Simultaneous assay by PET of pre- and postsynaptic markers of dopamine neurotransmission indicated that a striatal dopamine deficit correlated with alcohol craving, which was associated with a high relapse risk.

[18F]Fluoro-3,4-dihydroxyphenyl-L-alanine (FDOPA) was one of the first successful tracers for molecular imaging by positron emission tomography (PET), and has proven immensely valuable for studies of Parkinson’s disease. Following intravenous FDOPA injection, the decarboxylated metabolite [18F] fluorodopamine is formed and trapped within terminals of the nigrostriatal dopamine neurons; reduction in the simple ratio between striatum and cerebellum is indicative of nigrostriatal degeneration. However, the kinetic analysis of dynamic FDOPA-PET recordings is formidably complex due to the entry into brain of the plasma metabolite O-methyl-FDOPA and due to the eventual washout of decarboxylated metabolites. Linear graphical analysis relative to a reference tissue input function is popular and convenient for routine clinical studies in which serial arterial blood samples are unavailable. This simplified approach has facilitated longitudinal studies in large patient cohorts. Linear graphical analysis relative to the metabolite-corrected arterial FDOPA input yields a more physiological index of FDOPA utilization, the net blood-brain clearance. Using a constrained compartmental model, FDOPA-PET recordings can be used to calculate the relative activity of the enzyme DOPA decarboxylase in living brain. We have extended this approach so as to obtain an index of steady-state trapping of [ 18F]fluorodopamine in synaptic vesicles. Although simple methods of image analysis are sufficient for the purposes of routine clinical studies, the more complex approaches have revealed hidden aspects of brain dopamine in personality, healthy aging, and in the pathophysiologies of Parkinson’s disease and schizophrenia.

Sensation seeking is a core personality trait that declines with age in both men and women, as do also both density and availability of the dopamine D 2/3 receptors in striatum and cortical regions. In contrast, novelty seeking at a given age relates inversely to dopamine receptor availability. The simplest explanation of these findings is an inverted-U-shaped correlation between ratings of sensation seeking on the Zuckerman scale and dopamine D 2/3 receptor availability. To test the claim of an inverted-U-shaped relation between ratings of the sensation-seeking personality and measures of dopamine receptor availability, we used PET to record [ 11 C]raclopride binding in striatum of 18 healthy men. Here we report that an inverted-U shape significantly matched the receptor availability as a function of the Zuckerman score, with maximum binding potentials observed in the midrange of the scale. The inverted-U shape is consistent with a negative correlation between sensation seeking and the reactivity (“gain”) of dopaminergic neurotransmission to dopamine. The correlation reflects Zuckerman scores that are linearly linked to dopamine receptor densities in the striatum but nonlinearly linked to dopamine concentrations. Higher dopamine occupancy and dopamine concentrations explain the motivation that drives afflicted individuals to seek sensations, in agreement with reduced protection against addictive behavior that is characteristic of individuals with low binding potentials.

Dopamine is released under stress and modulates processing of aversive stimuli. We found that dopamine storage capacity in human amygdala, measured with 6-[ 18 F]fluoro-L-DOPA positron emission tomography, was positively correlated with functional magnetic resonance imaging blood oxygen leveldependent signal changes in amygdala and dorsal anterior cingulate cortex that were evoked by aversive stimuli. Furthermore, functional connectivity between these two regions was inversely related to trait anxiety. Our results suggest that individual dopamine storage capacity in amygdala subserves modulation of emotional processing in amygdala and dorsal cingulate, thereby contributing to individual differences in anxious temperament.An emphasis is frequently placed on the importance of dopamine in shaping complex behavior and in regulating neural responses to rewarding stimuli 1 , often overshadowing its contribution to aversive processing [2][3][4] . Animal studies demonstrate that dopamine release in the amygdala augments excitatory sensory input and attenuates inhibitory prefrontal input, resulting in augmented aversive conditioning 5 . Consistent with these findings, human pharmacological neuroimaging studies show that increased dopamine release potentiates human amygdala function 6,7 . These convergent findings suggest that variability in dopamine signaling may contribute to individual variability in amygdala function and related emotional behaviors.Blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) is an effective and reliable tool for measuring stable individual differences in amygdala function 8 . Positron emission tomography (PET) recordings with 6-[ 18 F]fluoro-L-DOPA (FDOPA) provide the basis for calculating the net influx of FDOPA to the brain relative to the metabolite-corrected plasma input (K in app ; ml g -1 min -1 ) and steady-state distribution volume in brain of FDOPA (V d ; ml g -1 ), defined below.We used combined BOLD fMRI and FDOPA-PET to examine the relationship between regional dopamine storage and functional reactivity to affective visual cues in the amygdala and in the functionally coupled anterior cingulate cortex (ACC) in 13 healthy adult men 9-11 . All subjects provided informed written consent according to the declaration of Helsinki and the study was approved by the local ethics committee of the We used event-related BOLD fMRI to measure amygdala reactivity during the passive viewing of standardized affectively negative and neutral visual stimuli (Supplementary Methods). The general linear model in SPM5 (Statistical Parametric Mapping, see Supplementary Methods) was used to calculate single-subject activation for the contrast of negative versus neutral stimuli. Consistent with prior studies (for example, see ref. 12), the presentation of negative versus neutral stimuli elicited significant activation in the left amygdala (x ¼ -21, y ¼ -1, z ¼ -15; t ¼ 3.23, P ¼ 0.036, FWE (family-wise error) corrected for volume of interest). We next examined functional coupling ...

