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Objective: Positron emission tomography and the fluorodeoxyglucose (FDG) method were used to determine the brain's metabolic response to neuroleptic challenge in a normal, disease-free state. Method: FDG measurements were obtained before and 12 hours after administration of 5 mg of haloperidol to 12 young normal men. These values were compared with test-retest FDG measures obtained from nine normal male control subjects who received no drug intervention. Results: After haloperidol administration, the haloperidol subjects showed significantly lower glucose utilization in the neocortex, limbic cortex, thalamus, and caudate nucleus but not in the putamen or cerebellum. After adjustment for global effects, significant reductions were still evident in the frontal, occipital, and anterior cingulate cortex, whereas the putamen and cerebellum showed significant increases. Conclusions: This study, measuring the brain's metabolic response to acute receptor blockade, is a first step in the development of an assay of CNS pharmacological activity. By determining the response to neuroleptic challenge in a normal state, the study establishes a comparison group for determining response to challenge in various psychiatric conditions.

Objective: To differentiate withdrawal-related abnormalities in brain glucose metabolism among alcoholics from abnormalities that may be irreversible or antedate alcohol use, the authors evaluated metabolic recovery during alcohol detoxification. Method: Regional brain glucose metabolism was measured with positron emission tomography and 2-deoxy-2-(18F)fluoro-D-glucose in 10 male alcoholics at 8-15 days, 16-30 days, and 31-60 days after last use of alcohol. The alcoholics' metabolic values were compared with those of 10 age-matched male healthy volunteers. Results: Brain metabolism increased significantly during detoxification. There were significant differences in global and regional measures between the first and last time points but not between the second and third points, suggesting that recovery occurred predominantly within 16-30 days. Regional increases in metabolism were greater in the frontal regions. Whereas during the first evaluation the alcoholics showed significantly lower metabolism in various brain regions than the comparison group, at the end of detoxification the alcoholics showed significantly lower absolute and relative metabolic values in the basal ganglia and lower relative metabolic values in the parietal cortex. Among the alcoholics, but not the comparison group, metabolism in the frontal, parietal, and left temporal cortexes was negatively correlated with years of alcohol use and with age. Conclusions: This study shows significant increases in brain metabolism during alcohol withdrawal and documents persistent low metabolic levels in the basal ganglia of detoxified alcoholics.

Objective: Changes in gamma-aminobutyric acid (GABA)-benzodiazepine receptor function have been implicated in alcohol tolerance, withdrawal, and dependence. The purpose of this study was to investigate whether recently detoxified alcoholic subjects had abnormalities in brain GABA-benzodiazepine receptor function. Method: The effect of 30 microgram/kg of lorazepam on regional brain glucose metabolism was studied in 12 normal subjects and 10 alcoholic subjects with the use of positron emission tomography and (18F)fluorodeoxyglucose. Results: Lorazepam decreased whole brain glucose metabolism in both the normal subjects (13% change) and the alcoholic subjects (10% change), and the response was correlated with the concentration of lorazepam in plasma. Whereas the normal and alcoholic subjects showed similar responses to lorazepam in occipital and cerebellar metabolism, the alcoholic subjects showed significantly less of a response than the comparison subjects in the thalamus, basal ganglia, and orbitofrontal cortex. The rate of response in the orbitofrontal cortex was significantly correlated with cerebellar metabolism at baseline. Conclusions: The alcoholic subjects had a blunted response to lorazepam that was specific to certain brain regions. The association between cerebellar metabolism and response to lorazepam suggests that the cerebellum may contribute to the decreased sensitivity to lorazepam which was seen in the alcoholic subjects.

Objective: The extent to which cerebral dysfunction in alcoholics is related to the direct effects of alcohol in the brain rather than to indirect mechanisms and/or alcohol withdrawal remains unclear. The purpose of this study was to evaluate whether healthy alcoholics with no evidence of alcohol-associated complications showed changes in brain glucose metabolism. Method: Positron emission tomography and [[F.sup.18]]-fluorodeoxyglucose were used to measure regional brain metabolism. The study group consisted of 22 normal, healthy, right-handed volunteers and 22 neurologically intact, healthy, right-handed alcoholics tested 6 to 32 days after alcohol discontinuation. Results: Alcoholics showed significantly lower whole brain metabolism than normal control subjects. Normalization of regional metabolic values to the whole brain metabolic rate revealed that the left parietal and right frontal cortices were the most affected regions. Although the whole brain metabolic rate was correlated with the amount of time since alcohol discontinuation, the 'normalized' decreases in left parietal and right frontal glucose metabolism were not. Conclusions: These findings support the contribution of the direct effect of alcohol as well as alcohol withdrawal on the changes in regional brain metabolism seen in alcoholics. They also provide evidence of cerebral changes in neurologically intact healthy alcoholics. (Am J Psychiatry 1992; 149:1016-1022)

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 [[sup.18.F]]-fluorodeoxyglucose (FDG) and positron emission tomography in 15 outpatients with the diagnosis of cocaine abuse and 17 normal comparion 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 brian 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., Under conditions of cocaine availability, a user will typically continue to use the drug until he or the cocaine supply is exhausted. However, this uncontrolled use pattern is not fully explained by cocaine's euphoric effect'; even under conditions in which a user develops a tolerance to the effect, the drug is still craved and used uncontrollably. There may be chemical changes in the brain that account for this phenomenon. In the present investigation, 15 cocaine abusers and 17 normal subjects were studied. Glucose metabolism was measured in several regions of the brain using positron emission tomography (PET). Subjects were also evaluated for affective (mood) symptoms using the Beck Depression Inventory. The cocaine abusers were male and averaged 29 years old, they had abused cocaine for at least 12 months, and were in various stages of withdrawal from the drug. The normal control subjects were male and were an average age of 32 years. All but three of the cocaine-dependent subjects had symptoms of depression and all had a sense of cocaine craving. Glucose metabolism varied between the groups and by stage of cocaine withdrawal within the dependent group. Cocaine-dependent subjects who were in early withdrawal (about one week since last use) had the highest glucose metabolism and the normal control subjects had the lowest. Within two-to-four weeks of withdrawal, the differences between cocaine-dependent subjects and normal controls disappeared. It is suggested that these changes are due to changes in dopamine activity, and that the decreased dopamine activity resulting from cocaine use causes an increase in the brain's metabolism of glucose. (Consumer Summary produced by Reliance Medical Information, Inc.)

It has been generally assumed that lack of response by some schizophrenic patients to neuroleptic therapy, treatment with antipsychotic drugs, indicates inadequate dosage of the drugs. This premise was challenged by investigators who concluded that this is not necessarily the case. Ten schizophrenic patients were measured for dopamine receptor occupancy and clinical response before and after dosages of haloperidol, a common antipsychotic. Reduced dopamine receptor status would have indicated that the drug was not having the desired biochemical effect of blocking the release of the hormone dopamine, a 'brain messenger,' and thus failing to moderate transmission of nervous signals. Results indicated that dopamine blockade was the same for patients who responded to treatment as it was for patients who did not respond. It was concluded that inadequate neuroleptic blockage of dopamine may not be responsible for the failure of the drug therapy. The possibility of the existence of other influential factors was discussed. Greater site density, i.e. the availability of more receptors, in the schizophrenic patient who did not respond was offered as an explanation. Another possibility suggested was that schizophrenia may progress in phases and that during certain phases patients are not responsive to neuroleptics. Investigators suggest that there are intrinsic differences in the pathophysiology of symptoms and a greater heterogeneity exists in schizophrenia than is generally considered.