Acute acetate administration increases endogenous opioid levels in the human brain: A [11C]carfentanil molecular imaging study.

INTRODUCTION: A recent study has shown that acetate administration leads to a fourfold increase in the transcription of proopiomelanocortin (POMC) mRNA in the hypothalamus. POMC is cleaved to peptides, including ß-endorphin, an endogenous opioid (EO) agonist that binds preferentially to the µ-opioid receptor (MOR). We hypothesised that an acetate challenge would increase the levels of EO in the human brain. We have previously demonstrated that increased EO release in the human brain can be detected using positron emission tomography (PET) with the selective MOR radioligand [11C]carfentanil. We used this approach to evaluate the effects of an acute acetate challenge on EO levels in the brain of healthy human volunteers. METHODS: Seven volunteers each completed a baseline [11C]carfentanil PET scan followed by an administration of sodium acetate before a second [11C]carfentanil PET scan. Dynamic PET data were acquired over 90 minutes, and corrected for attenuation, scatter and subject motion. Regional [11C] carfentanil BPND values were then calculated using the simplified reference tissue model (with the occipital grey matter as the reference region). Change in regional EO concentration was evaluated as the change in [11C]carfentanil BPND following acetate administration. RESULTS: Following sodium acetate administration, 2.5-6.5% reductions in [11C]carfentanil regional BPND were seen, with statistical significance reached in the cerebellum, temporal lobe, orbitofrontal cortex, striatum and thalamus. CONCLUSIONS: We have demonstrated that an acute acetate challenge has the potential to increase EO release in the human brain, providing a plausible mechanism of the central effects of acetate on appetite in humans.

Blunted endogenous opioid release following an oral dexamphetamine challenge in abstinent alcohol-dependent individuals.

Addiction has been proposed as a 'reward deficient' state, which is compensated for with substance use. There is growing evidence of dysregulation in the opioid system, which plays a key role in reward, underpinning addiction. Low levels of endogenous opioids are implicated in vulnerability for developing alcohol dependence (AD) and high mu-opioid receptor (MOR) availability in early abstinence is associated with greater craving. This high MOR availability is proposed to be the target of opioid antagonist medication to prevent relapse. However, changes in endogenous opioid tone in AD are poorly characterised and are important to understand as opioid antagonists do not help everyone with AD. We used [11C]carfentanil, a selective MOR agonist positron emission tomography (PET) radioligand, to investigate endogenous opioid tone in AD for the first time. We recruited 13 abstinent male AD and 15 control participants who underwent two [11C]carfentanil PET scans, one before and one 3 h following a 0.5 mg/kg oral dose of dexamphetamine to measure baseline MOR availability and endogenous opioid release. We found significantly blunted dexamphetamine-induced opioid release in 5 out of 10 regions-of-interest including insula, frontal lobe and putamen in AD compared with controls, but no significantly higher MOR availability AD participants compared with HC in any region. This study is comparable to our previous results of blunted dexamphetamine-induced opioid release in gambling disorder, suggesting that this dysregulation in opioid tone is common to both behavioural and substance addictions.

Neural and neurocognitive markers of vulnerability to gambling disorder: a study of unaffected siblings.

Psychological and neurobiological markers in individuals with gambling disorder (GD) could reflect transdiagnostic vulnerability to addiction or neuroadaptive consequences of long-term gambling. Using an endophenotypic approach to identify vulnerability markers, we tested the biological relatives of cases with GD. Male participants seeking treatment for GD (n = 20) were compared with a male control group (n = 18). Biological siblings of cases with GD (n = 17, unrelated to the current GD group) were compared with a separate control group (n = 19) that overlapped partially with the GD control group. Participants completed a comprehensive assessment of clinical scales, neurocognitive functioning, and fMRI of unexpected financial reward. The GD group displayed elevated levels of self-report impulsivity and delay discounting, and increased risk-taking on the Cambridge Gamble Task. We did not observe impaired motor impulsivity on the stop-signal task. Siblings of GD showed some overlapping effects; namely, elevated impulsivity (negative urgency) and increased risk-taking on the Cambridge Gamble Task. We did not observe any differences in the neural response to win outcomes, either in the GD or sibling analysis compared with their control group. Within the GD group, activity in the thalamus and caudate correlated negatively with gambling severity. Increased impulsivity and risk-taking in GD are present in biological relatives of cases with GD, suggesting these markers may represent pre-existing vulnerability to GD.

