Sex differences in the relationship of regional dopamine release to affect and cognitive function in striatal and extrastriatal regions using positron emission tomography and [18F]fallypride

The purpose of this study was to examine sex differences in the correlations of d‐amphetamine (d‐AMPH) induced displacements of [¹⁸F]fallypride in striatal and extrastriatal regions in relation to affect and cognition. Seven male and six female healthy subjects, whose mean age was 25.9 years, underwent positron emission tomography (PET) with [¹⁸F]fallypride at baseline and 3 h after a 0.43 mg/kg oral dose of d‐AMPH. Percent displacements in striatal and extrastriatal regions were calculated using regions of interest (ROI) analysis and on a pixel‐by‐pixel basis. Subjects underwent neuropsychological testing prior to the baseline PET study and one hour after d‐AMPH administration for the second PET. In order to examine the subjective effect of d‐AMPH, subjects rated PANAS at baseline and after administration of amphetamine. Correlations of changes in cognition and affect with regional dopamine (DA) release revealed several significant sex related differences. The results of this study demonstrate in vivo sex related differences in the relationship of regional DA release to affect and cognitive function. Synapse 2011. © 2010 Wiley‐Liss, Inc.     

Small effect of dopamine release and no effect of dopamine depletion on [18F]fallypride binding in healthy humans

Molecular imaging has been used to estimate both drug-induced and tonic dopamine release in the striatum and most recently extrastriatal areas of healthy humans. However, to date, studies of drug-induced and tonic dopamine release have not been performed in the same subjects. This study performed positron emission tomography (PET) with [18F]fallypride in healthy subjects to assess (1) the reproducibility of [18F]fallypride and (2) both D-amphetamine-induced and alpha-methyl-p-tyrosine (AMPT)-induced changes in dopamin release on [(18)F]fallypride binding in striatal and extrastriatal areas. Subjects underwent [18F]fallypride PET studies at baseline and following oral D-amphetamine administration (0.5 mg/kg) and oral AMPT administration (3 g/70 kg/day over 44 h). Binding potential (BP) (BP(ND)) of [18F]fallypride was calculated in striatal and extrastriatal areas using a reference region method. Percent change in regional BP(ND) was computed and correlated with change in cognition and mood. Test-retest variability of [18F]fallypride was low in both striatal and extrastriatal regions. D-Amphetamine significantly decreased BP(ND) by 8-14% in striatal subdivisions, caudate, putamen, substantia nigra, medial orbitofrontal cortex, and medial temporal cortex. Correlation between change in BP(ND) and verbal fluency was seen in the thalamus and substantia nigra. In contrast, depletion of endogenous dopamine with AMPT did not effect [18F]fallypride BP(ND) in both striatum and extrastriatal regions. These findings indicate that [18F]fallypride is useful for measuring amphetamine-induced dopamine release, but may be unreliable for estimating tonic dopamine levels, in striatum and extrastriatal regions of healthy humans.     

Effect of amphetamine on [(18)F]fallypride in vivo binding to D(2) receptors in striatal and extrastriatal regions of the primate brain: Single bolus and bolus plus constant infusion studies

[(18)F]fallypride is a new positron emission tomography (PET) dopamine D(2) receptor radiotracer that provides visualization of D(2) receptors in both striatal and extrastriatal areas. Here, the vulnerability of [(18)F]fallypride binding to endogenous dopamine (DA) levels was evaluated by examining the effect of amphetamine on [(18)F]fallypride binding in striatal and extrastriatal regions. Data were acquired in three male baboons at three different doses of i.v. amphetamine, using two different [(18)F]fallypride administration protocols (single bolus and bolus plus constant infusion). Scans were performed following a single bolus of [(18)F]fallypride under control conditions and following 1 mg/kg i.v. amphetamine and with an [(18)F]fallypride bolus plus constant infusion design under control, 0.5 mg/kg, and 0.3 mg/kg amphetamine i.v. conditions. Significant decreases in [(18)F]fallypride binding potential were seen in striatum (-49%, -18%, and -14%), thalamus (-25%, -23%, and -14%), and hippocampus (-36%, -24%, and -12%) following 1 mg/kg, 0.5 mg/kg, and 0.3 mg/kg doses of amphetamine, respectively. Additional analyses were performed suggesting that these results were not artifacts of nonreceptor-related effects such as regional flow changes or partial volume effects. In conclusion, [(18)F]fallypride binding is vulnerable to endogenous competition by DA in striatum as well as extrastriatal regions, suggesting that this ligand may be suitable for the study presynaptic DA function in striatal and extrastriatal areas.     

