Converging evidence implicates the dopaminergic system and the prefrontal and nigrostriatal regions in the pathophysiology of attention deficit hyperactivity disorder (ADHD). Using positron emission tomography (PET) with [fluorine-18]fluorodopa (F18-DOPA), we compared the integrity of the presynaptic dopaminergic function between 17 ADHD adults and 23 healthy controls. The ratio of the isotope concentration of specific regions to that of nonspecific regions reflects DOPA decarboxylase activity and dopamine storage processes. Of three composite regions (prefrontal cortex, striatum, and midbrain), only the prefrontal cortex showed significantly different F18-DOPA ratios in ADHD as compared with control adults (p < 0.01). The medial and left prefrontal areas were the most altered (lower F18-DOPA ratios by 52 and 51% in ADHD as compared with controls). Similarly, the interaction [sex x diagnosis] was significant only in the prefrontal cortex (p < 0.02): lower ratios in men than in women in ADHD and vice versa in controls. These findings suggest that a prefrontal dopaminergic dysfunction mediates ADHD symptoms in adults and that gender influences this abnormality. On the basis of previous neuroimaging findings in ADHD showing discrepant findings in adults and adolescents and on evidence for midbrain dopaminergic defect in adolescents, we hypothesize that the prefrontal dopaminergic abnormality in ADHD adults is secondary and results from an interaction of the primary subcortical dopaminergic deficit with processes of neural maturation and neural adaptation.

Nicotine influences cognition and behavior, but the mechanisms by which these effects occur are unclear. By using positron emission tomography, we measured cognitive activation (increases in relative regional cerebral blood flow) during a working memory task [2-back task (2BT)] in 11 abstinent smokers and 11 ex-smokers. Assays were performed both after administration of placebo gum and 4-mg nicotine gum. Performance on the 2BT did not differ between groups in either condition, and the pattern of brain activation by the 2BT was consistent with reports in the literature. However, in the placebo condition, activation in ex-smokers predominated in the left hemisphere, whereas in smokers, it occurred in the right hemisphere. When nicotine was administered, activation was reduced in smokers but enhanced in ex-smokers. The lateralization of activation as a function of nicotine dependence suggests that chronic exposure to nicotine or withdrawal from nicotine affects cognitive strategies used to perform the memory task. Furthermore, the lack of enhancement of activation after nicotine administration in smokers likely reflects tolerance. N icotine affects cognition and behavior (1). In smokers and nonsmokers, it produces small improvements in finger-tapping rate, motor response on tests of focused and sustained attention, and recognition memory (2). In smokers, tobacco deprivation can impair cognitive performance, and subsequent nicotine administration or smoking can reverse these deficits (3-5). Thus, nicotinereversible performance deficits in withdrawal may help sustain nicotine dependence (1). To elucidate the neuroanatomical substrates of the effects of nicotine on cognition, we used a test of working memory and positron emission tomography (PET), which permits the visualization of regional brain function (6). Our ultimate objective is to clarify the effects of nicotine on brain function in the hope that such information might improve our knowledge of the mechanisms of nicotine dependence. MethodsSubjects. A total of 11 smokers and 11 ex-smokers completed the study. All subjects gave written informed consent after receiving an explanation of the study and its procedures. Inclusion criteria were: age between 21 and 45 years, IQ Ͼ 85 (assessed by the Shipley Institute of Living Scale; ref. 7), and right handedness. Smokers had a history of smoking for at least 2 years, with current use Ͼ 20 cigarettes per day and a score Ͼ5 on the Fagerström test for nicotine dependence (range 0-10; ref. 8). For ex-smokers, prior exposure to nicotine without current smoking (nicotine abstinence for more than 1 month and no evidence of nicotine dependence for more than 3 years before the study) was required. History of exposure to nicotine was required to minimize the occurrence of side effects from nicotine gum. Exclusion criteria were current psychopathology (symptom checklist-90; ref. 9), history of psychiatric disorders (diagnostic interview schedule; ref. 10) including substance-abuse disorders other than nicotine dependence, and ev...

Patients with Lesch-Nyhan disease have abnormally few dopaminergic nerve terminals and cell bodies. The abnormality involves all dopaminergic pathways and is not restricted to the basal ganglia. These dopaminergic deficits are pervasive and appear to be developmental in origin, which suggests that they contribute to the characteristic neuropsychiatric manifestations of the disease.

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