all media campaigns and school-based educational programmes have been successful46. Tailored interventions that take into account socio-economic, cultural, age and gender characteristics of children and adolescents are more likely to improve the effectiveness of the interventions. At present, prevention strategies include not only educational interventions based on comprehensive school-based programmes and effective media campaigns and strategies that decrease access to drugs and alcohol, but also strategies that provide supportive community activities that engage adolescents in productive and creative ways. However, as we begin to understand the neurobiological consequences that underlie the adverse environmental factors that increase the risks for drug use and for addiction, we will be able to develop interventions to counteract these changes. Similarly, in the future, as we gain knowledge of the genes and the proteins that they encode that make a person more or less vulnerable to taking drugs and to addiction, more targets will be available to tailor interventions for those at higher risk. Treating addiction. The adaptations in the brain that result from chronic drug exposure are long lasting; therefore, addiction must be viewed as a chronic disease. Long-term treatment will be required for most cases, just as for other chronic diseases (such as hypertension, diabetes and asthma)47. This perspective modifies our expectations of treatment and provides a new understanding of relapse. First, discontinuation of treatment, as for other chronic diseases, is likely to result in relapse. Also, as for other chronic medical conditions, relapse should not be interpreted as a failure of treatment (as is the view in most cases of addiction), but instead as a temporary setback due to lack of compliance or tolerance to an effective treatment47. Indeed, the rates of relapse and recovery in the treatment of drug addiction are equivalent to those of other medical diseases47. The involvement of multiple brain circuits (reward, motivation, learning, inhibitory control and executive function) and their associated disruption of behaviour indicate the need for a multimodal approach in the treatment of the addicted individual. Therefore, interventions should not be limited to inhibiting the rewarding effects of a drug, but should also include strategies to enhance the saliency value of natural reinforcers (including social support), strengthen inhibitory control,

prevalence of smoking that is initiated after individuals experience depression could reflect, in part, the antidepressant effects of nicotine as well as the antidepressant effects of monoamine oxidase A and B (MAO-A and -B) inhibition by cigarette smoke40. On the other hand, the reported risk for depression with early drug abuse41 could reflect neuroadaptations in dopamine systems that might make individuals more vulnerable to depression. The higher risk of drug abuse in individuals with mental illnesses highlights the relevance of the early evaluation and treatment of mental diseases as an effective strategy to prevent drug addiction that starts as self-medication.
Strategies to combat addiction

The knowledge of the neurobiology of drugs and the adaptive changes that occur with addiction is guiding new strategies for prevention and treatment, and identifying areas in which further research is required.

Preventing addiction. The greater vulnerability of adolescents to experimentation with drugs of abuse and to subsequent addiction underscores why prevention of early exposure is such an important strategy to combat drug addiction. Epidemiological studies show that the prevalence of drug use in adolescents has changed significantly over the past 30 years, and some of the decreases seem to be related to education about the risks of drugs. For example, for marijuana, the prevalence rates of use in the United States in 1979 were as high as 50%, whereas in 1992 they were as low as 20% (REF. 42) (FIG. 4). This changing pattern of marijuana use seems to be related in part to the perception of the risks associated with the drug; when adolescents perceived the drug to be risky, the rate of use was low, whereas when they did not, the rate of use was high (FIG. 4). Similarly, the significant decreases in ecstasy use as well as cigarette smoking in adolescents seem to partly reflect effective educational campaigns43. These results show that, despite the fact that adolescents are at a stage in their

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(such as 12-step programmes (self-help support groups whose members attempt recovery from addiction, in part, by ‘admitting’ that they have a problem and by sharing experiences)) would be more effective if complemented with medications that could help the patient remain drug free. Pharmacological intervention. Pharmacological interventions can be grouped into two classes. First, there are those that interfere with the reinforcing effects of drugs of abuse (that is, medications that interfere with the binding of the drug, drug-induced dopamine increase, postsynaptic responses or with the drug’s delivery to the brain, or medications that trigger aversive responses). Second, there are those that compensate for the adaptations that either pre-dated or developed after long-term use (that is, medications that decrease the prioritized motivational value of the drug, enhance the saliency value of natural reinforcers, interfere with conditioned responses, interfere with stress-induced relapse or interfere with physical withdrawal). The usefulness

