Comparison of D2 dopamine receptor occupancy after oral administration of quetiapine fumarate immediate-release and extended-release formulations in healthy subjects

Quetiapine is an established drug for treatment of schizophrenia, bipolar disorder, and major depressive disorder. While initially manufactured as an immediate-release (IR) formulation, an extended-release (XR) formulation has recently been introduced. Pharmacokinetic studies show that quetiapine XR provides a lower peak and more stable plasma concentration than the IR formulation. This study investigated if the pharmacokinetic differences translate into different time curves for central D2 dopamine receptor occupancy. Eleven control subjects were examined with positron emission tomography (PET) and the radioligand [11C]raclopride. Eight subjects underwent all of the scheduled PET measurements. After baseline examination, quetiapine XR was administered once-daily for 8 d titrated to 300 mg/d on days 5–8, followed by 300 mg/d quetiapine IR on days 9–12. PET measurements were repeated after the last doses of quetiapine XR and IR at predicted times of peak and trough plasma concentrations. Striatal D2 receptor occupancy was calculated using the simplified reference tissue model. Peak D2 receptor occupancy was significantly higher with quetiapine IR than XR in all subjects (50±4% and 32±11%, respectively), consistent with lower peak plasma concentrations for the XR formulation. Trough D2 receptor occupancy was similarly low for both formulations (IR 7±7%, XR 8±6%). The lower peak receptor occupancy associated with quetiapine XR may explain observed pharmacodynamic differences between the formulations. Assuming that our findings in control subjects are valid for patients with schizophrenia, the study supports the view that quetiapine, like the prototype atypical antipsychotic clozapine, may show antipsychotic effect at lower D2 receptor occupancy than typical antipsychotics

Individual differences in the proneness to have flow experiences are linked to dopamine D2-receptor availability in the dorsal striatum

Flow is a subjective experience of high but effortless attention, enjoyment, and low self-awareness that can occur during the active performance of challenging tasks. The dispositional proneness to experience flow is associated with personality traits that are known to be influenced by dopaminergic neural systems. Here, for the first time, we investigated relations between flow proneness and dopaminergic function. Specifically, we tested the hypothesis that the availability of dopamine D2-receptors in the striatum is positively associated with flow proneness. Striatal D2-receptor availability was measured in a sample of 25 healthy adults using positron emission tomography and [ 11 C]raclopride. Flow proneness was measured using the Swedish Flow Proneness Questionnaire. As hypothesized, there was a significant correlation (r = .41) between striatal D2-receptor availability and flow proneness. An exploratory analysis of striatal subregions showed that the relation was mainly driven by the dorsal striatum, with a significantly higher correlation in the putamen than in the ventral striatum. The findings constitute the first demonstration of an association between flow proneness and dopaminergic function. We suggest that the proneness to experience flow is related to personality dimensions that are under dopaminergic control and characterized by low impulsiveness, stable emotion, and positive affect

Influence of the COMT Genotype on Working Memory and Brain Activity Changes During Development

Background: The Valine158Methionine (Val158Met) polymorphism of the COMT gene leads to lower enzymatic activity and higher dopamine availability in Met carriers. The Met allele is associated with better performance and reduced prefrontal cortex activation during working memory (WM) tasks in adults. Dopaminergic system changes during adolescence may lead to a reduction of basal dopamine levels, potentially affecting Met allele benefits during development. Methods: We investigated the association of COMT genotype with behavioral (n = 322) and magnetic resonance imaging data (n = 81–84) collected during performance of a visuospatial WM task and potential changes in these effects during development (reflected in age × genotype interactions). Data were collected from a cross-sectional and longitudinal typically developing sample of 6- to 20-year-olds. Results: Visuospatial WM capacity exhibited an age × genotype interaction, with a benefit of the Met allele emerging after 10 years of age. There was a parallel age × genotype interaction on WM-related activation in the right inferior frontal gyrus and intraparietal sulcus (IPS), with increases in activation with age in the Val/Val group only. Main effects of COMT genotype were also observed in the IPS, with greater gray matter volumes bilaterally and greater right IPS activation in the Val/Val group compared with the Met carriers. Conclusions: These results suggest that COMT genotype effects on WM brain activity and behavior are not static during development. The full developmental picture should be considered when trying to understand the impact of genetic polymorphisms on the mature cognition of healthy adult or psychiatric populations

