Effect of amphetamine on extrastriatal D2 dopamine receptor binding in the primate brain: a PET study

[(11)C]raclopride binding to D2 dopamine receptors in the striatum is sensitive to drug-induced changes of endogenous dopamine concentration. We recently developed the new radioligand [(11)C]FLB 457, which is suitable for positron emission tomography (PET) studies of extrastriatal D2 dopamine receptors. The purpose of this PET study was to examine the effect of amphetamine on [(11)C]FLB 457 binding in extrastriatal regions. Each of three cynomolgus monkeys was examined at baseline conditions, 15 min and 3 h after I.V. injection of amphetamine (2 mg/kg). The effect of amphetamine was calculated from the ratio of specific [(11)C]FLB 457 binding to the binding in the cerebellum, a region which was used as reference for free and nonspecific binding in the brain. The changes of the ratio in the striatum, the thalamus, and the neocortex were between -1.2% and -15.5% at 15 min and -2.1% and -16.3% at 3 h, respectively, after amphetamine administration. The reductions of the binding ratios in the extrastriatal regions are similar to those reported for [(11)C]raclopride binding in the striatum. These data in a limited series of monkeys suggest that [(11)C]FLB 457 binding to D2 dopamine receptors in extrastriatal regions is sensitive to changes in the concentration of endogenous dopamine.     

Effect of endogenous dopamine on endogenous dopamine on extrastriated [11C]FLB 457 binding measured by PET

Central dopaminergic systems are known to be implicated in the pathophysiology of schizophrenia and recent in vivo dopamine receptor imaging studies have focused on the measurement of extrastriatal dopamine receptor. However, there are only a limited number of ligands that can measure the low-density D2 receptor in extrastriatal regions and their sensitivity to endogenous dopamine in extrastriatal regions has not yet been fully examined. In this study, the effect of endogenous dopamine on the extrastriatal binding of [(11)C]FLB 457 was examined in the rhesus monkey after facilitation with 1 mg/kg of methamphetamine (MAP) and was compared with the effect on the striatal binding of [(11)C]raclopride. The indices of receptor binding were obtained by four methods using cerebellum as a reference region. The bindings of [(11)C]FLB 457 in the frontal cortex, temporal cortex, and thalamus were not significantly changed after MAP treatment, while the striatal binding of [(11)C]raclopride was decreased by more than 20%. These results suggest that [(11)C]FLB 457 is not sensitive to endogenous dopamine in the extrastriatal regions of rhesus monkeys, despite a sufficient dose of MAP to decrease the binding of [(11)C]raclopride in the striatum.     

Quantification of PET studies with the very high-affinity dopamine D2/D3 receptor ligand [11C]FLB 457: re-evaluation of the validity of using a cerebellar reference region.

The very high-affinity position emission tomography (PET) radioligand [(11)C]FLB 457 was developed in order to study extrastriatal tissues, where the density of dopamine D(2)/D(3) receptors is one to two orders of magnitude lower than in the striatum. The present study investigated the validity of using the cerebellum as a reference region. Ten healthy volunteers underwent a 90-min dynamic PET study after the bolus injection of [(11)C]FLB 457. The total volume of distribution (VD(t)) was estimated for the thalamus, hippocampus, frontal cortex, and cerebellum using a two-tissue compartmental model with a metabolite-corrected arterial plasma input function. VD(t) was sensitive to co-injected stable FLB 457 in all regions, including the cerebellum. Ex vivo saturation studies were also conducted in 17 rats where the dose of stable ligand was varied over five orders of magnitude. Specific binding was estimated to account for more than half of the rat cerebellar uptake of [(11)C]FLB 457, questioning the latter as an estimate of nonspecific binding in human PET studies. To check whether the cerebellum is a reference region, the binding potential (BP) was calculated either from the VD(t) ratio or using the simplified reference tissue model (SRTM). A non-negligible density of D(2)/D(3) receptors in the cerebellum was shown to lead to underestimation of BP as well as erroneous estimation of differential occupancies. Binging potential estimates from the SRTM were found to be sensitive to changes in cerebral blood flow, providing further evidence for caution in the use of the cerebellum as a reference region in measures of [(11)C]FLB 457 binding.     

