Summary by Nora D. Volkow, MD, and Ruben Baler, PhD, NIDA, NIH
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Based on “Principles of Addiction Medicine” Chapter by Nora D. Volkow, MD, and Kenneth R. Warren, PhD
Drugs, both legal (e.g., alcohol, nicotine) and illegal (e.g., cocaine, methamphetamine, heroin, marijuana), as well as abused psychotherapeutics (opioid analgesics, stimulant medications, benzodiazepines) can be abused for several reasons, including the pursuit of pleasure, altered mental states, improved performance, or, in some cases, symptom alleviation from a psychiatric disorder. However, stunning advances in the neurosciences have shown that, whatever the reason behind the initiation of an abuse trajectory, chronic drug abuse affects the brain leading to the behavioral disruptions that characterize addicted individuals. For example, drugs of abuse induce long-lasting changes in many neuronal circuits, including those involved in the processing of response to rewarding and aversive stimuli (including stress), interoception, emotions, decision making, and cognitive control, turning drug use into an automatic compulsive behavior. When considered together, these effects amount to a compelling argument for considering addiction a bona fide chronic and relapsing disease of the brain. Importantly, they also point the way for the development of more effective interventions for the prevention and treatment of addiction.
ADDICTION: A DEVELOPMENTAL DISORDER
Experimentation with psychoactive substances often starts in adolescence, a developmental stage characterized by risk taking, novelty seeking, and heightened sensitivity to peer pressure, which might reflect incomplete development of brain regions involved in, for example, executive control, motivation, and decision making. In addition, epidemiologic evidence shows that the process of addiction is much more likely to be triggered in an adolescent brain: convergent lines of evidence suggest that exposure to drugs or alcohol during adolescence may result in different neuroadaptations from those that occur during adulthood. For example, recent studies demonstrate that the adolescent period is distinctly sensitive to long-term alteration by chronic exposure to ethanol or nicotine, which may explain the greater vulnerability of young initiates to addiction to alcohol or other drugs, respectively.
NEUROBIOLOGY OF DRUGS OF ABUSE
Many different neurotransmitters have been implicated in the effects of various types of abused substances, but dopamine has been consistently associated with the reinforcing effects of most of them. Through various, often indirect mechanisms, drugs of abuse increase extracellular dopamine concentrations in limbic regions, including the nucleus accumbens (NAc) in ways that surpass the fast dopamine increases that occur in the NAc when triggered by natural reinforcers such as food or sex. This is important because abnormally high or protracted increases of dopamine-mediated neuronal activity in subcortical and cortical brain structures are translated into corrupted messages about reward prediction, stimulus–response, approach behavior, learning, and decision making.
The effects of such supraphysiologic dopamine stimulation become more pronounced, widespread, and long lasting once substance use becomes chronic. For example, whether tested during early or protracted withdrawal, addicted subjects show lower levels of dopamine D2 receptors in striatum (including NAc), which are associated with decreases in baseline activity in frontal brain regions implicated in salience attribution (orbitofrontal cortex [OFC]) and inhibitory control (anterior cingulate gyrus), whose disruption results in compulsivity and impulsivity. In addition, drug-induced increases in dopamine also facilitate conditioned learning, so previously neutral stimuli that are associated with the drug become salient. These previously neutral stimuli can then increase dopamine and elicit the desire for the drug by themselves. This explains why an addicted individual is at risk of relapsing when exposed to an environment where he or she has previously taken the drug. Thus, it appears that drug abuse creates an imbalance between the dopaminergic circuits that underlie reward and conditioning and those that underlie executive function, an imbalance that is postulated to contribute to the compulsive drug use and loss of control in addiction.
NEUROBIOLOGY OF DRUG ADDICTION
Drug and alcohol addiction can be conceptualized as a reward deficit disorder characterized by a transition from controlled to impulsive and compulsive drug intake that is mediated by both positive and negative reinforcement. Once a person has transitioned to compulsive drug use, negative reinforcement (a behavioral mechanism recruited to alleviate a negative emotional state in the absence of drug) becomes a main driver of continued, escalating drug use. The characteristic compulsive drug intake despite adverse consequences that characterizes this stage appears to rely on neuroadaptations in the brain reward and stress systems, such as decreases of dopamine and GABA in the ventral striatum coupled with enhancement of corticotropin-releasing factor (CRF) in the extended amygdala as well as blunting of the activity in the hypothalamic–pituitary–adrenal (HPA) axis. More recently, evidence has emerged of what might be described as an antireward system centered in the habenula that is activated with exposure to aversive stimuli or when expected rewards do not materialize, and which inhibits DA cell firing. Preclinical studies have revealed that the activity of the habenula, which is increased by repeated drug exposures, might underlie the negative mood linked with drug withdrawal. Similarly, an up-regulation of dynorphin signaling through kappa receptors is implicated in the increased sensitivity to stress associated with chronic drug exposures.