PET Measurement of rCBF in the presence of a neurochemical tracer

Functional neurochemical imaging can indicate neurotransmitter release by detecting changes in receptor occupancy. A dual tracer positron emission tomography (PET) technique is presented here to extend such studies by simultaneously measuring changes in regional cerebral blood flow (rCBF). This would permit correlations of task or drug induced changes in rCBF and neurochemical function. In this proposed method, the rapidly varying signal from a blood flow tracer is distinguished from the slowly changing signal due to a long-lived neurochemical tracer. As a proof of principle, baseline studies were carried out in rhesus monkeys. Two monkeys were anesthetized with isoflurane, and [18F]fallypride (t1/2=110 min), a dopamine D2 receptor antagonist, was injected. Starting 99-137 min after injection, PET images were acquired every 10 s while the blood flow tracer [17F]fluoromethane (t1/2=65 s) was administered by inhalation in a repeating pattern of 45 s on/45 s off. The observed time-activity curves for 2 ml brain regions were fit with a three compartment lung-body-brain model of fluoromethane kinetics with whole brain perfusion fixed. Comparing consecutive 6 min scans, reproducibility of relative rCBF and striatal [18F]fallypride concentration were 9 and 8%, respectively.     

Sex differences in extrastriatal dopamine d(2)-like receptors in the human brain

OBJECTIVE: The study examined gender differences in extrastriatal dopamine D2-like receptor levels in the human brain in vivo. METHOD: [(11)C]FLB 457, a high-affinity radioligand for extrastriatal D(2)-like receptors, and a three-dimensional positron emission tomography system were used to measure D(2)-like receptor binding potentials in frontal cortex, temporal cortex, and thalamus in 12 healthy men and 12 healthy women. RESULTS: Women had higher D(2)-like receptor binding potentials than men in the three brain regions studied, and the difference in the frontal cortex was statistically significant. In a more detailed regional analysis, the difference between the sexes was most pronounced for the left and right anterior cingulate cortex. CONCLUSIONS: This study provides in vivo evidence for a gender difference in dopamine D(2)-like receptor levels, which could be reflected in gender-associated differences in clinical disorders linked to the dopamine system.     

Stress‐induced dopamine release in human medial prefrontal cortex—18F‐Fallypride/PET study in healthy volunteers

Background: In laboratory animals, environmental stressors markedly activate the mesocortical dopamine system. The present study tested whether this occurs in humans. Methods: The effects of a laboratory psychological stressor (Montreal Imaging Stress Task, MIST) on mesocortical dopamine release in healthy young adults (11 males, mean age ± SD, 20.6 ± 2.4 years) was measured using positron emission tomography and [¹⁸F]fallypride. Each subject was scanned in two separate days in counterbalanced order: one with the MIST and one with the control task. Binding potential (BP_ND) maps of the whole brain were calculated for each scan, using a simplified reference tissue compartmental model. Then BP_ND was compared between subjects. Heart rate, galvanic skin response, and salivary cortisol level were measured during the scans. Results: The psychological stressor significantly decreased [¹⁸F]fallypride binding values in the dorsal part of the medial prefrontal cortex (dmPFC), corresponding to the rostal part of the cingulate motor zone. The greater the stress‐induced decrease in [¹⁸F]fallypride binding in the dmPFC, the greater the stress‐induced increases in heart rate. Conclusions: The present study provides evidence of stress‐induced dopamine release in the mPFC in humans, in vivo. Synapse 67:821–830, 2013 . © 2013 Wiley Periodicals, Inc.     