Reference region modeling approaches for amphetamine challenge studies with [11C]FLB 457 and PET

Detecting fluctuations in synaptic dopamine levels in extrastriatal brain regions with [¹¹C]FLB 457 and positron emission tomography (PET) is a valuable tool for studying dopaminergic dysfunction in psychiatric disorders. The evaluation of reference region modeling approaches would eliminate the need to obtain arterial input function data. Our goal was to explore the use of reference region models to estimate amphetamine-induced changes in [¹¹C]FLB 457 dopamine D2/D3 binding. Six healthy tobacco smokers were imaged with [¹¹C]FLB 457 at baseline and at 3 hours after amphetamine (0.4  to 0.5 mg/kg, per os) administration. Simplified reference tissue models, SRTM and SRTM2, were evaluated against the 2-tissue compartmental model (2TC) to estimate [¹¹C]FLB 457 binding in extrastriatal regions of interest (ROIs), using the cerebellum as a reference region. No changes in distribution volume were observed in the cerebellum between scan conditions. SRTM and SRTM2 underestimated binding, compared with 2TC, in ROIs by 26% and 9%, respectively, with consistent bias between the baseline and postamphetamine scans. Postamphetamine, [¹¹C]FLB 457 binding significantly decreased across several brain regions as measured with SRTM and SRTM2; no significant change was detected with 2TC. These data support the sensitivity of [¹¹C]FLB 457 for measuring amphetamine-induced dopamine release in extrastriatal regions with SRTM and SRTM2.     

Dopamine D2/D3 receptor binding in the anterior cingulate cortex and executive functioning

The objective was to investigate the association between extrastriatal dopamine D(2)/D(3) receptor binding and performance on the Wisconsin Card Sorting Test (WCST), a measure of executive functioning. Thirty-two healthy volunteers performed the WCST and underwent positron emission tomography and a high-affinity D(2)/D(3) receptor tracer, [(11)C]FLB 457. All WCST error parameters, in particular nonperseverative errors, correlated positively with [(11)C]FLB 457 binding in the cognitive division of the right anterior cingulate cortex. An independent voxel-based receptor parametric mapping analysis confirmed these findings. The results indicate that executive functioning in healthy volunteers is modulated by D(2)/D(3) receptors in the anterior cingulate cortex.     

Quantification of [11C]FLB 457 binding to extrastriatal dopamine receptors in the human brain.

Positron emission tomography (PET) has hitherto been used to examine D2 dopamine receptor binding in the striatum, a region with a high density of receptors. Research has been hampered by the lack of suitable radioligands for detection of the low-density D2 dopamine receptor populations in the limbic and cortical dopamine systems that are implicated in the pathophysiology of schizophrenia. [11C]FLB 457 is a new radioligand with the very high affinity of 20 pmol/L (K(i)) for the D2 and D3 dopamine receptor subtypes. This study in eight healthy subjects was designed to evaluate the suitability of [11C]FLB 457 for quantification of extrastriatal D2/D3 dopamine receptors. PET-data were acquired in the three-dimensional mode and the arterial input function was corrected for labeled metabolites. The standard three-compartment model and four derived approaches were applied to calculate and compare the binding potentials. Besides the striatum, conspicuous radioactivity was found in extrastriatal regions such as the thalamus, the anterior cinguli, and the temporal and frontal cortices. The time activity curves could be described by the three compartment model. The different approaches gave similar binding potential values and the rank order between regions was consistent with that found in vitro. The short time of a PET measurement using [11C]FLB 457 (63 minutes) seemed not to be sufficient for reliable determination of the high binding potential in the striatum. These results are of principal importance because they show the potential for PET quantification of minute receptor populations in the human brain.     

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.     

