Thinking Outside a Less Intact Box: Thalamic Dopamine D2 Receptor Densities Are Negatively Related to Psychometric Creativity in Healthy Individuals

Several lines of evidence support that dopaminergic neurotransmission plays a role in creative thought and behavior. Here, we investigated the relationship between creative ability and dopamine D2 receptor expression in healthy individuals, with a focus on regions where aberrations in dopaminergic function have previously been associated with psychotic symptoms and a genetic liability to schizophrenia. Scores on divergent thinking tests (Inventiveness battery, Berliner Intelligenz Struktur Test) were correlated with regional D2 receptor densities, as measured by Positron Emission Tomography, and the radioligands [11C]raclopride and [11C]FLB 457. The results show a negative correlation between divergent thinking scores and D2 density in the thalamus, also when controlling for age and general cognitive ability. Hence, the results demonstrate that the D2 receptor system, and specifically thalamic function, is important for creative performance, and may be one crucial link between creativity and psychopathology. We suggest that decreased D2 receptor densities in the thalamus lower thalamic gating thresholds, thus increasing thalamocortical information flow. In healthy individuals, who do not suffer from the detrimental effects of psychiatric disease, this may increase performance on divergent thinking tests. In combination with the cognitive functions of higher order cortical networks, this could constitute a basis for the generative and selective processes that underlie real life creativity

Binding of Pramipexole to Extrastriatal Dopamine D2/D3 Receptors in the Human Brain: A Positron Emission Tomography Study Using 11C-FLB 457

The purpose of this study was to determine the binding sites of pramipexole in extrastriatal dopaminergic regions because its antidepressive effects have been speculated to occur by activating the dopamine D2 receptor subfamily in extrastriatal areas. Dynamic positron emission tomography (PET) scanning using 11C-FLB 457 for quantification of D2/D3 receptor subtype was performed on 15 healthy volunteers. Each subject underwent two PET scans before and after receiving a single dose of pramipexole (0, 0.125, or 0.25 mg). The study demonstrated that pramipexole significantly binds to D2/D3 receptors in the prefrontal cortex, amygdala, and medial and lateral thalamus at a dose of 0.25 mg. These regions have been indicated to have some relation to depression and may be part of the target sites where pramipexole exerts its antidepressive effects

Striatal vs extrastriatal dopamine D2 receptors in antipsychotic response - a double-blind PET study in schizophrenia

Blockade of dopamine D2 receptors remains a common feature of all antipsychotics. It has been hypothesized that the extrastriatal (cortical, thalamic) dopamine D2 receptors may be more critical to antipsychotic response than the striatal dopamine D2 receptors. This is the first double-blind controlled study to examine the relationship between striatal and extrastriatal D2 occupancy and clinical effects. Fourteen patients with recent onset psychosis were assigned to low or high doses of risperidone (1 mg vs 4 mg/day) or olanzapine (2.5 mg vs 15 mg/day) in order to achieve a broad range of D2 occupancy levels across subjects. Clinical response, side effects, striatal ([11C]-raclopride-positron emission tomography (PET)), and extrastriatal ([11C]-FLB 457-PET) D2 receptors were evaluated after treatment. The measured D2 occupancies ranged from 50 to 92% in striatal and 4 to 95% in the different extrastriatal (frontal, temporal, thalamic) regions. Striatal and extrastriatal occupancies were correlated with dose, drug plasma levels, and with each other. Striatal D2 occupancy predicted response in positive psychotic symptoms (r=0.62, p=0.01), but not for negative symptoms (r=0.2, p=0.5). Extrastriatal D2 occupancy did not predict response in positive or negative symptoms. The two subjects who experienced motor side effects had the highest striatal occupancies in the cohort. Striatal D2 blockade predicted antipsychotic response better than frontal, temporal, and thalamic occupancy. These results, when combined with the preclinical data implicating the mesolimbic striatum in antipsychotic response, suggest that dopamine D2 blockade within specific regions of the striatum may be most critical for ameliorating psychosis in schizophrenia.peer-reviewe

rTMS of the Left Dorsolateral Prefrontal Cortex Modulates Dopamine Release in the Ipsilateral Anterior Cingulate Cortex and Orbitofrontal Cortex