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Figure 4 | Use and risk perception of marijuana. The prevalence rate for marijuana use in the past 12 months and the perception of marijuana as a dangerous drug in 12th graders (18–19 years old) from 1979 to 2003 (REF. 42). When teenagers perceived marijuana as dangerous, the prevalence of drug use was low and vice versa.

decrease conditioned responses and improve mood if disrupted. The most obvious multimodal approach is the combination of pharmacological and behavioural interventions,

which might target different underlying factors and therefore have synergistic effects. For example, it might be predicted that addiction treatments that use behavioural interventions

Table 1 | Medications for Treating Drug and Alcohol Addiction*
Clinical target Alcoholism FDA approved60 Disulfiram (Antabuse; Wyeth-Ayerst) Naltrexone Acamprosate ‡ Topiramate61 (Topamax; Ortho-McNeil) ‡ Valproate62 Ondansetron63 Nalmefene64 Baclofen65 (Lioresal; Novartis) Pyrrolopyrimidine compound66 (Antalarmin; George Chrousos et al.) Rimonabant (Acomplia; Sanofi-Synthelabo)67 Nicotine replacement Bupropion Deprenyl69 Rimonabant (Acomplia; Sanofi-Synthelabo)67 Methoxsalen70 Nicotine conjugate vaccine71 (NicVax; Nabi Biopharmaceuticals) Naltrexone Methadone Buprenorphine Cocaine addiction Under investigation Topiramate73 (Topamax; Ortho-McNeil) γ-vinyl GABA (GVG)74 (Sabril; Hoechst Marion Roussel) ‡ Gabapentin75 (Neurontin; Parke-Davis) ‡ Tiagabine76 (Gabitril; Abbott) Baclofen77 (Lioresal; Novartis) Modafinil78 Disulfiram79 (Antabuse; Wyeth-Ayerst) Cocaine vaccine71 (TA-CD; Xenova)
‡ ‡

Medication

Biological target Aldehyde dehydrogenase (triggers aversive response) Mu opioid receptor (antagonist; interferes with reinforcement) Glutamate related GABA/glutamate GABA/glutamate 5-HT3 receptor Mu opioid receptor (antagonist) GABAB receptor (agonist) CRF1 receptor (inhibits stress-triggered responses) CB1 receptor (antagonist) Nicotinic receptor (substitution with different pharmacokinetics) DA transporter blocker (amplifies DA signals) MAO-B inhibitor (inhibits metabolism of DA) CB1-receptor (antagonist) CYP2A6 (inhibits nicotine metabolism) Blocks entry into brain

Under investigation

Nicotine addiction FDA approved68 Under investigation

Heroin/opiate addiction FDA approved72 Mu opioid receptor (antagonist) Mu opioid receptor (substitution with different pharmacokinetics) Mu opioid receptor (substitution) GABA (agonist) GABA transaminase (inhibits GABA metabolism) GABA/glutamate (synthesis) GABA transporter (inhibitor) GABAB receptor (agonist) Glutamate (?) Unknown for cocaine Blocks entry into brain

*Medications used for physical withdrawal are not included. ‡Antiepileptic drugs that have been shown to decrease both drug-induced dopamine (DA) increases and conditioned responses. FDA, Food and Drug Administration; GABA, γ-aminobutyric acid; GABAB, GABA type B; 5-HT3, 5-hydroxytryptamine (serotonin) receptor subtype 3; MAO-B, monoamine oxidase B.

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Challenges for society
Brain

Lungs Heart

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Figure 5 | Monoamine oxidase B concentration and cigarette smoking. Positron emission tomography (PET) images of the concentration of the enzyme MAO-B (monoamine oxidase B) in the body of a healthy control and of a cigarette smoker. There are significant decreases in the concentration of the enzyme throughout the body of the smoker. Reproduced, with permission, from REF. 59 © (2003) National Academy of Sciences, USA.

