Evidence accumulated over more than 45 years has indicated that environmental stimuli can induce craving for drugs of abuse in individuals who have addictive disorders. However, the brain mechanisms that subserve such craving have not been elucidated. Here a positron emission tomographic study shows increased glucose metabolism in cortical and limbic regions implicated in several forms of memory when human volunteers who abuse cocaine are exposed to drug-related stimuli. Correlations of metabolic increases in the dorsolateral prefrontal cortex, medial temporal lobe (amygdala), and cerebellum with self-reports of craving suggest that a distributed neural network, which integrates emotional and cognitive aspects of memory, links environmental cues with cocaine craving.Most individuals who suffer from dependence on cocaine and other addictive drugs return to substance abuse within a year of initiating abstinence (1, 2). Addicts often attribute relapse to intense desire or "craving," which may arise in an environment associated with drug use (3-5). Moreover, drug-related cues can induce craving in laboratory settings (6-8). Substantial interest focuses on the mechanisms by which drug-related stimuli elicit craving (3, 5, 9-12) despite concerns that craving does not inevitably lead to drug taking (13). Little is known, however, about the biological basis of cue-elicited drug craving, except that cocaine users exposed to drug-related cues exhibit diffuse decreases in the power of the electroencephalogram (8). The purpose of the present study was to identify brain regions that mediate cue-elicited cocaine craving. To this end, regional cerebral metabolic rate for glucose (rCMRglc), an index of local brain function (14, 15), was measured in cocaine abusers and normal volunteers in a neutral test session and in another session during which cocaine-related stimuli were presented. METHODS Subjects. Thirteen cocaine abusers (COC group; 25-42 years old; 12 men, 1 woman; 12 Black, 1 White) and 5 normal volunteers (24-29 years old; 4 men, 1 woman; all Black) participated in the study. Evidence of physical disease, history of head trauma with loss of consciousness, or fulfillment of criteria for any axis I psychiatric diagnosis other than substance abuse or dependence or for any axis II disorder other than borderline or antisocial personality disorder were exclusionary criteria (16). Subjects in the COC group reported long-term cocaine use (median 8 years; range 2.5-20 years) with a current median use of 2.5 g/week (range 0.2-4.3 g/week). They also reported using opiates (5/13 subjects), marijuana (9/13), alcohol (13/13), and nicotine (11/13), but were not physically dependent on opiates or alcohol, nor were any of them receiving treatment for drug abuse. Some control subjects used nicotine (3/5), and alcohol (3/5); one reported a single use of marijuana more than a decade before the study. All volunteers in both groups had been abstinent from nicotine, alcohol, and caffeine for 12-15 h prior to each test session. Eight...

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Cocaine abusers demonstrate faulty decision-making as manifested by their inability to discontinue self-destructive drug-seeking behaviors. The orbitofrontal cortex (OFC) plays an important role in decision-making. In this preliminary study we tested whether 25-day-abstinent cocaine abusers show alterations in normalized cerebral blood flow (rCBF) in the OFC using PET with 15 O during the Iowa Gambling Task (a decision-making task). This task measures the ability to weigh short-term rewards against long-term losses. A control task matched the sensorimotor aspects of the task but did not require decision-making. Cocaine abusers (N = 13) showed greater activation during performance of the Iowa Gambling Task in the right OFC and less activation in the right dorsolateral prefrontal cortex (DLPFC) and left medial prefrontal cortex (MPFC) compared to a control group (N = 13). Better Iowa Gambling Task performance was associated with greater activation in the right OFC in both groups. Also, the amount of cocaine used (grams/week) prior to the 25 days of enforced abstinence was negatively correlated with activation in the left OFC. Greater activation in the OFC in cocaine abusers compared to a control group may reflect differences in the anticipation of reward while less activation in the DLPFC and MPFC may reflect differences in planning and working memory. These findings suggest that cocaine abusers show persistent functional abnormalities in prefrontal neural networks involved in decision-making and these effects are related to cocaine abuse. Compromised decision-making could contribute to the development of addiction and undermine attempts at abstinence.

We evaluated the effects of the lipophilic nonpeptide corticotropin-releasing hormone (CRH) type 1 receptor antagonist antalarmin on the behavioral, neuroendocrine, and autonomic components of the stress response in adult male rhesus macaques. After oral administration, significant antalarmin concentrations were detected in the systemic circulation and the cerebrospinal fluid by a mass spectrometry-gas chromatography assay developed specifically for this purpose. Pharmacokinetic and dose-response studies suggested that an oral dose of 20 mg/kg was optimal for behavioral and endocrine effects. We then administered this dose in a double-blind, placebo-controlled fashion to monkeys exposed to an intense social stressor: namely, placement of two unfamiliar males in adjacent cages separated only by a transparent Plexiglas screen. Antalarmin significantly inhibited a repertoire of behaviors associated with anxiety and fear such as body tremors, grimacing, teeth gnashing, urination, and defecation. In contrast, antalarmin increased exploratory and sexual behaviors that are normally suppressed during stress. Moreover, antalarmin significantly diminished the increases in cerebrospinal fluid CRH as well as the pituitary-adrenal, sympathetic, and adrenal medullary responses to stress. We conclude that CRH plays a broad role in the physiological responses to psychological stress in primates and that a CRH type 1 receptor antagonist may be of therapeutic value in human psychiatric, reproductive, and cardiovascular disorders associated with CRH system hyperactivity.