No effect of dopamine depletion on the binding of the high‐affinity D2/3 radiotracer [11C]FLB 457 in the human cortex

The use of PET and SPECT endogenous competition‐binding techniques has contributed to the understanding of the role of dopamine (DA) in several neuropsychiatric disorders. An important limitation of these imaging studies is the fact that measurements of changes in synaptic DA 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 that in the striatum. Recently, we published a comparison study of 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. Our findings support the use of [¹¹C]FLB 457 to measure changes in cortical synaptic DA induced by amphetamine. The goal of this study is to examine the effects of DA depletion with α‐methyl‐para‐tyrosine (α‐MPT) on [¹¹C]FLB 457 binding in the cortex. Six healthy volunteers underwent two PET scans, first under control conditions and subsequently after DA depletion. The simplified reference tissue model as well as kinetic modeling with an arterial input function was used to derive the binding potential (BP_ND) in seven cortical regions. We found no effect of DA depletion with α‐MPT on [¹¹C]FLB 457 binding in any of the regions examined. In contrast to the measurement of DA release, the combination of low D₂ receptor density and low basal DA levels in the cortex greatly reduce the power to detect alterations in [¹¹C]FLB 457 binding secondary to DA depletion. Synapse 64:879–885, 2010. © 2010 Wiley‐Liss, Inc.     

Extrastriatal dopamine D2 and D3 receptors in early and advanced Parkinson's disease

OBJECTIVE: To investigate whether dopamine D2 and D3 receptor subtypes (D2/3Rs) outside the caudate-putamen are affected in PD. BACKGROUND: Alterations in striatal D2-like dopamine receptors in PD have been extensively demonstrated using PET, but there are no studies focusing on extrastriatal D2/3Rs. METHODS: Fourteen unmedicated patients with idiopathic early PD with predominantly left-sided symptoms, 14 levodopa-medicated patients with advanced PD, and 20 normal age-matched controls were examined using PET. PET scanning was performed with a novel high-affinity D2/3R radioligand ([11C]FLB 457) and a PET scanner in three-dimensional mode. RESULTS: In advanced PD, the binding potential of [11C]FLB 457 in the dorsolateral prefrontal cortex was decreased by 40% (p < 0.01), in the anterior cingulate cortex by 20% (p < 0.01), and in the medial thalamus by 17% (p < 0.05) compared with healthy controls. In early PD, the extrastriatal [11C]FLB 457 binding potentials were not significantly different compared with the control group. However, the binding potential in the anterior cingulate cortex (29%; p < 0. 05) was higher in early PD compared with advanced PD. CONCLUSIONS: These results imply that the D2/3 receptor subtypes outside the striatum are affected in advanced PD but not in the early stages of the disease, and that this receptor decline is present in the anterior cingulate cortex, the dorsolateral prefrontal cortex, and the thalamus.     

No support for regional selectivity in clozapine-treated patients: a PET study with [(11)C]raclopride and [(11)C]FLB 457

OBJECTIVE: The authors' goal was to test the hypothesis of extrastriatal D(2) receptor selectivity as the mechanism of action of clozapine. METHOD: Positron emission tomography (PET) was used to examine extrastriatal as well as striatal dopamine D(2) receptor occupancy in four patients treated with clozapine and three patients treated with haloperidol. The reference radioligand [(11)C]raclopride was used for determination of D(2) receptor occupancy in the striatum. The radioligand [(11)C]FLB 457 was chosen for determination of D(2) receptor occupancy in the thalamus, the temporal cortex, and the frontal cortex. RESULTS: In patients treated with haloperidol the D(2) receptor occupancy was high in all examined brain regions. In clozapine-treated patients the D(2) receptor occupancy was relatively low in both the striatum and the extrastriatal regions. CONCLUSIONS: The results from the present study give no support for the hypothesis of regional selectivity as the mechanism of action for clozapine.     

Prefrontal dopaminergic receptor abnormalities and executive functions in Parkinson's disease