of some of the medications for drug addiction has been clearly validated; for others the data are still preliminary, and for most the results are limited to promising preclinical findings. TABLE 1 summarizes proven medications as well as medications for which there are preliminary clinical data. Many of these promising new medications target different neurotransmitters (such as GABA, cannabinoids or glutamate) from the older drugs, offering a wider range of therapeutic options. Cognitive–behavioural intervention. In a similar fashion, behavioural interventions can be classified by their intended remedial function, such as to strengthen inhibitory control circuits, to provide alternative reinforcers and to strengthen executive function. Traditionally, behavioural therapy has focused on symptom-based targets rather than underlying causes of addiction. However, for other brain disorders, new views of brain plasticity, which recognize the capacity of neurons in the adult brain to increase synaptic connections and in certain instances to regenerate48, have resulted in more focused cognitive–behavioural interventions designed to increase the efficiency of dysfunctional brain circuits. This has been applied in attempts to improve reading in children with learning disabilities49 and to facilitate motor

and memory rehabilitation after brain injury50, but has not yet been applied to the remediation of brain circuits altered by drug abuse. Dual approaches that pair cognitive– behavioural strategies with medications to compensate or counteract the neurobiological changes induced by chronic drug exposure might, in the future, provide more robust and longer lasting treatments for addiction than either given in isolation. Treating co-morbidities. Abuse of multiple substances, such as alcohol and nicotine or alcohol and cocaine, should be considered in the proper management of the addicted individual. Similarly, co-morbidities with mental illness will require treatment for the mental illness concurrent with treatment for drug abuse. As drugs of abuse adversely affect many organs in the body (FIG. 5), uncontrolled consumption contributes to the burden of many medical diseases, including cancer, cardiovascular and pulmonary diseases, HIV/AIDS and hepatitis C, as well as to accidents and violence. Therefore, substance-abuse treatment will help to prevent or improve the outcome for medical diseases. For example, drug abuse is a leading contributor to the spread of HIV/ AIDS, and treatment of addiction in some instances prevents its dissemination51,52.

In most cases, drug abuse and addiction alienates the individual from both family and community, increasing isolation and interfering with treatment and recovery. As both the family and the community provide integral aspects of effective treatment and recovery, this identifies an important challenge: to reduce the stigma of addiction that interferes with intervention and proper rehabilitation. Effective treatment of drug addiction in many individuals requires consideration of social policy, such as the treatment of drug addiction in the criminal justice system, the role of unemployment in vulnerability to the use of drugs and family dysfunctions that contribute to stress and that might block the efficacy of otherwise effective interventions. For example, studies have shown that providing drug treatment to prisoners who were substance abusers and continuing the treatment after they left the prison dramatically reduced not only their rate of relapse to drugs, but also their rate of re-incarceration53,54. Similarly, drug courts in the United States, which incorporate drug treatment into the judicial system, have proved to be beneficial in decreasing drug use and arrests of offenders who are involved in drug-taking55. However, despite these preliminary positive results, there are still many unanswered questions that future research should address. For example, what are the active ingredients in the treatment of the drug offender? How does the system deal with the fact that few offenders stay in treatment long enough to receive the minimally required services? What are the implications of these findings for pre-trial diversion laws, post-prison re-entry initiatives and so on? The recognition of addiction as a disease that affects the brain might be essential for large-scale prevention and treatment programmes that require the participation of the medical community. Engagement of paediatricians and family physicians (including the teaching of addiction medicine as part of medical students’ training) might facilitate early detection of drug abuse in childhood and adolescence. Moreover, screening for drug use could help clinicians better manage medical diseases that are likely to be adversely affected by the concomitant use of drugs, such as cardiac and pulmonary diseases. Unfortunately, physicians, nurses, psychologists and social workers receive little training in the management of addiction, despite it being one of the most common chronic disorders.