Background: Brain dopamine is implicated in the regulation of movement, attention, reward and learning and plays an important role in Parkinson’s disease, schizophrenia and drug addiction. Animal experiments have demonstrated that brain stimulation is able to induce significant dopaminergic changes in extrastriatal areas. Given the up-growing interest of noninvasive brain stimulation as potential tool for treatment of neurological and psychiatric disorders, it would be critical to investigate dopaminergic functional interactions in the prefrontal cortex and more in particular the effect of dorsolateral prefrontal cortex (DLPFC) (areas 9/46) stimulation on prefrontal dopamine (DA). Methodology/Principal Findings: Healthy volunteers were studied with a high-affinity DA D2-receptor radioligand, [ 11 C]FLB 457-PET following 10 Hz repetitive transcranial magnetic stimulation (rTMS) of the left and right DLPFC. rTMS on the left DLPFC induced a significant reduction in [ 11 C]FLB 457 binding potential (BP) in the ipsilateral subgenual anterior cingulate cortex (ACC) (BA 25/12), pregenual ACC (BA 32) and medial orbitofrontal cortex (BA 11). There were no significant changes in [ 11 C]FLB 457 BP following right DLPFC rTMS. Conclusions/Significance: To our knowledge, this is the first study to provide evidence of extrastriatal DA modulation following acute rTMS of DLPFC with its effect limited to the specific areas of medial prefrontal cortex. [ 11 C]FLB 457-PET combined with rTMS may allow to explore the neurochemical functions of specific cortical neural networks and help t

Amphetamine-Induced Displacement of [ 18 F] Fallypride in Striatum and Extrastriatal Regions in Humans

This study examined D-amphetamine (D-AMPH)-induced displacements of [ 18 F] fallypride in striatal and extrastriatal regions and the correlations of these displacements with cognition, affect, and sensation-seeking behavior. In all, 14 normal subjects, six females and eight males (ages 21-32, mean age 25.9 years), underwent positron emission tomography (PET) with [ 18 F]fallypride before and 3 h after a 0.43 mg/kg oral dose of D-AMPH. Levels of dopamine (DA) D 2 receptor density were calculated with the reference region method of Lammerstma. Percent displacements in striatal and extrastriatal regions were calculated for the caudate, putamen, ventral striatum, medial thalamus, amygdala, substantia nigra, and temporal cortex. Correlations of changes in cognition, affect, and sensation seeking with parametric images of D-AMPH-induced DA release were computed. Significant displacements were seen in the caudate, putamen, ventral striatum substantia nigra, and temporal cortex with a trend level change in the amygdala. Greatest displacements were seen in striatal subdivisionsF5.6% in caudate, 11.2% in putamen, 7.2% in ventral striatum, and 6.6% in substantia nigra. Lesser decrements were seen in amygdalaF4.4%, temporal cortexF3.7%, and thalamusF2.8%. Significant clusters of correlations of regional DA release with cognition and sensation-seeking behavior were observed. The current study demonstrates that [ 18 F]fallypride PET studies using oral D-AMPH (0.43 mg/kg) can be used to study D-AMPH-induced DA release in the striatal and extrastriatal regions in humans, and their relationship with cognition and sensation-seeking behavior

E2110の前臨床評価を目的としたPETによる薬物動態学/薬力学(PK/PD)解析

Tohoku University須原哲也課

Development of novel fluorine-18 labeled PET radioligands for monoamine oxidase B (MAO-B)

