Alan I. Leshner

Bio: Alan I. Leshner is an academic researcher from National Institute on Drug Abuse. The author has contributed to research in topics: Substance abuse & Addiction. The author has an hindex of 11, co-authored 23 publications receiving 2145 citations.

Addiction is a brain disease, and it matters.

Abstract: Scientific advances over the past 20 years have shown that drug addiction is a chronic, relapsing disease that results from the prolonged effects of drugs on the brain. As with many other brain diseases, addiction has embedded behavioral and social-context aspects that are important parts of the disorder itself. Therefore, the most effective treatment approaches will include biological, behavioral, and social-context components. Recognizing addiction as a chronic, relapsing brain disorder characterized by compulsive drug seeking and use can impact society's overall health and social policy strategies and help diminish the health and social costs associated with drug abuse and addiction.

Drugs of abuse and the brain.

Abstract: New insights into our understanding of drug abuse and addiction have revealed that the desire to use drugs and the process of addiction depend on effects on brain function. Drugs of abuse have been hypothesized to produce their rewarding effects by neuropharmacological actions on a common brain reward circuit called the extended amygdala. The extended amygdala involves the mesolimbic dopamine system and specific subregions of the basal forebrain, such as the shell of the nucleus accumbens, the bed nucleus of the stria terminalis, and the central nucleus of the amygdala. The psychomotor stimulants cocaine and amphetamine activate the mesolimbic dopamine system; opiates activate opioid peptide receptors within and independent of the mesolimbic dopamine system. Sedative hypnotics alter multiple neurotransmitter systems in this circuitry, including: 1) gamma aminobutyric acid; 2) dopamine; 3) serotonin; 4) glutamate; and 5) opioid peptides. Nicotine and tetrahydrocannabinol both activate mesolimbic dopamine function and possibly opioid peptide systems in this circuitry. Repeated and prolonged drug abuse leads to compulsive use, and the mechanism for this transition involves, at the behavioral level, a progressive dysregulation of brain reward circuitry and a recruitment of brain stress systems such as corticotropin-releasing factor. The molecular mechanisms of signal transduction in these systems are a likely target for residual changes in that they convey allostatic changes in reward set point, which lead to vulnerability to relapse.

Science-Based Views of Drug Addiction and Its Treatment

Abstract: MORE THAN TWO THIRDS OF people with addiction see a primary care or urgent care physician every 6 months, and many others are regularly seen by other medical specialists. These physicians are therefore in a prime position to help patients who may have drug abuse problems by recognizing and diagnosing the addiction, helping to direct patients to a program that can meet their treatment needs, and helping to monitor progress after specialty treatment and during recovery. Many physicians, however, find the domain of drug abuse particularly daunting and often avoid the issue with their patients. This is understandable given the relatively short shrift drug abuse is given in formal medical education. There is a widespread misperception that drug abuse treatment is not effective, which may account for the reluctance of physicians to even broach the subject of drug abuse or treatment with their patients. On the other hand, over the past 15 to 20 years, advances in science have revolutionized our fundamental understanding of the nature of drug abuse and addiction and what to do about it. In addition, there are now extensive data showing that addiction is eminently treatable if the treatment is welldelivered and tailored to the needs of the particular patient. There is an array of both behavioral and pharmacological treatments that can effectively reduce drug use, help manage drug cravings and prevent relapses, and restore people to productive functioning in society. Of course, not all drug abuse treatments are equally effective, and there is no single treatment appropriate for all patients. Fortunately, recent scientific advances have provided insights both into the nature of drug abuse and addiction and into the principles that characterize the most effective treatment approaches and programs. These treatment principles should make the primary care or nonaddiction specialty care physician’s tasks of screening and referral much easier.

Drug abuse and developmental psychopathology.

Abstract: Drug abuse research and theory has become much more sophisticated over the last 2 decades, and some of the advancements parallel concepts that are part of the developmental psychopathology approach. The application of the developmental psychopathology perspective to recent drug abuse research findings can provide a greater understanding of that information and point to important areas of future research. Among the drug abuse research areas discussed here and viewed from this perspective are antecedent and co-occurring psychopathological conditions and other problem behaviors; the diversity of the nature of, paths to, and processes and outcomes related to drug abuse; the role of intermediary influences; the interaction of individual and environmental predisposing and protective factors; the role of families and other social institutions in intervention; and developmental stage characteristics. Directions for future research are also discussed.

