Activation of memory circuits during cue-elicited cocaine craving.

Abstract

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...

Acute Cocaine Administration Depresses Cortical Activity

“…More recently, we and others have shown that repeated administration of drugs of abuse, such as cocaine, affect cellular (Trantham et al, 2002;Nasif et al, 2003) and metabolic functions (Grant et al, 1996;Childress et al, 1999;Volkow and Fowler, 2000) in the PFC. Moreover, it is known that psychomotor stimulants act on limbic and cognitive circuits, and drug-induced neuroadaptations in the corticolimbic circuits are increasingly gaining prominence in hypotheses of drug addiction (Pierce and Kalivas, 1997;Wolf, 1998;Jentsch and Taylor, 1999;Berke and Hyman, 2000).…”

Extinction of Cocaine Self-Administration Produces a Differential Time-Related Regulation of Proenkephalin Gene Expression in Rat Brain

“…Several animal studies have suggested the "extended amygdala" as a neural substrate for the behavioral effects of self-administered cocaine (Robledo and Koob 1993;Caine and Koob 1994;Hurd et al 1997;McGregor and Roberts 1993;Robbins et al 1989;Robledo et al 1996). In humans, recent evidence from brain-imaging studies suggest a role for dopamine-rich brain regions, including the nucleus accumbens and amygdala, in cocaine craving (Grant et al 1996;Breiter et al 1997;Childress et al 1999). Along this line, considering the particular conditions of this work, it is tempting to speculate that, in addition to previously documented inhibition of mesocorticolimbic activity (Rossetti et al 1992;Kuhar and Pilotte 1996), a decrease in proenkephalin gene expression in the Ce may represent a possible mechanism mediating in cocaine withdrawal states.…”

Orbitofrontal cortex dysfunction in abstinent cocaine abusers performing a decision-making task

“…These studies have consistently revealed increased activation in the OFC, the anterior cingulate, the right insular region, and the amygdala in response to cocaine-related cues (Bonson et al, 2002;Childress et al, 1999;Wang et al 1999;Grant et al, 1996). Other studies have also shown that cocaine abuse is related to a disruption in the striato-thalamo-orbitofrontal circuit (Volkow et al, 1993;Volkow and Fowler, 2000;Goldstein et al, 2001).…”