Compulsive drug consumption also involves poor inhibitory control and poor executive functioning, which are mediated by prefrontal cortical regions of the brain including the right inferior frontal cortex. For example, for alcohol, regions of the prefrontal cortex (PFC) are selectively damaged by chronic intermittent use and result in poor decision making that can perpetuate the addiction cycle. The combined research of the last decade reveals that drug-induced impairments in the PFC areas exert a twofold impact on addiction, first through its perturbed regulation of limbic reward regions and second through its involvement in higher-order executive function. Therefore, the abnormalities in these frontal regions could underlie both 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. They are also likely to contribute to the impaired judgment and cognitive deficits seen in many addicted individuals.
At the cellular level, drugs have been reported to alter the expression of specific transcription factors, as well as a wide variety of proteins involved in neurotransmission in several key brain regions. And there is growing evidence suggesting that epigenetic mechanisms mediate many of the drug-induced changes in the patterns of gene expression that lead to the long-lasting changes in structural, synaptic, and behavioral plasticity in the brain.
At the neurotransmitter level, addiction-related adaptations have been documented not only for dopamine but also for glutamate, GABA, opiates, cannabinoids, serotonin, and various neuropeptides, and these changes contribute to the abnormal function of neuronal 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 in striatum) is associated with reduced baseline activity in the OFC and in the anterior cingulate gyrus—brain regions that are involved in salience attribution and inhibitory control.
However, since PET measures identify DA changes on the basis of competition for binding to D2/D3 receptors, we cannot rule out the possibility of abnormal DA signaling through D1 receptors (even if transient), which could explain the paradoxical enhanced incentive motivation for cocaine seen in addicted individuals who otherwise show dramatically reduced signaling through D2 receptors during intoxication. Indeed, stimulation by cocaine of D1 receptors has different effects from stimulation of D2 receptors in rodents; such that while signaling through D1 receptors enhances cocaine reward, signaling through D2 receptors opposes its rewarding effects.
Moreover, drug-induced neuroadaptations in ancillary circuits related to habit formation and behavioral conditioning are predominantly induced by D1 receptor signaling and mediated by synaptic changes in glutamatergic neurotransmission. This is relevant for disease progression because the ensuing conditioned responses that result from D1 receptor stimulation could help explain the intense desire for the drug (craving) and the compulsive use when addicted subjects are exposed to drug cues.
VULNERABILITY TO ADDICTION
Genetic Factors
It is estimated that 40% to 60% of the vulnerability to addiction is attributable to genetic factors. Animal studies have identified several genes that are involved in drug responses and whose experimental modification markedly affects drug self-administration. In addition, animal studies have also identified candidate genes and genetic loci for alcohol and drug responses, which overlap with genes and loci identified in human studies. Progress in identifying candidate genes involved in substance use disorders and in the responses to drugs and alcohol continues at a rapid pace. However, identifying the biologic function of these new candidate genes has emerged as a major challenge for the next decade. The hope is that a better understanding of the myriad interacting genetic factors and environmental risk factors that influence addiction risk and trajectory will help increase the efficacy of prevention and treatment strategies in substance use disorders and reduce the likelihood of relapse in those that are addicted. One of the best examples of successfully moving from gene identification to biologic function is the association between drug-metabolizing genes and protection against substance use disorders. These polymorphisms operate by modulating the accumulation of toxic (aversive) metabolites; therefore, if substances of abuse are consumed by individuals who carry variants that result in poor metabolism of the substance, then the accumulation of high concentration of the drug or intermediate metabolites serves as a negative stimulus to prevent further consumption.
More recent evidence points to polymorphisms in receptor genes that mediate the drug effects that are also associated with a higher risk of addiction. For example, a number of convergent results support a CHRNA5/A3/B4 gene cluster association with nicotine dependence and with the risk of such smoking-related diseases as lung cancer and peripheral arterial disease.
Environmental Factors
Environmental factors that have been consistently associated with a propensity to self-administer drugs include low socioeconomic status, poor parental support, within–peer group deviancy, physical and psychological abuse, and drug availability. Stress might be a common feature in a wide variety of environmental factors that increase the risk for drug abuse and may help explain, for example, why social isolation (which increases anxiety) during a critical period of adolescence increases addiction vulnerability.
Imaging techniques now allow us to investigate how environmental factors affect the brain and how these, in turn, affect the behavioral responses to drugs of abuse. For example, animal studies have shown that environmental manipulations that increase D2 receptors in NAc markedly decrease drug consumption, a finding that could provide a mechanism by which a social stressor could modify the propensity to self-administer drugs. Many of the long-lasting changes in gene expression and in neuronal circuit organization that are induced by environmental events such as stress and drug exposures (including alcohol) are now being studied as a means to identify how the environment can contribute to addiction. They also provide a unique window into probing the complex epigenetic mechanisms that connect environmental conditions to genetic output.