The main pattern of cognitive impairments seen in early to moderate stages of Parkinson's disease (PD) includes deficits of executive functions. These nonmotor complications have a significant impact on the quality of life and day‐to‐day activities of PD patients and are not effectively managed by current therapies, a problem which is almost certainly due to the fact that the disease extends beyond the nigrostriatal system. To investigate the role of extrastriatal dopamine in executive function in PD, PD patients and a control group were studied with positron‐emission‐tomography using a high‐affinity dopamine D2/D3 receptor tracer, [¹¹C]FLB‐457. All participants were scanned twice while performing an executive task and a control task. Patients were off medication for at least 12 h. The imaging analysis revealed that parkinsonian patients had lower [¹¹C]FLB‐457 binding than control group independently of task conditions across different brain regions. Cognitive assessment measures were positively correlated with [¹¹C]FLB‐457 binding in the bilateral dorsolateral prefrontal cortex and anterior cingulate cortex only in control group, but not in PD patients. Within the control group, during the executive task (as compared to control task), there was evidence of reduced [¹¹C]FLB‐457 binding (indicative of increased dopamine release) in the right orbitofrontal cortex. In contrast, PD patients did not show any reduction in binding during the executive task (as compared with control task). These findings suggest that PD patients present significant abnormalities in extrastriatal dopamine associated with executive processing. These observations provide important insights on the pathophysiology of cognitive dysfunction in PD. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.     

Adverse subjective experience with antipsychotics and its relationship to striatal and extrastriatal D2 receptors: a PET study in schizophrenia

OBJECTIVES: Antipsychotic medications improve psychosis but often induce a state of dysphoria in patients. Blockade of the dopamine D(2) receptors, which is thought to mediate their efficacy, has also been implicated in producing this adverse subjective experience. The authors present the first double-blind controlled study to examine the relationship between striatal and extrastriatal dopamine D(2) receptor binding potential and occupancy values and adverse subjective experience. METHOD: Patients with recent-onset psychosis (N=12) were randomly assigned to low or high doses of olanzapine or risperidone. Subjective experiences, motor side effects, and striatal and extrastriatal dopamine D(2) receptors (determined with [(11)C]raclopride and [(11)C]FLB 457 PET scans, respectively) were evaluated after 2 weeks of continuous antipsychotic treatment. RESULTS: Higher dopamine D(2) receptor occupancy and binding potentials in the striatal (dorsal and ventral), temporal, and insular regions were associated with subjective experience. The finding was confirmed with two convergent methods of analysis (region-of-interest and voxel-based statistics), and the same relationship was observed using two different dopamine receptor measures (observed binding potential values and age- and sex-corrected occupancy values). CONCLUSIONS: Higher D(2) receptor occupancy is associated with negative subjective experience in patients taking risperidone or olanzapine. These negative subjective effects may be related to the high discontinuation rates seen in usual practice. Understanding the neurobiological mechanism of these negative subjective experiences and developing antipsychotics with novel (i.e., non D(2)) mechanisms may be critical in improving the treatment of psychosis.     

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.     

Extrastriatal dopamine D<Subscript>2</Subscript> receptors in Parkinson's disease: a longitudinal study

Most antiparkinsonian drugs are known to act through central dopamine D(2) receptor agonism. A previous longitudinal positron emission tomography (PET) study has indicated that, in the striatum of Parkinson's disease (PD) patients, dopamine D(2) receptor binding declines at a relatively fast annual rate of 2-4% (compared to the rate of <1%/year in healthy individuals). In the present study, the examination of longitudinal changes in D(2) receptors was extended to extrastriatal brain regions in PD. Eight early PD patients were examined twice with PET, approximately 3 years apart, using a high-affinity extrastriatal D(2)/D(3) receptor tracer, [(11)C]FLB 457. Both the MRI-referenced region-of-interest method and the voxel-based statistical analysis method were used independently in the analysis. Regional D(2)-like availabilities (binding potentials) in the left dorsolateral prefrontal cortex, the left temporal cortex and the left and right medial thalami were significantly decreased at the second examination by 20-37% (corresponding to an annual decline of 6-11%). Thus, the annual loss of extrastriatal D(2) availability in PD is up to three times faster than the rate previously reported in the putamen. Our longitudinal study shows first evidence concerning cortical D(2) receptor loss in the progression of PD, although it is not possible to distinguish between the effects of the therapy and the disease.     