Pre- and post-synaptic dopamine imaging and its relation with frontostriatal cognitive function in Parkinson disease: PET studies with [11C]NNC 112 and [18F]FDOPA

Frontostriatal cognitive dysfunction is common in Parkinson disease (PD), but the explanation for its heterogeneous expressions remains unclear. This study examined the dopamine system within the frontostriatal circuitry with positron emission tomography (PET) to investigate pre- and post-synaptic dopamine function in relation to the executive processes in PD. Fifteen non-demented PD patients and 14 healthy controls underwent [(18)F]FDOPA (for dopamine synthesis) and [(11)C]NNC 112 (for D(1) receptors) PET scans and cognitive testing. Parametric images of [(18)F]FDOPA uptake (K(i)) and [(11)C]NNC 112 binding potential (BP(ND)) were calculated using reference tissue models. Group differences in K(i) and BP(ND) were assessed with both volume of interest and statistical parametric mapping, and were correlated with cognitive tests. Measurement of [(18)F]FDOPA uptake in cerebral cortex was questionable because of higher K(i) values in white than adjacent gray matter. These paradoxical results were likely to be caused by violations of the reference tissue model assumption rendering interpretation of cortical [(18)F]FDOPA uptake in PD difficult. We found no regional differences in D(1) receptor density between controls and PD, and no overall differences in frontostriatal performance. Although D(1) receptor density did not relate to frontostriatal cognition, K(i) decreases in the putamen predicted performance on the Wisconsin Card Sorting Test in PD only. These results suggest that striatal dopamine denervation may contribute to some frontostriatal cognitive impairment in moderate stage PD.     

Personality traits and striatal dopamine synthesis capacity in healthy subjects

OBJECTIVE: Neuroimaging and genetic studies suggest that individual differences in the brain dopaminergic system contribute to the normal variability of human personality (e.g., social detachment and novelty seeking). The authors studied whether presynaptic dopamine function is also associated with personality traits. METHOD: Presynaptic dopamine synthesis capacity in the brain was measured with positron emission tomography and [(18)F]fluorodopa in 33 healthy adults, and personality traits were assessed with the Karolinska Scales of Personality. Associations were studied by using a linear regression model controlling for the effects of age and gender on both variables. RESULTS: High scores on two of the anxiety-related personality scales, somatic anxiety and muscular tension, and on one aggressivity-related scale, irritability, were significantly associated with low [(18)F]fluorodopa uptake in the caudate. No statistically significant associations were observed between [(18)F]fluorodopa uptake and the detachment scale or scales related to novelty-seeking behavior (impulsiveness and monotony avoidance). CONCLUSIONS: The results suggest a role for the dopaminergic system in the regulation of anxiety in healthy subjects. Together with previous studies, they also indicate differential involvement of various components of the dopaminergic system in normal and pathological personality traits.     

Surrogate markers for cerebral blood flow correlate with [18F]‐fallypride binding potential at dopamine D2/3 receptors in human striatum

Positron emission tomography (PET) with the high affinity dopamine D_2/3 receptor ligand [¹⁸F]‐fallypride affords estimates of the binding potential (BP_ND) in extra‐striatal regions of low receptor abundance, but the sufficient recording time for accurate measurements in striatum has been called into question. We have earlier argued that transient equilibrium measurements are obtained in striatum with [¹⁸F]‐fallypride PET recordings of 3 h duration, which may be the practical limit for clinical investigations without interrupted scanning. However, the high extraction fraction of [¹⁸F]‐fallypride predicts flow‐dependence of tracer delivery to brain, which may be a source of variance of the apparent BP_ND in regions of high binding. To test this prediction, we conducted a retrospective analysis of [¹⁸F]‐fallypride PET data from a group of 50 healthy volunteers (age 18–58 years [mean ± SD: 32.6 ± 10.6), who had participated in clinical studies without arterial input measurements. We used the initial 120‐s integral (AUC) of the venous confluence (VC) as a surrogate marker for cerebral blood flow (CBF) and tested for correlations between regional estimates of BP_ND calculated by the simplified reference tissue model (SRTM) and the individual VC‐AUC. The magnitude of BP_ND in a high binding region (putamen), but not in a low binding region (thalamus) correlated positively with VC‐AUC, suggesting that approximately 9% of the variance in the [¹⁸F]‐fallypride BP_ND in putamen can be attributed to individual differences in this surrogate marker for CBF, a contribution equal in magnitude to the effects of age on BP_ND in putamen of the present healthy control group. Synapse, 2013. © 2012 Wiley Periodicals, Inc.     