Monoamine oxidases (MAO-A and MAO-B) are important enzymes regulating the levels of monoaminergic neurotransmitters. Selectiv e and irreversible MAO-B inhibitors such as L -deprenyl and rasagiline are clinically used for the t reatment of psychiatric and neurological disorders. Positron em ission tomography (PET) is a non- invasive imaging technique which has widely been util ized to visualize the localization of MAO-B in monkey and human brains and thereby has b een useful for studying neurodegenerative diseases and epilepsy. This thesi s deals with the synthesis and evaluation of novel fluorine-18 labeled PET radioligan ds for detection of MAO-B activity. The present thesis demonstrates that nine fluorinat ed propargyl amines were synthesized and tested for inhibition of MAO-B. In o rder to label those compounds with fluorine-18 seven chloro-precursors and two sulph amidate-precursors were also synthesized by multi step organic synthesis. Radiola beling of six chloro-precursors with fluorine-18 was accomplished by a one-step nucl eophilic substitution reaction. Radiolabeling of two sulphamidate-precursors with fl uorine-18 was performed in two steps, compromising a nucleophilic substitution foll owed by the removal of the protecting group. The incorporation yield of the fluo rination reactions varied from 40- 70%. The radiochemical purity was >99% and the specif ic radioactivities were in a range of 190-240 GBq/μmol at the time of administrat ion. In vitro MAO inhibition and/or autoradiography (ARG) experimen ts demonstrated a high selectivity for MAO-B over MAO-A for five of the compounds namely [ 18 F]fluorodeprenyl, [ 18 F]fluororasagiline, [ 18 F]fluoro- N ,4-dimethyl- N -(prop-2-ynyl) pentan-2-amine, [ 18 F]fluorodeprenyl-D 2 and [ 18 F]fluororasagiline-D 2 . All five compounds were examined by PET and showed a high initial brain uptake in known MAO-B rich regions in cynomolgus monkey. [ 18 F]Fluorodeprenyl showed a kinetic behavior similar to [ 11 C]deprenyl where its fast irreversible binding to th e enzyme renders the distribution of this radioligand in tissue limited by blood flow rather than the MAO-B enzyme concentration. [ 18 F]Fluororasagiline and [ 18 F]fluoro- N ,4-dimethyl- N -(prop-2-ynyl)pentan-2-amine showed continuous increase of the radioactivity throughout the PET measurement that might be an indic ation of a blood-brain barrier penetrating radiometabolite which might in turn compl icate a reliable quantification. Only [ 18 F]fluorodeprenyl-D 2 and [ 18 F]fluororasagiline-D 2 showed fast wash-out from the brain and less accumulation in cortical and sub- cortical regions. Radiometabolite studies demonstrated that both deuterated analogues were more stable measured in monkey plasma when compared to the non-deuterated a nalogues. These results together suggest that both [ 18 F]fluorodeprenyl-D 2 and [ 18 F]fluororasagiline-D 2 may be improved PET radioligands and potential mole cular imaging biomarker candidates for PET studies in neuroi nflammation and neurodegeneration, accompanied with astrocyte activat ion

Genetic Factors in the Regulation of Striatal and Extrastriatal Dopamine D2 Receptor Expression