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The participation of the medical community in many countries, including the United States, is further curtailed by the lack of reimbursement by most private medical insurance policies for the evaluation or treatment of drug abuse and addiction. This lack of reimbursement limits the treatment infrastructure and the choices that the addicted person has with respect to their treatment. It also sends a negative message to medical students who are interested in clinical practice, discouraging them from choosing a speciality for which the reimbursement of their services is limited by the lack of parity. Another considerable obstacle in the treatment of addiction is the limited involvement of the pharmaceutical industry in the development of new medications. Issues such as stigma, lack of reimbursement for drug-abuse treatment and the lack of a large market all contribute to the limited involvement of the pharmaceutical industry in the development of medications to treat drug addiction. The importance of this issue was identified by the Institute of Medicine of the United States, which recommended a programme to provide incentives to the pharmaceutical industry as a way of helping to address this problem56. The translation of scientific findings in drug abuse into prevention and treatment initiatives clearly requires partnership with federal agencies such as the Substance Abuse and Mental Health Services Administration (SAMHSA, which is responsible for U.S. programmes to prevent and treat drug abuse) and the Office of National Drug Control Policy (ONDCP, which is responsible for U.S. programmes to control availability and reduce demand for drugs of abuse). Furthermore, improved prevention and treatment programmes could result from collaborations with other agencies and groups, such as the Department of Education (which can bring prevention interventions into the school environment), the Department of Justice (which can implement treatment strategies that will minimize the chances of recidivism and re-incarceration of inmates with drug-abuse problems) and state and local agencies (which can bring evidence-based and science-based treatments into the communities). As we learn more about the neurobiology of normal and pathological human behaviour, a challenge for society will be to use this knowledge to effectively guide public policy. For example, as we understand the neurobiological substrates that underlie voluntary actions, how will society define the boundaries of personal responsibility in those individuals who have impairments in these brain circuits? This will have implications not only for the management of drug offenders, but also of other offenders with diagnoses such as antisocial personality disorder or conduct disorder. At present, critics of the medical model of addiction argue that this model removes the responsibility of the addicted individual from his/her behaviour. However, the value of the medical model of addiction as a public policy guide is not to excuse the behaviour of the addicted individual, but to provide a framework to understand it and to treat it more effectively.
Summary
1. Volkow, N. D., Fowler, J. S. & Wang, G. J. The addicted human brain: insights from imaging studies. J. Clin. Invest. 111, 1444–1451 (2003). Leshner, A. I. Addiction is a brain disease, and it matters. Science 278, 45–47 (1997). Nestler, E. J. Molecular basis of long-term plasticity underlying addiction. Nature Rev. Neurosci. 2, 119–128 (2001). Wagner, F. A. & Anthony, J. C. From first drug use to drug dependence: developmental periods of risk for dependence upon marijuana, cocaine, and alcohol. Neuropsychopharmacology 26, 479–488 (2002). Spear, L. P. The adolescent brain and age-related behavioral manifestations. Neurosci. Biobehav. Rev. 24, 417–463 (2000). Sowell, E. R. et al. Mapping cortical change across the human life span. Nature Neurosci. 6, 309–315 (2003). Adriani, W. et al. Evidence for enhanced neurobehavioral vulnerability to nicotine during periadolescence in rats. J. Neurosci. 23, 4712–4716 (2003). Kandel, D. B. & Chen, K. Extent of smoking and nicotine dependence in the United States: 1991–1993. Nicotine. Tob. Res. 2, 263–274 (2000). Slawecki, C. J. & Roth, J. Comparison of the onset of hypoactivity and anxiety-like behavior during alcohol withdrawal in adolescent and adult rats. Alcohol Clin. Exp. Res. 28, 598–607 (2004). Grant, B. F., Stinson, F. S. & Harford, T. C. Age at onset of alcohol use and DSM-IV alcohol abuse and dependence: a 12-year follow-up. J. Subst. Abuse 13, 493–504 (2001). Koob, G. F. & Bloom, F. E. Cellular and molecular mechanisms of drug dependence. Science 242, 715–723 (1988). Di Chiara, G. Nucleus accumbens shell and core dopamine: differential role in behavior and addiction. Behav. Brain Res. 137, 75–114 (2002). Wise, R. A. Brain reward circuitry: insights from unsensed incentives. Neuron 36, 229–240 (2002). Madras, B. K., Fahey, M. A., Bergman, J., Canfield, D. R. & Spealman, R. D. Effects of cocaine and related drugs in nonhuman primates. I. [3H]cocaine binding sites in caudate-putamen. J. Pharmacol. Exp. Ther. 251, 131–141 (1989). Kreek, M. J., LaForge, K. S. & Butelman, E. Pharmacotherapy of addictions. Nature Rev. Drug Discov. 1, 710–726 (2002). Schultz, W., Tremblay, L. & Hollerman, J. R. Reward processing in primate orbitofrontal cortex and basal ganglia. Cereb. Cortex 10, 272–284 (2000). Lu, L., Grimm, J. W., Shaham, Y. & Hope, B. T. Molecular neuroadaptations in the accumbens and ventral tegmental area during the first 90 days of forced abstinence from cocaine self-administration in rats. J. Neurochem. 85, 1604–1613 (2003). Horvitz, J. C. Mesolimbocortical and nigrostriatal dopamine responses to salient non-reward events. Neuroscience 96, 651–656 (2000). McClure, S. M., Daw, N. D. & Montague, P. R. A computational substrate for incentive salience. Trends Neurosci. 26, 423–428 (2003). Schultz, W. Reward signaling by dopamine neurons. Neuroscientist 7, 293–302 (2001). Ito, R., Dalley, J. W., Howes, S. R., Robbins, T. W. & Everitt, B. J. Dissociation in conditioned dopamine release in the nucleus accumbens core and shell in response to cocaine cues and during cocaine-seeking behavior in rats. J. Neurosci. 20, 7489–7495 (2000). Volkow, N. D., Fowler, J. S., Wang, G. J. & Swanson, J. M. Dopamine in drug abuse and addiction: results from imaging studies and treatment implications. Mol. Psychiatry 9, 557–569 (2004). Robinson, T. E., Gorny, G., Mitton, E. & Kolb, B. Cocaine self-administration alters the morphology of dendrites and dendritic spines in the nucleus accumbens and neocortex. Synapse 39, 257–266 (2001). Volkow, N. D. & Fowler, J. S. Addiction, a disease of compulsion and drive: involvement of the orbitofrontal cortex. Cereb. Cortex 10, 318–325 (2000). McFarland, K., Davidge, S. B., Lapish, C. C. & Kalivas, P. W. Limbic and motor circuitry underlying footshock-induced reinstatement of cocaine-seeking behavior. J. Neurosci. 24, 1551–1560 (2004). Martin-Soelch, C. et al. Changes in reward-induced brain activation in opiate addicts. Eur. J. Neurosci. 14, 1360–1368 (2001). Porrino, L. J., Lyons, D., Smith, H. R., Daunais, J. B. & Nader, M. A. Cocaine self-administration produces a progressive involvement of limbic, association, and sensorimotor striatal domains. J. Neurosci. 24, 3554–3562 (2004).