Sex differences in striatal presynaptic dopamine synthesis capacity in healthy subjects.

BACKGROUND: There are sex differences in the clinical features of several neuropsychiatric illnesses associated with dopamine dysfunction. The effects of sex on brain dopaminergic function have been sparsely studied in human subjects using modern imaging techniques. We have previously reported that the apparent affinity of [(11)C]raclopride for striatal D(2) dopamine receptors in vivo is lower in women than in men, whereas D(2) receptor density is not different. This finding indirectly suggests that women have a higher synaptic concentration of dopamine in the striatum. We explored further the basis of this phenomenon in an independent study and hypothesized that striatal presynaptic dopamine synthesis capacity would also be elevated in women. METHODS: A total of 23 healthy men and 12 healthy women (age range 20-60 years) were studied using positron emission tomography and [(18)F]fluorodopa. RESULTS: Women had significantly higher striatal [(18)F]fluorodopa uptake (Ki values) than men. The difference was more marked in the caudate (+26%) than in the putamen (+12%). In addition, there was a negative correlation between striatal [(18)F]fluorodopa Ki values and age in men but not in women. CONCLUSIONS: The results further substantiate sex differences in striatal dopaminergic function in humans. This finding may be associated with sex differences in vulnerability and clinical course of neuropsychiatric disorders with dopaminergic dysregulation, e.g., schizophrenia, alcohol dependence, and Parkinson's disease.     

Greater availability of brain dopamine transporters in major depression shown by [99m Tc]TRODAT-1 SPECT imaging

OBJECTIVE: Studies of laboratory animals have shown that administration of antidepressants of all pharmacological classes produces changes in dopamine transporter binding affinity. These observations suggest that dopamine transporter function may play a critical role in the pathophysiology of depression. The present study was an examination of the availability of brain dopamine transporter sites in patients with major depression and in healthy comparison subjects. METHOD: Single photon emission computed tomographic (SPECT) brain scans were acquired for 15 drug-free depressed patients and 46 age- and gender-matched healthy comparison subjects by using [(99m)Tc]TRODAT-1, a selective dopamine transporter imaging agent. Specific regions of interest in the basal ganglia and supratentorial areas of the brain were examined. Specific uptake values of dopamine transporter [(99m)Tc]TRODAT-1 binding affinity were calculated from the SPECT scan data, and the values for the patients and healthy subjects were compared. RESULTS: The specific uptake values of [(99m)Tc]TRODAT-1 binding were significantly higher in the right anterior putamen (23%), right posterior putamen (36%), left posterior putamen (18%), and left caudate nucleus (12%) of the patients than in the comparison subjects. These differences persisted when the data were further analyzed according to gender and age. CONCLUSIONS: Dopamine transporter affinity may be higher than normal in the basal ganglia of depressed patients. These findings suggest that dopamine function may be altered in depression and may also be a mechanism of antidepressant activity.     