Positron emission tomography (PET) studies on healthy individuals have revealed a marked interindividual variability in striatal dopamine D2 receptor density that can be partly accounted for by genetic factors. The examination of the extrastriatal lowdensity D2 receptor populations has been impeded by the lack of suitable tracers. However, the quantification of these D2 receptor populations is now feasible with recently developed PET radioligands. The objective of this thesis was to study brain neurobiological correlates of common functional genetic variants residing in candidate genes relevant for D2 receptor functioning. For this purpose, healthy subjects were studied with PET imaging using [11C]raclopride and [11C]FLB457 as radioligands. The candidate genes examined in this work were the human D2 receptor gene (DRD2) and the catechol-Omethyltransferase gene (COMT). The region-specific genotypic influences were explored by comparing D2 receptor binding properties in the striatum, the cortex and the thalamus. As an additional study objective, the relationship between cortical D2 receptor density and a cognitive phenotype i.e. verbal memory and learning was assessed. The main finding of this study was that DRD2 C957T genotype altered markedly D2 receptor density in the cortex and the thalamus whereas in the striatum the C957T genotype affected D2 receptor affinity, but not density. Furthermore, the A1 allele of the DRD2-related TaqIA polymorphism showed increased cortical and thalamic D2 receptor density, but had the opposite effect on striatal D2 receptor density. The DRD2 –141C Ins/Del or the COMT Val158Met genotypes did not change D2 receptor binding properties. Finally, unlike previously reported, cortical D2 receptor density did not show any significant correlation with verbal memory function. The results of this study suggest that the C957T and the TaqIA genotypes have region-specific neurobiological correlates in brain dopamine D2 receptor availability in vivo. The biological mechanisms underlying these findings are unclear, but they may be related to the region-specific regulation of dopamine neurotranssion, gene/receptor expression and epigenesis. These findings contribute to the understanding of the genetic regulation of dopamine and D2 receptor-related brain functions in vivo in man. In addition, the results provide potentially useful endophenotypes for genetic research on psychiatric and neurological disorders.Siirretty Doriast

Striatal and extrastriatal dopamine D2/3 receptors studied with [11C]raclopride and high-resolution PET

The human striatum is a heterogeneous structure representing a major part of the dopamine (DA) system’s basal ganglia input and output. Positron emission tomography (PET) is a powerful tool for imaging DA neurotransmission. However, PET measurements suffer from bias caused by the low spatial resolution, especially when imaging small, D2/3 -rich structures such as the ventral striatum (VST). The brain dedicated high-resolution PET scanner, ECAT HRRT (Siemens Medical Solutions, Knoxville, TN, USA) has superior resolution capabilities than its predecessors. In the quantification of striatal D2/3 binding, the in vivo highly selective D2/3 antagonist [11C] raclopride is recognized as a well-validated tracer. The aim of this thesis was to use a traditional test-retest setting to evaluate the feasibility of utilizing the HRRT scanner for exploring not only small brain regions such as the VST but also low density D2/3 areas such as cortex. It was demonstrated that the measurement of striatal D2/3 binding was very reliable, even when studying small brain structures or prolonging the scanning interval. Furthermore, the cortical test-retest parameters displayed good to moderate reproducibility. For the first time in vivo, it was revealed that there are significant divergent rostrocaudal gradients of [11C]raclopride binding in striatal subregions. These results indicate that high-resolution [11C]raclopride PET is very reliable and its improved sensitivity means that it should be possible to detect the often very subtle changes occurring in DA transmission. Another major advantage is the possibility to measure simultaneously striatal and cortical areas. The divergent gradients of D2/3 binding may have functional significance and the average distribution binding could serve as the basis for a future database. Key words: dopamine, PET, HRRT, [11C]raclopride, striatum, VST, gradients, test-retest.Dopamiini D2/3 reseptorien kuvantaminen korkean resoluution PET kameralla ja [11C]raclopridi merkkiaineella. Aivojen tyvitumakkeisiin kuuluva aivojuovio on keskeinen dopamiiniaineenvaihdunnan kannalta. PET menetelmällä voidaan tutkia dopamiiniaineenvaihduntaa reseptoritasolla, mutta sen heikkous on huono spatiaalinen resoluutio, etenkin tutkittaessa pieniä aivoalueita kuten aivojuovion ventraalista osaa (VST). Tässä väitöskirjatutkimuksessa on käytetty aivotutkimukseen suunniteltua korkean resoluution PET-kameraa (ECAT HRRT, Siemens Medical Solutions, Knoxville, TN, USA) ja D2/3 dopamiinireseptoreihin spesifisesti sitoutuvaa [11C]raclopridi PET-merkkiainetta. Tämän väitöskirjatutkimuksen tarkoituksena on selvittää toistomittauksella HRRT kameran soveltuvuutta pienten (VST) ja toisaalta vähän D2/3 reseptoreita sisältävien (aivojen kuorikerros) aivoalueiden kuvantamiseen. HRRT-kameran käyttökelpoisuus osoittautui erittäin hyväksi pienempien aivoalueiden tutkimisessa eikä luotettavuus kärsinyt vaikka kahden mittauksen välistä intervallia pidennettiin. Kuorikerroksen mittauksen luotettavuus oli myös tyydyttävä/hyvä. Lisäksi ensimmäistä kertaa PET menetelmää käyttäen pystyttiin havaitsemaan erisuuntaisia gradientteja [11C]raclopridin sitoutumisessa D2/3 reseptoreihin. Löydösten perusteella korkean resoluution [11C]raclopridi PET menetelmä on erittäin luotettava ja se mahdollisesti lisää mittauksen sensitiivisyyttä havaita hienovaraisia dopamiiniaineenvaihdunnan muutoksia. [11C]raclopridia voisi tulevaisuudessa mahdollisesti käyttää samanaikaisesti sekä aivojuovion että aivojen kuorikerroksen tutkimiseen, joka toisi lisäinformaatiota dopamiinijärjestestelmän toiminnallisesta järjestäytymisestä aivoissa. Havaituilla erilaisilla gradienteilla [11C]raclopridin sitoutumisessa voi olla funktionaalista merkitystä ja keskimääräistä sitoutumista voitaisiin käyttää myös tietokannan pohjana.Siirretty Doriast