Comorbidity with Mental Illness
The risk for substance abuse and addiction in individuals with mental illness is significantly higher than in the general population. This high rate of comorbidity probably reflects, in part, overlapping environmental, genetic, and neurobiologic factors that influence substance use disorders and mental illness. In addition, substance use disorders often present with abuse of more than one substance and in combination with psychiatric disorders. Almost 30% of people with psychiatric disorders exhibit substance abuse with 25% abusing alcohol, 40% abusing nicotine, and 15% abusing other drugs. These co-occurrences are problematic because they can complicate treatment and lead to synergistic negative health effects that are worse than either disorder alone.
It has been proposed that comorbidity might be due to the use of the abused drugs to self-medicate the mental illness in cases in which the onset of mental illness is followed by abuse of some types of drug. But, in some instances, drug abuse is followed by mental illness, which has led some to propose that chronic drug exposure could lead to neurobiologic changes that might explain the increased risk of mental illness.
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 might start as self-medication.
STRATEGIES TO COMBAT ADDICTION
Preventing Addiction
The greater vulnerability of adolescents to experimentation with drugs of abuse and to subsequent addiction underscores why preventing early exposure is such an important strategy to combat drug addiction. Epidemiologic 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. The changing pattern in marijuana use, for example, 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. Despite the fact that adolescents are at a stage in their 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 use. At present, prevention strategies include not only educational interventions based on comprehensive school-based programs 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. To that end, interventions should focus on enhancing key skills, including self-control, emotional awareness, communication, and social problem solving.
However, as we begin to understand the neurobiologic 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. In addition, as we deepen our knowledge of how different genes influence a person’s vulnerability to taking drugs and to become addicted, more targets will be uncovered 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. This is why long-term treatment will be required for most addiction cases, just as it is for other chronic diseases, like hypertension, diabetes, or asthma. By recognizing the likelihood of relapse, this perspective radically modifies our expectations of addiction treatment outcomes, establishing the need for a more rational, chronic management model for addiction treatment.
The involvement of multiple brain circuits (reward, motivation, learning, interoception, stress reactivity, mood, and executive function/inhibitory control) and the associated behavioral disruptions point to 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 also explore and include strategies to enhance the saliency value of natural reinforcers (including social support), strengthen executive function (including improving inhibitory control and decision making), decrease drug-related conditioned responses, improve mood if disrupted, and decrease the sensitivity to stress.
Among the recommended multimodal approaches, most rely on the combination of pharmacologic and behavioral interventions, which might target different underlying factors and therefore yield synergistic effects. Such combined treatment is strongly recommended because behavioral and pharmacologic treatments are thought to operate through different yet complementary mechanisms that can have additive or even synergistic effects.
Finally, the treatment of comorbid conditions requires the treatment of the mental illness concurrent with the treatment for the substance use disorder. Because drugs of abuse adversely affect many organs in the body, they can contribute 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 many other clinical conditions.
CHALLENGES FOR SOCIETY
In most cases, drug abuse and addiction alienate the individual from both family and community, increasing isolation and interfering with treatment and recovery. Because 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 and the impact of poverty and of chronic adverse circumstances, such as unemployment on family/social dysfunctions and on overall vulnerability to the use of drugs.
The recognition of addiction as a disease that affects the brain might be essential for large-scale prevention and treatment programs that require the participation of the medical community. Engagement of pediatricians 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 to 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 and nurses receive little training in the management of addiction, despite it being one of the most common chronic disorders, a situation that National Institute on Drug Abuse (NIDA) is trying to address through targeted efforts.
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 perceived 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 had been identified by the Institute of Medicine of the United States, which recommended, back in 1995, a program to provide incentives to the pharmaceutical industry as a way of helping to address this problem.
As we learn more about the neurobiology of normal and pathologic human behavior, a challenge for society will be to harness this knowledge to effectively guide public policy. For example, presently, critics of the medical model of addiction argue that this model removes the responsibility of the addicted individual from his or her behavior. However, the value of the medical model of addiction as a public policy guide does not reside in its misguided use as an excuse for the maladaptive behavior of the addicted individual, but in its ability to provide a framework to understand the underlying disease and treat it more effectively.
SUMMARY
Remarkable scientific advances have been made in genetics, molecular biology, behavioral neuropharmacology, and brain imaging that offer important new insights into how the human brain works and instantiates behavior. 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 and stereotypic behaviors seen in addiction. This new knowledge is helping us to understand why addicted individuals 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. It is also changing our approach to the prevention and treatment of addiction. However, the translation of these findings into clinical practice is hampered by structural roadblocks, including the limited involvement of the medical community in the screening and treatment of addiction and of the pharmaceutical industry in the development of new medications.
KEY POINTS
1. Chronic drug abuse affects the brain’s structure and function in ways that explain the stereotypic, maladaptive behaviors that characterize addiction.
2. Young people are at higher risk not only of initiating drug use but also of becoming addicted.
3. Addiction combines an abnormally overvalued motivational salience of the drug with a significantly impaired ability to inhibit prepotent impulses and make adaptive decisions.
4. Addiction entails deficits in multiple brain circuits, including reward, motivation, memory, interoception, and executive function, which is why the most effective treatments involve multipronged approaches.
REVIEW QUESTIONS
1. Which of the following neural circuits is never affected by the addiction process?
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