No evidence for attenuated stress-induced extrastriatal dopamine signaling in psychotic disorder

Stress is an important risk factor in the etiology of psychotic disorder. Preclinical work has shown that stress primarily increases dopamine (DA) transmission in the frontal cortex. Given that DA-mediated hypofrontality is hypothesized to be a cardinal feature of psychotic disorder, stress-related extrastriatal DA release may be altered in psychotic disorder. Here we quantified for the first time stress-induced extrastriatal DA release and the spatial extent of extrastriatal DA release in individuals with non-affective psychotic disorder (NAPD). Twelve healthy volunteers (HV) and 12 matched drug-free NAPD patients underwent a single infusion [¹⁸F]fallypride positron emission tomography scan during which they completed the control and stress condition of the Montreal Imaging Stress Task. HV and NAPD did not differ in stress-induced [¹⁸F]fallypride displacement and the spatial extent of stress-induced [¹⁸F]fallypride displacement in medial prefrontal cortex (mPFC) and temporal cortex (TC). In the whole sample, the spatial extent of stress-induced radioligand displacement in right ventro-mPFC, but not dorso-mPFC or TC, was positively associated with task-induced subjective stress. Psychotic symptoms during the scan or negative, positive and general subscales of the Positive and Negative Syndrome Scale were not associated with stress-induced [¹⁸F]fallypride displacement nor the spatial extent of stress-induced [¹⁸F]fallypride displacement in NAPD. Our results do not offer evidence for altered stress-induced extrastriatal DA signaling in NAPD, nor altered functional relevance. The implications of these findings for the role of the DA system in NAPD and stress processing are discussed.     

Smoking-induced ventral striatum dopamine release

OBJECTIVE: Substantial evidence from animal models demonstrates that dopamine release in the ventral striatum underlies the reinforcing properties of nicotine. The authors used [(11)C]raclopride bolus-plus-continuous-infusion positron emission tomography (PET) to determine smoking-induced ventral striatum dopamine release in humans. METHOD: Twenty nicotine-dependent smokers (who smoked > or =15 cigarettes/day) underwent a [(11)C]raclopride bolus-plus-continuous-infusion PET session. During the session, subjects had a 10-minute break outside the PET apparatus during which 10 subjects smoked a cigarette and 10 did not smoke (as a control condition). RESULTS: The group that smoked had greater reductions in [(11)C]raclopride binding potential in ventral striatum regions of interest than the group that did not smoke, particularly in the left ventral caudate/nucleus accumbens and left ventral putamen (range for smoking group=-25.9% to -36.6% reduction). Significant correlations were found between change from before to after the smoking break in craving ratings and change from before to after the break in binding potential for these two regions. CONCLUSIONS: Nicotine-dependent subjects who smoked during a break in PET scanning had greater reductions in [(11)C]raclopride binding potential (an indirect measure of dopamine release) than nicotine-dependent subjects who did not smoke. The magnitude of binding potential changes was comparable to that found in studies that used similar methods to examine the effects of other addictive drugs.     

Objective PET study of glucose metabolism asymmetries in children with epilepsy: Implications for normal brain development

Clinical interpretation of cerebral positron emission tomography with 2‐deoxy‐2[F‐18]fluoro‐d ‐glucose (FDG‐PET) images often relies on evaluation of regional asymmetries. This study was designed to establish age‐related variations in regional cortical glucose metabolism asymmetries in the developing human brain. FDG‐PET scans of 58 children (age: 1–18 years) were selected from a large single‐center pediatric PET database. All children had a history of epilepsy, normal MRI, and normal pattern of glucose metabolism on visual evaluation. PET images were analyzed objectively by statistical parametric mapping with the use of age‐specific FDG‐PET templates. Regional FDG uptake was measured in 35 cortical regions in both hemispheres using an automated anatomical labeling atlas, and left/right ratios were correlated with age, gender, and epilepsy variables. Cortical glucose metabolism was mostly symmetric in young children and became increasingly asymmetric in older subjects. Specifically, several frontal cortical regions showed an age‐related increase of left > right asymmetries (mean: up to 10%), while right > left asymmetries emerged in posterior cortex (including portions of the occipital, parietal, and temporal lobe) in older children (up to 9%). Similar trends were seen in a subgroup of 39 children with known right‐handedness. Age‐related correlations of regional metabolic asymmetries showed no robust gender differences and were not affected by epilepsy variables. These data demonstrate a region‐specific emergence of cortical metabolic asymmetries between age 1–18 years, with left > right asymmetry in frontal and right > left asymmetry in posterior regions. The findings can facilitate correct interpretation of cortical regional asymmetries on pediatric FDG‐PET images across a wide age range.     

