OBJECTIVE: Studies of the neurobiological processes underlying drug addiction primarily have focused on limbic subcortical structures. Here the authors evaluated the role of frontal cortical structures in drug addiction. METHOD: An integrated model of drug addiction that encompasses intoxication, bingeing, withdrawal, and craving is proposed. This model and findings from neuroimaging studies on the behavioral, cognitive, and emotional processes that are at the core of drug addiction were used to analyze the involvement of frontal structures in drug addiction. RESULTS: The orbitofrontal cortex and the anterior cingulate gyrus, which are regions neuroanatomically connected with limbic structures, are the frontal cortical areas most frequently implicated in drug addiction. They are activated in addicted subjects during intoxication, craving, and bingeing, and they are deactivated during withdrawal. These regions are also involved in higher-order cognitive and motivational functions, such as the ability to tr...

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Drug Addiction and Its Underlying Neurobiological Basis: Neuroimaging Evidence for the Involvement of the Frontal Cortex

The effects of drug dependence on social systems has helped shape the generally held view that drug dependence is primarily a social problem, not a health problem. In turn, medical approaches to prevention and treatment are lacking. We examined evidence that drug (including alcohol) dependence is a chronic medical illness. A literature review compared the diagnoses, heritability, etiology (genetic and environmental factors), pathophysiology, and response to treatments (adherence and relapse) of drug dependence vs type 2 diabetes mellitus, hypertension, and asthma. Genetic heritability, personal choice, and environmental factors are comparably involved in the etiology and course of all of these disorders. Drug dependence produces significant and lasting changes in brain chemistry and function. Effective medications are available for treating nicotine, alcohol, and opiate dependence but not stimulant or marijuana dependence. Medication adherence and relapse rates are similar across these illnesses. Drug dependence generally has been treated as if it were an acute illness. Review results suggest that long-term care strategies of medication management and continued monitoring produce lasting benefits. Drug dependence should be insured, treated, and evaluated like other chronic illnesses.

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Drug Dependence, a Chronic Medical Illness: Implications for Treatment, Insurance, and Outcomes Evaluation

We present a brief overview of the incentive sensitization theory of addiction. This posits that addiction is caused primarily by drug-induced sensitization in the brain mesocorticolimbic systems that attribute incentive salience to reward-associated stimuli. If rendered hypersensitive, these systems cause pathological incentive motivation (‘wanting’) for drugs. We address some current questions including: what is the role of learning in incentive sensitization and addiction? Does incentive sensitization occur in human addicts? Is the development of addiction-like behaviour in animals associated with sensitization? What is the best way to model addiction symptoms using animal models? And, finally, what are the roles of affective pleasure or withdrawal in addiction?

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The incentive sensitization theory of addiction: some current issues

OBJECTIVE: Since signals for cocaine induce limbic brain activation in animals and cocaine craving in humans, the objective of this study was to test whether limbic activation occurs during cue-induced craving in humans. METHOD: Using positron emission tomography, the researchers measured relative regional cerebral blood flow (CBF) in limbic and comparison brain regions of 14 detoxified male cocaine users and six cocaine-naive comparison subjects during exposure to both non-drug-related and cocaine-related videos and during resting baseline conditions. RESULTS: During the cocaine video, the cocaine users experienced craving and showed a pattern of increases in limbic (amygdala and anterior cingulate) CBF and decreases in basal ganglia CBF relative to their responses to the nondrug video. This pattern did not occur in the cocaine-naive comparison subjects, and the two groups did not differ in their responses in the comparison regions (i.e., the dorsolateral prefrontal cortex, cerebellum, thalamus, and visu...

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Limbic Activation During Cue-Induced Cocaine Craving

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.

/pdf/addiction-is-a-brain-disease-and-it-matters-4z8hk6xh55.pdf

Addiction is a brain disease, and it matters.

Objective The authors investigated changes in brain function associated with cocaine dependence and withdrawal to provide clues regarding the processes that lead to the uncontrollable self-administration of cocaine. Method They measured regional brain metabolism with [18F]-fluorodeoxyglucose (FDG) and positron emission tomography in 15 outpatients with the diagnosis of cocaine abuse and 17 normal comparison subjects. Ten of the patients were studied less than 1 week after they had last had cocaine, and five were studied 2-4 weeks after withdrawal. Results Patients studied within 1 week of cocaine withdrawal but not those studied within 2-4 weeks of cocaine withdrawal had higher levels of global brain metabolism as well as higher levels of regional brain metabolism in the basal ganglia and orbitofrontal cortex than did normal subjects, probably as a consequence of less brain dopamine activity. There was also a significant relationship between the number of days since cocaine withdrawal and regional brain glucose metabolism in the orbitofrontal cortex and in the basal ganglia, and the correlations between cocaine craving and metabolic activity were significant in the prefrontal cortex and the orbitofrontal cortex. Conclusions Although the time-dependent fall in metabolic activity suggests that the higher metabolic activity observed less than a week after cocaine withdrawal may represent a nonspecific expression of drug withdrawal, the selectivity of changes in glucose metabolism for the basal ganglia and for the orbitofrontal cortex suggests that the regional metabolic changes seen in cocaine abusers during detoxification are related to changes in brain dopamine activity.

Changes in brain glucose metabolism in cocaine dependence and withdrawal.

Effects of chronic cocaine abuse on postsynaptic dopamine receptors

Because crack cocaine appears to have a preferential effect on the metabolic and electrophysiological activity of the frontal and temporal regions of the brain (Pascual-Leone et al., 1991a, 1991b; Volkow, 1992), we hypothesized that cognitive measures of those regions would be impaired in crack cocaine users relative to measures in normal volunteers. We used logistic regression to determine the relationship of cocaine usage to neuropsychological test performance. We compared 38 patients with an average of 3.6 (SD = 2.5) years of crack cocaine use and 24.5 (SD = 28.1) days of abstinence to 54 normal volunteers on a battery of neuropsychological tests. Statistical adjustments were made for the effects of age, education, socioeconomic class, and level of depression. Our findings were mixed with regard to purported measures of executive/frontal functioning, with worse performance associated with cocaine usage on the Booklet Categories Test, but better performance associated on others (number of categories on the Wisconsin Card Sorting Test, Controlled Oral Word Association). Cocaine usage was associated with impairment on measures of spatial, but not verbal memory, confrontation naming, and Trail-making Test, Part B, a measure of perceptual-motor speed and cognitive flexibility. In summary, it appears that continuous crack cocaine use produces a dissociative pattern in neuropsychological test performance with improvement on some measures, but deterioration on others. The permanence of these effects remains to be determined with longitudinal studies.

Robert Alpert

Papers

Changes in brain glucose metabolism in cocaine dependence and withdrawal.

Effects of chronic cocaine abuse on postsynaptic dopamine receptors

Effects of crack cocaine on neurocognitive function