Persistent Hyperdopaminergia Decreases the Peak Frequency of Hippocampal Theta Oscillations during Quiet Waking and REM Sleep

Long-term changes in dopaminergic signaling are thought to underlie the pathophysiology of a number of psychiatric disorders. Several conditions are associated with cognitive deficits such as disturbances in attention processes and learning and memory, suggesting that persistent changes in dopaminergic signaling may alter neural mechanisms underlying these processes. Dopamine transporter knockout (DAT-KO) mice exhibit a persistent five-fold increase in extracellular dopamine levels. Here, we demonstrate that DAT-KO mice display lower hippocampal theta oscillation frequencies during baseline periods of waking and rapid-eye movement sleep. These altered theta oscillations are not reversed via treatment with the antidopaminergic agent haloperidol. Thus, we propose that persistent hyperdopaminergia, together with secondary alterations in other neuromodulatory systems, results in lower frequency activity in neural systems responsible for various cognitive processes

In vivo PET imaging of the neuroinflammatory response in rat spinal cord injury using the TSPO tracer [F-18]GE-180 and effect of docosahexaenoic acid

Centre for Trauma Sciences, funded by the Barts & The London Charity, GE Healthcare Ltd, the Experimental Medicine Awards from the Blizard Institute and the Imaging Centre at the Barts Cancer Institute

Early Presymptomatic and Long-Term Changes of Rest Activity Cycles and Cognitive Behavior in a MPTP-Monkey Model of Parkinson's Disease

It is increasingly recognized that non-motor symptoms are a prominent feature of Parkinson's disease and in the case of cognitive deficits can precede onset of the characteristic motor symptoms. Here, we examine in 4 monkeys chronically treated with low doses of the neurotoxin MPTP the early and long-term alterations of rest-activity rhythms in relationship to the appearance of motor and cognitive symptoms.Behavioral activity recordings as well as motor and cognitive assessments were carried out continuously and in parallel before, during and for several months following MPTP-treatment (12–56 weeks). Cognitive abilities were assessed using a task that is dependent on the functional integrity of the fronto-striatal axis. Rest-activity cycles were monitored continuously using infrared movement detectors of locomotor activity. Motor impairment was evaluated using standardized scales for primates. Results show that MPTP treatment led to an immediate alteration (within one week) of rest-activity cycles and cognitive deficits. Parkinsonian motor deficits only became apparent 3 to 5 weeks after initiating chronic MPTP administration. In three of the four animals studied, clinical scores returned to control levels 5–7 weeks following cessation of MPTP treatment. In contrast, both cognitive deficits and chronobiological alterations persisted for many months. Levodopa treatment led to an improvement of cognitive performance but did not affect rest-activity rhythms in the two cases tested.Present results show that i) changes in the rest activity cycles constituted early detectable consequences of MPTP treatment and, along with cognitive alterations, characterize the presymptomatic stage; ii) following motor recovery there is a long-term persistence of non-motor symptoms that could reflect differential underlying compensatory mechanisms in these domains; iii) the progressive MPTP-monkey model of presymptomatic ongoing parkinsonism offers possibilities for in-depth studies of early non-motor symptoms including sleep alterations and cognitive deficits

Glia Imaging Differentiates Multiple System Atrophy from Parkinson's Disease: A Positron Emission Tomography Study with [C-11]PBR28 and Machine Learning Analysis