Assessment of neuroinflammation and microglial activation in Alzheimer's disease with radiolabelled PK11195 and single photon emission computed tomography. A pilot study

OBJECTIVES: Inflammation contributes to degeneration in Alzheimer's disease (AD), not simply as a secondary phenomenon, but primarily as a significant source of pathology. [(123)I]iodo-PK11195 is a single photon emission computed tomography (SPECT) ligand for the peripheral benzodiazepine receptor, the latter being expressed on microglia (brain resident macrophages) and upregulated under inflammatory circumstances. The objectives were to assess AD inflammation by detecting [(123)I]iodo-PK11195 uptake changes and investigate how uptake values relate with perfusion SPECT and neuropsychological findings. METHODS: Ten AD and 9 control subjects were included. [(123)I]iodo-PK11195 SPECT images were realigned into stereotactic space where binding indices, normalized on cerebellar uptake, were calculated. RESULTS: The mean [(123)I]iodo-PK11195 uptake was increased in AD patients compared with controls in nearly all neocortical regions; however, statistical significance was only reached in the frontal and right mesotemporal regions. Significant correlations were found between regional increased [(123)I]iodo-PK11195 uptake and cognitive deficits. CONCLUSIONS: [(123)I]iodo-PK11195 is a cellular disease activity marker and allows in vivo assessment of microglial inflammation in AD.     

Regional cerebral metabolism associated with anxiety symptoms in affective disorder patients.

BACKGROUND: We studied the relationship between regional cerebral metabolism and the severity of anxiety in mood disorder patients, controlling for depression severity. METHODS: Fifty-two medication-free patients with unipolar or bipolar illness underwent positron emission tomography with [(18)F]-fluorodeoxyglucose. Hamilton Depression Rating Scale and Spielberger Anxiety-State Scale scores were obtained for the week of the scan. Analyses were performed on globally normalized images and were corrected for multiple comparisons. RESULTS: After covarying for depression scores, age, and gender, Spielberger Anxiety-State Scale scores correlated directly with regional cerebral metabolism in the right parahippocampal and left anterior cingulate regions, and inversely with metabolism in the cerebellum, left fusiform, left superior temporal, left angular gyrus, and left insula. In contrast, covarying for anxiety scores, age, and gender, Hamilton Depression Rating Scale scores correlated directly with regional cerebral metabolism in the bilateral medial frontal, right anterior cingulate, and right dorsolateral prefrontal cortices. CONCLUSIONS: Comorbid anxiety symptoms are associated with specific cerebral metabolic correlates that partially overlap with those in the primary anxiety disorders and differ from those associated with depression severity.     

Positron emission tomography imaging of amphetamine‐induced dopamine release in the human cortex: A comparative evaluation of the high affinity dopamine D2/3 radiotracers [11C]FLB 457 and [11C]fallypride

The use of PET and SPECT endogenous competition binding techniques has contributed to the understanding of the role of dopamine in several neuropsychiatric disorders. An important limitation of these imaging studies is the fact that measurements of acute changes in synaptic dopamine have been restricted to the striatum. The ligands previously used, such as [¹¹C]raclopride and [¹²³I]IBZM, do not provide sufficient signal to noise ratio to quantify D₂ receptors in extrastriatal areas, such as cortex, where the concentration of D₂ receptors is much lower than in the striatum. Given the importance of cortical DA function in cognition, a method to measure cortical dopamine function in humans would be highly desirable. The goal of this study was to compare the ability of two high affinity DA D₂ radioligands [¹¹C]FLB 457 and [¹¹C]fallypride to measure amphetamine‐induced changes in DA transmission in the human cortex. D₂ receptor availability was measured in the cortical regions of interest with PET in 12 healthy volunteers under control and postamphetamine conditions (0.5 mg kg^?1, oral), using both [¹¹C]FLB 457 and [¹¹C]fallypride (four scans per subjects). Kinetic modeling with an arterial input function was used to derive the binding potential (BP_ND) in eight cortical regions. Under controlled conditions, [¹¹C]FLB 457 BP_ND was 30–70% higher compared with [¹¹C]fallypride BP_ND in cortical regions. Amphetamine induced DA release led to a significant decrease in [¹¹C]FLB 457 BP_ND in five out the eight cortical regions evaluated. In contrast, no significant decrease in [¹¹C]fallypride BP_ND was detected in cortex following amphetamine. The difference between [¹¹C]FLB 457 and [¹¹C]fallypride ability to detect changes in the cortical D₂ receptor availability following amphetamine is related to the higher signal to noise ratio provided by [¹¹C]FLB 457. These findings suggest that [¹¹C]FLB 457 is superior to [¹¹C]fallypride for measurement of changes in cortical synaptic dopamine. Synapse 63:447–461, 2009. © 2009 Wiley‐Liss, Inc.     

