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...

Background and Purpose-Premenopausal women are at lower risk than men for stroke, but the comparative vulnerability to tissue injury once a cerebrovascular incident occurs is unknown. We hypothesized that female rats sustain less brain damage than males during experimental focal ischemia and that the gender difference in ischemic outcome can be eliminated by ovariectomy. Methods-Age-matched male (M), intact female (F), and ovariectomized female (O; plasma estradiol: 4.1Ϯ1.6 pg/mL compared with 7.4Ϯ1.5 in F and 4.0Ϯ1.1 in M) rats from two different strains, normotensive Wistar and stroke-prone spontaneously hypertensive rats, were subjected to 2 hours of intraluminal middle cerebral artery occlusion, followed by 22 hours of reperfusion. Cerebral blood flow (CBF) was monitored throughout the ischemic period by laser-Doppler flowmetry. Infarction volume in the cerebral cortex (Ctx) and caudoputamen (CP) was determined by 2,3,5-triphenyltetrazolium chloride staining. In a separate cohort of M, F, and O Wistar rats, absolute rates of regional CBF were measured at the end of the ischemic period by quantitative autoradiography using [ 14 C]iodoantipyrine. Results-F rats of either strain had a smaller infarct size in Ctx and CP and a higher laser-Doppler flow during ischemia compared with respective M and O rats. Mean end-ischemic CBF was higher in F compared with M and O rats in CP, but not in Ctx. Cerebrocortical tissue volume with end-ischemic CBF Ͻ10 mL/100 g/min was smaller in F than M rats, but not different from O rats. Conclusions-We conclude that endogenous estrogen improves stroke outcome during vascular occlusion by exerting both neuroprotective and flow-preserving effects. (Stroke. 1998;29:159-166.)

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.

Background: We examined whether face-emotion labeling deficits are illness-specific or an

In all, 19 research subjects, with current histories of frequent cocaine use, were exposed to cocaine-related cues to elicit drug craving. We measured the change of occupancy of dopamine at D2-like receptors with positron emission tomography (PET) and inferred a change of intrasynaptic dopamine (endogenous dopamine release), based on the displacement of radiotracer [11 C]raclopride. Receptor occupancy by dopamine increased significantly in putamen of participants who reported cue-elicited craving compared to those who did not. Further, the intensity of craving was positively correlated with the increase in dopamine receptor occupancy in the putamen. These results provide direct evidence that occupancy of dopamine receptors in human dorsal striatum increased in proportion to subjective craving, presumably because of increased release of intrasynaptic dopamine.

Background and Purpose-The importance of postmenopausal estrogen replacement therapy for stroke in females remains controversial. We previously showed that female rats sustain less infarction in reversible middle cerebral artery occlusion (MCAO) than their ovariectomized counterparts and that vascular mechanisms are partly responsible for improved tissue outcomes. Furthermore, exogenous estrogen strongly protects the male brain, even when administered in a single injection before MCAO injection. The present study examined the hypothesis that replacement of 17␤-estradiol to physiological levels improves stroke outcome in ovariectomized, estrogen-deficient female rats, acting through blood flow-mediated mechanisms. Methods-Age-matched, adult female Wistar rats were ovariectomized and treated with 0, 25, or 100 g of 17␤-estradiol administered through a subcutaneous implant or with a single Premarin (USP) injection (1 mg/kg) given immediately before ischemia was induced (nϭ10 per group). Each animal subsequently underwent 2 hours of MCAO by the intraluminal filament technique, followed by 22 hours of reperfusion. Ipsilateral parietal cortex perfusion was monitored by laser-Doppler flowmetry throughout ischemia. Cortical and caudate-putamen infarction volumes were determined by 2,3,5-triphenyltetrazolium chloride staining and digital image analysis. End-ischemic regional cerebral blood flow was measured in ovariectomized females with 0-or 25-g implants (nϭ4 per group) by 14 C-iodoantipyrine quantitative autoradiography. Results-Plasma estradiol levels were 3.0Ϯ0.6, 20Ϯ8, and 46Ϯ10 pg/mL in the 0-, 25-, and 100-g groups, respectively.Caudate-putamen infarction (% of ipsilateral caudate-putamen) was reduced by long-term, 25-g estrogen treatment (13Ϯ4% versus 31Ϯ6% in the 0-g group, PϽ0.05, and 22Ϯ3% in the 100-g group). Similarly, cortical infarction (% of ipsilateral cortex) was reduced only in the 25-g group (3Ϯ2% versus 12Ϯ3% in the 0-g group, PϽ0.05, and 6Ϯ3% in the 100-g group. End-ischemic striatal or cortical blood flow was not altered by estrogen treatment at the neuroprotective dose. Infarction volume was unchanged by acute treatment before MCAO when estrogen-treated animals were compared with saline vehicle-treated animals. Conclusions-Long-term estradiol replacement within a low physiological range ameliorates ischemic brain injury in previously ovariectomized female rats. The neuroprotective mechanism is flow-independent, not through preservation of residual ischemic regional cerebral blood flow. Furthermore, the therapeutic range is narrow, because the benefit of estrogen in transient vascular occlusion is diminished at larger doses, which yield high, but still physiologically relevant, plasma 17␤-estradiol levels. Lastly, unlike in the male brain, single-injection estrogen exposure does not salvage ischemic tissue in the female brain. Therefore, although exogenous steroid therapy protects both male and female estrogen-deficient brain, the mechanism may not be identical and depends on long-term hormone aug...

The Gambling Task can be used with adolescents. Testing with the Gambling Task revealed a deficit in decision making in adolescents with behavior disorders, who are at risk for substance abuse. This deficit may represent a vulnerability factor for the development of substance abuse.

The findings suggest that the neural circuits engaged during decision making differ in subjects with ADHD and healthy comparison subjects. This difference may explain observed deficits in motivated behaviors in ADHD. A better understanding of the nature of these deficits could ultimately be applied to refine treatment strategies for ADHD.