Background The clinical diagnosis of multiple system atrophy (MSA) is challenged by overlapping features with Parkinson's disease (PD) and late-onset ataxias. Additional biomarkers are needed to confirm MSA and to advance the understanding of pathophysiology. Positron emission tomography (PET) imaging of the translocator protein (TSPO), expressed by glia cells, has shown elevations in MSA. Objective In this multicenter PET study, we assess the performance of TSPO imaging as a diagnostic marker for MSA.Methods We analyzed [C-11]PBR28 binding to TSPO using imaging data of 66 patients with MSA and 24 patients with PD. Group comparisons were based on regional analysis of parametric images. The diagnostic readout included visual reading of PET images against clinical diagnosis and machine learning analyses. Sensitivity, specificity, and receiver operating curves were used to discriminate MSA from PD and cerebellar from parkinsonian variant MSA. Results We observed a conspicuous pattern of elevated regional [C-11]PBR28 binding to TSPO in MSA as compared with PD, with "hotspots" in the lentiform nucleus and cerebellar white matter. Visual reading discriminated MSA from PD with 100% specificity and 83% sensitivity. The machine learning approach improved sensitivity to 96%. We identified MSA subtype-specific TSPO binding patterns. Conclusions We found a pattern of significantly increased regional glial TSPO binding in patients with MSA. Intriguingly, our data are in line with severe neuroinflammation in MSA. Glia imaging may have potential to support clinical MSA diagnosis and patient stratification in clinical trials on novel drug therapies for an alpha-synucleinopathy that remains strikingly incurable. </p

Developmental changes in human dopamine neurotransmission: cortical receptors and terminators

<p>Abstract</p> <p>Background</p> <p>Dopamine is integral to cognition, learning and memory, and dysfunctions of the frontal cortical dopamine system have been implicated in several developmental neuropsychiatric disorders. The dorsolateral prefrontal cortex (DLPFC) is critical for working memory which does not fully mature until the third decade of life. Few studies have reported on the normal development of the dopamine system in human DLPFC during postnatal life. We assessed pre- and postsynaptic components of the dopamine system including tyrosine hydroxylase, the dopamine receptors (D1, D2 short and D2 long isoforms, D4, D5), catechol-<it>O</it>-methyltransferase, and monoamine oxidase (A and B) in the developing human DLPFC (6 weeks -50 years).</p> <p>Results</p> <p>Gene expression was first analysed by microarray and then by quantitative real-time PCR. Protein expression was analysed by western blot. Protein levels for tyrosine hydroxylase peaked during the first year of life (p < 0.001) then gradually declined to adulthood. Similarly, mRNA levels of dopamine receptors D2S (p < 0.001) and D2L (p = 0.003) isoforms, monoamine oxidase A (p < 0.001) and catechol-<it>O</it>-methyltransferase (p = 0.024) were significantly higher in neonates and infants as was catechol-<it>O</it>-methyltransferase protein (32 kDa, p = 0.027). In contrast, dopamine D1 receptor mRNA correlated positively with age (p = 0.002) and dopamine D1 receptor protein expression increased throughout development (p < 0.001) with adults having the highest D1 protein levels (p ≤ 0.01). Monoamine oxidase B mRNA and protein (p < 0.001) levels also increased significantly throughout development. Interestingly, dopamine D5 receptor mRNA levels negatively correlated with age (r = -0.31, p = 0.018) in an expression profile opposite to that of the dopamine D1 receptor.</p> <p>Conclusions</p> <p>We find distinct developmental changes in key components of the dopamine system in DLPFC over postnatal life. Those genes that are highly expressed during the first year of postnatal life may influence and orchestrate the early development of cortical neural circuitry while genes portraying a pattern of increasing expression with age may indicate a role in DLPFC maturation and attainment of adult levels of cognitive function.</p

Histaminergic system in brain disorders: lessons from the translational approach and future perspectives

Histamine and its receptors were first described as part of immune and gastrointestinal systems, but their presence in the central nervous system and importance in behavior are gaining more attention. The histaminergic system modulates different processes including wakefulness, feeding, and learning and memory consolidation. Histamine receptors (H1R, H2R, H3R, and H4R) belong to the rhodopsin-like family of G protein-coupled receptors, present constitutive activity, and are subjected to inverse agonist action. The involvement of the histaminergic system in brain disorders, such as Alzheimer’s disease, schizophrenia, sleep disorders, drug dependence, and Parkinson’s disease, is largely studied. Data obtained from preclinical studies point antagonists of histamine receptors as promising alternatives to treat brain disorders. Thus, clinical trials are currently ongoing to assess the effects of these drugs on humans. This review summarizes the role of histaminergic system in brain disorders, as well as the effects of different histamine antagonists on animal models and humans