Enhanced resting activity of the oral somatosensory cortex in obese subjects

The cerebral mechanisms underlying excess food intake in obese subjects are poorly understood. We used PET and 2-deoxy-2[18F]fluoro-D-glucose to assess differences in regional brain metabolism between obese and lean subjects at rest. Brain metabolic images were analyzed using statistical parameter maps. We found that obese subjects have significantly higher metabolic activity in the bilateral parietal somatosensory cortex in the regions where sensation to the mouth, lips and tongue are located. The enhanced activity in somatosensory regions involved with sensory processing of food in the obese subjects could make them more sensitive to the rewarding properties of food related to palatability and could be one of the variables contributing to their excess food consumption.     

PET study of [(18)F]6-fluoro-L-dopa uptake in neuroleptic- and mood-stabilizer-naive first-episode nonpsychotic mania: effects of treatment with divalproex sodium

OBJECTIVE: Although dopaminergic hyperactivity has been implicated in mania, the precise location in the brain of the abnormality is unclear. This study assessed presynaptic dopamine function in neuroleptic- and mood-stabilizer-naive nonpsychotic first-episode manic patients before and after treatment with divalproex sodium by measuring [(18)F]6-fluoro-L-dopa ([(18)F]DOPA) uptake in the striatum with positron emission tomography (PET). METHOD: Thirteen patients with DSM-IV bipolar I disorder, manic episode, and 13 healthy comparison subjects underwent [(18)F]DOPA PET scans. Ten of the 13 patients had repeat PET scans 2-6 weeks after beginning treatment with divalproex sodium monotherapy. [(18)F]DOPA uptake rate constants (K(i) values) in the striatum were calculated by using graphical analysis with activity from the occipital cortex as the input function. RESULTS: No significant differences in [(18)F]DOPA uptake rate constants in the striatum were found between the manic patients and the comparison subjects. After treatment with divalproex sodium, [(18)F]DOPA rate constants were significantly reduced in the patients and were lower in the patients than in the comparison subjects. CONCLUSIONS: Although presynaptic dopamine function as reflected by [(18)F]DOPA uptake is not altered in mania, presynaptic dopamine function in manic patients was lower after treatment with divalproex sodium.     

Extraversion and striatal dopaminergic receptor availability in young adults: an [18F]fallypride PET study

Extraversion is a core personality trait associated with individual differences in reward sensitivity and has been linked to the dopaminergic brain system. We investigated whether dopaminergic receptor availability in the striatum was directly associated with individual differences in extraversion using the high-affinity radiotracer [1?F]fallypride and PET. Seventeen healthy male and female participants completed an [1?F]fallypride PET scan at rest. Extraversion was assessed using the revised Eysenck Personality Questionnaire. Dopamine receptor availability in predefined striatal regions of interest was assessed as [1?F]fallypride binding potential using a reference tissue model for [1?F]fallypride. Both region of interest and voxel-based whole-brain analyses showed that extraversion was significantly correlated with dopaminergic receptor availability in the striatum bilaterally. This finding contributes to our understanding of the dopaminergic neural mechanisms underlying individual differences in extraversion.