Previous positron emission tomography (PET) studies with levodopa analogs have revealed a modestly increased capacity for dopamine synthesis in the striatum of patients with schizophrenia compared with healthy age-matched control subjects. We hypothesized that not just the synthesis but also the turnover of radiolabeled dopamine is elevated in patients. To test the hypothesis, we reanalyzed 2-h-long

Fluid intelligence represents the capacity for flexible problem solving and rapid behavioral adaptation. Rewards drive flexible behavioral adaptation, in part via a teaching signal expressed as reward prediction errors in the ventral striatum, which has been associated with phasic dopamine release in animal studies. We examined a sample of 28 healthy male adults using multimodal imaging and biological parametric mapping with 1) functional magnetic resonance imaging during a reversal learning task and 2) in a subsample of 17 subjects also with positron emission tomography using 6-[18F]fluoro-L-DOPA to assess dopamine synthesis capacity. Fluid intelligence was measured using a battery of nine standard neuropsychological tests. Ventral striatal BOLD correlates of reward prediction errors were positively correlated with fluid intelligence and, in the right ventral striatum, also inversely correlated with dopamine synthesis capacity (FDOPA Kinapp). When exploring aspects of fluid intelligence, we observed that prediction error signaling correlates with complex attention and reasoning. These findings indicate that individual differences in the capacity for flexible problem solving may be driven by ventral striatal activation during reward-related learning, which in turn proved to be inversely associated with ventral striatal dopamine synthesis capacity.

Conventional methods for the graphical analysis of 6-[ 18 F]fluorodopa (FDOPA)/positron emission tomography (PET) recordings (K in app ) may be prone to negative bias because of oversubtraction of the precursor pool in the region of interest, and because of diffusion of decarboxylated FDOPA metabolites from the brain. These effects may reduce the sensitivity of FDOPA/PET for the detection of age-related changes in dopamine innervations. To test for these biasing effects, we have used a constrained compartmental analysis to calculate the brain concentrations of the plasma metabolite 3-O-methyl-FDOPA (OMFD) during 120 mins of FDOPA circulation in healthy young, healthy elderly, and Parkinson's disease subjects. Calculated brain OMFD concentrations were subtracted frame-byframe from the dynamic PET recordings, and maps of the FDOPA net influx to brain were calculated assuming irreversible trapping (K app ). Comparison of K in app and K app maps revealed a global negative bias in the conventional estimates of FDOPA clearance. The present OMFD subtraction method revealed curvature in plots of K app at early times, making possible the calculation of the corrected net influx (K) and also the rate constant for diffusion of decarboxylated metabolites from the brain (k loss ). The effective distribution volume (EDV 2 ; K/k loss ) for FDOPA, an index of dopamine storage capacity in brain, was reduced by 85% in putamen of patients with Parkinson's disease, and by 58% in the healthy elderly relative to the healthy young control subjects. Results of the present study support claims that storage capacity for dopamine in both caudate and putamen is more profoundly impaired in patients with Parkinson's disease than is the capacity for DOPA utilization, calculated by conventional FDOPA net influx plots. The present results furthermore constitute the first demonstration of an abnormality in the cerebral utilization of FDOPA in caudate and putamen as a function of normal aging, which we attribute to loss of vesicular storage capacity.

Dopamine neurotransmission influences those cognitive processes, which are generally regarded as prefrontal cortical functions. In previous positron-emission-tomography (PET) studies, net blood-brain clearance of [18F]-fluoro-l-DOPA (FDOPA) correlated with impaired cognitive performance in patients with Parkinson's disease or schizophrenia. We hypothesized that FDOPA influx also correlates with performance of cognitive tasks associated with prefrontal functioning in healthy volunteers. The net blood-brain clearance of FDOPA (K(in)(app)) was mapped in a group of 11 healthy volunteers and calculated in striatal volumes-of-interest. The Wisconsin-Card-Sorting-Test (WCST), Stroop-Test, Trail-Making-Test (TMT-A/B), and Continuous-Performance-Test (CPT-M) had been administered previously to the same subjects. No correlation of K(in) (app) with perseverative errors in WCST or age could be found. However, there were significant positive correlations between the magnitude of K(in)(app) in caudate nucleus, putamen, and midbrain with performance of the TMT-B, CPT-M, and the Stroop test. Highest correlations were found between the time needed to perform the Stroop interference task and the K(in)(app) of striatal areas (Caudate nucleus: -0.780, P = 0.005; putamen: -0.870, P < 0. 001). Thus, the present findings reveal a strong correlation between dopamine synthesis capacity in striatum of healthy volunteers and performance of cognitive tasks linked to the prefrontal cortex.