Failure to detect amphetamine‐induced dopamine release in the cortex with [11C]FLB 457 positron emission tomography (PET): Methodological considerations

Studies in nonhuman primates and humans have demonstrated that amphetamine‐induced dopamine release in the cortex can be measured with [¹¹C]FLB 457 and PET imaging. This technique has been successfully used in recent clinical studies to show decreased dopamine transmission in the prefrontal cortex in schizophrenia and alcohol dependence. Here, we present data from a cohort of twelve healthy controls in whom an oral amphetamine challenge (0.5 mg kg^?1) did not lead to a significant reduction in [¹¹C]FLB 457 BP_ND (i.e., binding potential relative to non‐displaceable uptake). Two factors that likely contributed to the inability to displace [¹¹C]FLB 457 BP_ND in this cohort relative to successful cohorts are: (a) the acquisition of the baseline and post‐amphetamine scans on different days as opposed to the same day and (b) the initiation of the post‐amphetamine [¹¹C]FLB 457 scan at ～5 hours as opposed to ～3 hours following oral amphetamine. Furthermore, we show [¹¹C]FLB 457 reproducibility data from a legacy dataset to support greater variability in cortical BP_ND when the test and retest scans are acquired on different days as compared to the same day. These results highlight the methodological challenges that continue to plague the field with respect to imaging dopamine release in the cortex.     

Evaluation of dopamine D₂/₃ specific binding in the cerebellum for the positron emission tomography radiotracer [¹¹C]FLB 457: implications for measuring cortical dopamine release

In a recent positron emission tomography (PET) study, we demonstrated the ability to measure amphetamine‐induced dopamine (DA) release in the human cortex with the DA D_2/3 radioligand [¹¹C]FLB 457. As previous studies in animals have shown that a relatively high fraction of the [¹¹C]FLB 457 signal in the cerebellum represents specific binding to D_2/3 receptors, there was concern that the use of the cerebellum as a measure of nonspecific binding (i.e., reference region) to derive [¹¹C]FLB 457 binding potential (BP) (BP_ND) would bias cortical DA release measurements. Thus, we evaluated the fractional contribution of specific binding to D_2/3 receptors in the human cerebellum for [¹¹C]FLB 457. Six healthy human subjects (5M/1F) were studied twice with [¹¹C]FLB 457, once at baseline and again following a single oral dose of 15 mg of aripiprazole, a D_2/3 partial agonist. [¹¹C]FLB 457 distribution volume (V_T) was estimated using kinetic analysis in the cortical regions of interest and potential reference regions. The change in [¹¹C]FLB 457 V_T following aripiprazole ranged from ?33 to ?42% in the cortical regions of interest (ROIs). The aripiprazole‐induced change in [¹¹C]FLB 457 V_T in three potential reference regions suggests significant specific binding the cerebellum (CER, –17 ± 12%), but not pons (PON, –10 ± 10%) and centrum semiovale (CESVL, –3 ± 12%). Nevertheless, a reanalysis of the published [¹¹C]FLB 457 test–retest and amphetamine studies suggests that the use of the PON V_T and CESVL V_T as an estimate of nonspecific binding to derive [¹¹C]FLB 457 BP_ND in DA release studies is unlikely to be successful because it leads to less reproducible outcome measures, which in turn diminishes the ability to measure DA release in the cortex. D_2/3 blocking studies with aripiprazole and [¹¹C]FLB 457 suggest specific binding to D_2/3 receptors in the cerebellum. These data also suggest that the contribution of specific binding to D_2/3 receptors in the cerebellum is lower than that in the cortical ROIs and that CER V_T is mostly representative of nonspecific binding. Nevertheless, caution is advised when using reference tissue methods that rely solely on the cerebellum signal as an input function to quantify [¹¹C]FLB 457 BP_ND. Synapse, 2011. © 2011 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.     

Occupancy of dopamine D2/3 receptors in rat brain by endogenous dopamine measured with the agonist positron emission tomography radioligand [11C]MNPA