Drug Abuse and Addiction Treatment Research: The Next Generation

Abstract: A GROUP of articles in this issue of theArchivesfocuses on drug abuse and addiction. Most of these articles deal with treatment in one aspect or another. In aggregate, they are a bit like a cafeteria, providing a sampling of some of the most important and difficult issues facing the field. These issues include the pervasiveness of comorbidity between mental disorders and substance abuse and the realities of polydrug use as the norm in drug abuse and addiction. Another issue addressed that has not received enough attention concerns matching treatments to the individual needs of the patient. Questions of treatment and services matching are particularly timely in the current climate, in which managed care is dominating health services provision systems and evolving rapidly. See also pages 696, 700, 706, 713, 721, 730, and 737 These articles are a part of what might be thought of as a new generation

Neural systems of reinforcement for drug addiction: from actions to habits to compulsion

Abstract: Drug addiction is increasingly viewed as the endpoint of a series of transitions from initial drug use--when a drug is voluntarily taken because it has reinforcing, often hedonic, effects--through loss of control over this behavior, such that it becomes habitual and ultimately compulsive. Here we discuss evidence that these transitions depend on interactions between pavlovian and instrumental learning processes. We hypothesize that the change from voluntary drug use to more habitual and compulsive drug use represents a transition at the neural level from prefrontal cortical to striatal control over drug seeking and drug taking behavior as well as a progression from ventral to more dorsal domains of the striatum, involving its dopaminergic innervation. These neural transitions may themselves depend on the neuroplasticity in both cortical and striatal structures that is induced by chronic self-administration of drugs.

Characterization of the decision-making deficit of patients with ventromedial prefrontal cortex lesions.

Abstract: On a gambling task that models real-life decisions, patients with bilateral lesions of the ventromedial prefrontal cortex (VM) opt for choices that yield high immediate gains in spite of higher future losses. In this study, we addressed three possibilities that may account for this behaviour: (i) hypersensitivity to reward; (ii) insensitivity to punishment; and (iii) insensitivity to future consequences, such that behaviour is always guided by immediate prospects. For this purpose, we designed a variant of the original gambling task in which the advantageous decks yielded high immediate punishment but even higher future reward. The disadvantageous decks yielded low immediate punishment but even lower future reward. We measured the skin conductance responses (SCRs) of subjects after they had received a reward or punishment. Patients with VM lesions opted for the disadvantageous decks in both the original and variant versions of the gambling task. The SCRs of VM lesion patients after they had received a reward or punishment were not significantly different from those of controls. In a second experiment, we investigated whether increasing the delayed punishment in the disadvantageous decks of the original task or decreasing the delayed reward in the disadvantageous decks of the variant task would shift the behaviour of VM lesion patients towards an advantageous strategy. Both manipulations failed to shift the behaviour of VM lesion patients away from the disadvantageous decks. These results suggest that patients with VM lesions are insensitive to future consequences, positive or negative, and are primarily guided by immediate prospects. This 'myopia for the future' in VM lesion patients persists in the face of severe adverse consequences, i.e. rising future punishment or declining future reward.

Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli.

Abstract: Drug abuse and dependence define behavioral states involving increased allocation of behavior towards drug seeking and taking at the expense of more appropriate behavioral patterns. As such, addiction can be viewed as increased control of behavior by the desired drug (due to its unconditioned, rewarding properties). It is also clear that drug-associated (conditioned) stimuli acquire heightened abilities to control behaviors. These phenomena have been linked with dopamine function within the ventral striatum and amygdala and have been described specifically in terms of motivational and incentive learning processes. New data are emerging that suggest that regions of the frontal cortex involved in inhibitory response control are directly affected by long-term exposure to drugs of abuse. The result of chronic drug use may be frontal cortical cognitive dysfunction, resulting in an inability to inhibit inappropriate unconditioned or conditioned responses elicited by drugs, by related stimuli or by internal drive states. Drug-seeking behavior may thus be due to two related phenomena: (1) augmented incentive motivational qualities of the drug and associated stimuli (due to limbic/amygdalar dysfunction) and (2) impaired inhibitory control (due to frontal cortical dysfunction). In this review, we consider the neuro-anatomical and neurochemical substrates subserving inhibitory control and motivational processes in the rodent and primate brain and their putative impact on drug seeking. The evidence for cognitive impulsivity in drug abuse associated with dysfunction of the frontostriatal system will be discussed, and an integrative hypothesis for compulsive reward-seeking in drug abuse will be presented.

Sleep Deprivation and Vigilant Attention

Abstract: Sleep deprivation severely compromises the ability of human beings to respond to stimuli in a timely fashion. These deficits have been attributed in large part to failures of vigilant attention, which many theorists believe forms the bedrock of the other more complex components of cognition. One of the leading paradigms used as an assay of vigilant attention is the psychomotor vigilance test (PVT), a high signal-load reaction-time test that is extremely sensitive to sleep deprivation. Over the last twenty years, four dominant findings have emerged from the use of this paradigm. First, sleep deprivation results in an overall slowing of responses. Second, sleep deprivation increases the propensity of individuals to lapse for lengthy periods (>500ms), as well as make errors of commission. Third, sleep deprivation enhances the time-on-task effect within each test bout. Finally, PVT results during extended periods of wakefulness reveal the presence of interacting circadian and homeostatic sleep drives. A theme that links these findings is the interplay of “top-down” and “bottom-up” attention in producing the unstable and unpredictable patterns of behavior that are the hallmark of the sleep-deprived state.