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Remarkable scientific advances have been made in genetics, molecular biology, behavioural neuropharmacology and brain imaging that offer new insights into how the human brain works and moulds behaviour. In the case of addiction, we can now investigate questions that were previously inaccessible, such as how environmental factors and genes affect the responses of the brain to drugs and produce neural adaptations that lead to the aberrant behavioural manifestations of addiction. This new knowledge is helping us to understand why drug addicts relapse even in the face of threats such as divorce, loss of child custody and incarceration, even when, in some cases, the drug is no longer perceived as pleasurable, and is changing how we should approach prevention and treatment of addiction. The field is at a crossroads where major advances in understanding the neurobiology of addiction have helped identify promising new medications, but where the translation of these findings into clinical practice is limited by several factors, including the limited involvement of the medical community in the treatment of addiction, the restricted involvement of the pharmaceutical industry, the lack of reimbursement by private insurance policies and the stigma associated with drug addiction. One of the main challenges for agencies like the National Institute on Drug Abuse (NIDA) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA) is to develop knowledge that will help to overcome these obstacles.
Nora Volkow is at the National Institute on Drug Abuse, Bethesda, Maryland 20892, USA. Ting-Kai Li is at the National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892, USA. e-mail: nvolkow@nida.nih.gov
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Acknowledgments
The authors thank T. Condon, M. Egli, J. Fowler, C. Kassed, R. Litten, A. Noronha and J. Swanson for thoughtful comments and editorial assistance.

Competing interests statement
The authors declare no competing financial interests.

Online links
FURTHER INFORMATION Encyclopedia of Life Sciences: http://www.els.net/ Addiction | Adaptations: meanings | Alcoholism | Cocaine and amphetamines | Opiates National Institute on Drug Abuse: http://www.drugabuse.gov/NIDAHome.html Office of National Drug Control Policy: http://www.whitehousedrugpolicy.gov/ Substance Abuse and Mental Health Services Administration: http://www.samhsa.gov/index.aspx Access to this interactive links box is free online.

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Fallacies in behavioural interpretation of auditory cortex plasticity
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SPECIFIC LONG-TERM MEMORY TRACES IN PRIMARY AUDITORY CORTEX
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