Estimates of dopamine D(2/3) receptor occupancy by endogenous dopamine using positron emission tomography (PET) in animals have varied almost threefold. This variability may have been caused by incomplete depletion of dopamine or by the use of antagonist radioligands, which appear less sensitive than agonist radioligands to changes in endogenous dopamine. PET scans were performed in rats with the agonist PET radioligand [(11)C]MNPA ([O-methyl-(11)C]2-methoxy-N-propylnorapomorphine). [(11)C]MNPA was injected as a bolus plus constant infusion to achieve steady-state concentration in the body and equilibrium receptor binding in the brain. Radioligand binding was compared at baseline and after treatment with reserpine plus alpha-methyl-para-tyrosine, which cause approximately 95% depletion of endogenous dopamine. Depletion of dopamine increased radioligand binding in striatum but had little effect in cerebellum. Striatal [(11)C]MNPA binding potential was 0.93 +/- 0.12 at baseline and increased to 1.99 +/- 0.25 after dopamine depletion. Occupancy of D(2/3) receptors by endogenous dopamine at baseline was calculated to be approximately 53%. Striatal binding was displaceable with raclopride, but not with BP 897 (a selective D(3) compound), thus confirming the D(2) receptor specificity of [(11)C]MNPA binding. Radioactivity extracted from rat brain contained only 8-10% radiometabolites and was insignificantly altered by administration of reserpine plus alpha-methyl-para-tyrosine. Hence, dopamine depletion did not increase the PET measurements via an effect on radiotracer metabolism. Our in vivo estimate of dopamine's occupancy of D(2/3) receptors at baseline is higher than that previously reported using antagonist radioligands and PET, but is similar to that reported using agonist radioligands and ex vivo measurements.     

Striatal dopamine D2/D3 receptor availability correlates with individual response characteristics to pain

We studied in healthy humans the contribution of cerebral dopamine D2/D3 receptors to individual differences in response characteristics to painful stimulation. Positron emission tomography was used to measure the dopamine D2/D3 binding potential (D2/D3 BP) with [(11)C]raclopride in the striatum (n = 8) and with [(11)C]FLB 457 in the extrastriatal regions (n = 11). Sensitivity to cutaneous heat pain was assessed by a traditional threshold method and by an analysis based on the signal detection theory which allows the separation of an individual subject's discriminative capacity from the response criterion, i.e. the area under the receiver operating characteristic curve provides a measure of the sensory discriminability (sensory factor) and the response criterion gives an estimate of the subject's response bias or attitude (nonsensory factor). The pain threshold and response criterion were inversely correlated with the D2/D3 BP in the right putamen, whereas the discriminative capacity was not significantly correlated with the D2/D3 BP in any brain region. The correlation of the D2/D3 BP in the putamen with the pain threshold and the subject's response criterion may rather be explained by a dopaminergic effect on nonsensory factors determining the subject's attitude towards pain than by a dopaminergic effect on the subject's discriminative capacity. Alternatively, striatal dopamine D2/D3 receptors could control a modulatory pathway producing a parallel shift in the stimulus-response function for sensory signals, mimicking a change in the subject's response criterion.     

Low dopamine d(2) receptor binding in subregions of the thalamus in schizophrenia

OBJECTIVE: Several structural and functional brain imaging studies have pointed to a disturbance of thalamic subnuclei in patients with schizophrenia. The dopamine hypothesis of schizophrenia has, however, not been thoroughly examined in terms of this complex structure, which has connections with most brain regions of central interest in schizophrenia research. The aim of the present study was to examine dopamine D(2) receptor binding in subregions of the thalamus in patients with schizophrenia. METHOD: The authors used positron emission tomography and the radioligand [(11)C]FLB457 to examine dopamine D(2) receptor binding in thalamic subregions of 10 drug-naive patients with schizophrenia. Binding potential was calculated by the reference tissue method and used as an index for dopamine D(2) receptor binding. Comparisons were made with 19 healthy subjects. Subregions of interest were defined on individual magnetic resonance images using a percentage-based operational approach. Clinical symptoms were rated by using the Brief Psychiatric Rating Scale (BPRS). RESULTS: The [(11)C]FLB457 binding potential was lower in the central medial and posterior subregions of the thalamus in patients with schizophrenia. At a functional level, there was a significant negative correlation between binding potential and BPRS positive symptom scores. CONCLUSIONS: The subregions with low D(2) receptor binding comprise primarily the dorsomedial nucleus and pulvinar, two important components in circuitries previously suggested in the pathophysiology of schizophrenia. Aberrant dopaminergic neurotransmission in thalamic subregions might be a mechanism underlying positive symptoms in schizophrenia.