Towards a Novel Treatment of Huntington´s Disease

The function of the human brain is based on complex interactions between billions of neurons. The brain function declines as a result of normal aging, but is also disturbed in neuropsychiatric and neurodegenerative disorders. Huntington’s disease is a hereditary autosomal-dominant neurodegenerative disorder that manifests with a complex range of symptoms resulting in severe motor deficiencies, cognitive decline, behavioral disturbances, and premature death. To date, no preventive, disease-modifying, or even symptomatic therapy exists. Normal function of the brain is maintained by different neurotransmitters, which act through their receptors. One such example is the monoamine neurotransmitter dopamine, which plays a central role in normal brain function. The dopamine system is involved in a wide range of functions such as motor function, reward, cognition and emotion, and is importantly connected to the modulation of glutamate functions in the brain. There is evidence that dopaminergic systems are disturbed in Huntington’s disease, and that the delicate balance between dopamine and glutamate interplay is disrupted in the disorder. Dopaminergic stabilizers belong to a novel class of CNS compounds that can both enhance and counteract psychomotor activity depending on the initial level. Such effects are believed to be mediated by state dependent modulation of monoaminergic and glutamatergic functions. One such compound, pridopidine (ACR16), is currently in development for the treatment of Huntington’s disease. The aim of this thesis was to better understand the physiopharmacology of dopaminergic stabilizers and to investigate their effects in healthy subjects and patients with Huntington’s disease. To explore the possibilities for this therapy in Huntington’s disease, three experimental studies using positron emission tomography were undertaken. These studies yielded a number of findings. It could be shown that the extrastriatal density of dopamine D2 receptors is well preserved in patients with Huntington’s disease. This finding has implications for pridopidine therapy since the D2 receptor is believed to be the primary target receptor for the compound. In addition, it was shown that in patients with Huntington’s disease, pridopidine treatment induced general state dependent changes in cerebral metabolic activity, and increases in cerebral metabolic activity in brain regions believed to be important for mediating compensatory mechanisms in the disorder. In another study elucidating the mechanisms of action of dopaminergic stabilizers in healthy subjects, it could be shown that a single dose of the compound produced modest reductions in the availability of striatal dopamine D2 receptors, and more marked fluctuations in the availability of cortical and striatal dopamine D1 receptors. The results from this mechanistic study suggest that dopaminergic stabilizers exert their glutamate modulating properties via indirect effects of dopamine D1 receptors. Moreover, in the framework of this thesis, an overview of available imaging biomarkers to study the progression of Huntington’s disease is presented, providing guidance for methods to be applied in studies aimed at modifying disease progressio