Serotonin release measured in the human brain: a PET study with [11C]CIMBI-36 and d-amphetamine challenge.

Positron emission tomography (PET) enables non-invasive estimation of neurotransmitter fluctuations in the living human brain. While these methods have been applied to dopamine and some other transmitters, estimation of 5-hydroxytryptamine (5-HT; Serotonin) release has proved to be challenging. Here we demonstrate the utility of the novel 5-HT2A receptor agonist radioligand, [11C]CIMBI-36, and a d-amphetamine challenge to evaluate synaptic 5-HT changes in the living human brain. Seventeen healthy male volunteers received [11C]CIMBI-36 PET scans before and 3 h after an oral dose of d-amphetamine (0.5 mg/kg). Dynamic PET data were acquired over 90 min, and the total volume of distribution (VT) in the frontal cortex and the cerebellum derived from a kinetic analysis using MA1. The frontal cortex binding potential (BPNDfrontal) was calculated as (VTfrontal/VTcerebellum) - 1. ∆BPNDfrontal = 1 - (BPNDfrontal post-dose/BPNDfrontal baseline) was used as an index of 5-HT release. Statistical inference was tested by means of a paired Students t-test evaluating a reduction in post-amphetamine [11C]CIMBI-36 BPNDfrontal. Following d-amphetamine administration, [11C]CIMBI-36 BPNDfrontal was reduced by 14 ± 13% (p = 0.002). Similar effects were observed in other cortical regions examined in an exploratory analysis. [11C]CIMBI-36 binding is sensitive to synaptic serotonin release in the human brain, and when combined with a d-amphetamine challenge, the evaluation of the human brain serotonin system in neuropsychiatric disorders, such as major depression and Parkinson's disease is enabled.

Neural correlates of the DMT experience assessed with multivariate EEG.

Studying transitions in and out of the altered state of consciousness caused by intravenous (IV) N,N-Dimethyltryptamine (DMT - a fast-acting tryptamine psychedelic) offers a safe and powerful means of advancing knowledge on the neurobiology of conscious states. Here we sought to investigate the effects of IV DMT on the power spectrum and signal diversity of human brain activity (6 female, 7 male) recorded via multivariate EEG, and plot relationships between subjective experience, brain activity and drug plasma concentrations across time. Compared with placebo, DMT markedly reduced oscillatory power in the alpha and beta bands and robustly increased spontaneous signal diversity. Time-referenced and neurophenomenological analyses revealed close relationships between changes in various aspects of subjective experience and changes in brain activity. Importantly, the emergence of oscillatory activity within the delta and theta frequency bands was found to correlate with the peak of the experience - particularly its eyes-closed visual component. These findings highlight marked changes in oscillatory activity and signal diversity with DMT that parallel broad and specific components of the subjective experience, thus advancing our understanding of the neurobiological underpinnings of immersive states of consciousness.

First evaluation of PET-based human biodistribution and radiation dosimetry of 11C-BU99008, a tracer for imaging the imidazoline2 binding site.

BACKGROUND: We measured whole body distribution of 11C-BU99008, a new PET biomarker for non-invasive identification of the imidazoline2 binding site. The purpose of this phase I study was to evaluate the biodistribution and radiation dosimetry of 11C-BU99008 in healthy human subjects. METHODS: A single bolus injection of 11C-BU99008 (296 ± 10.5 MBq) was administered to four healthy subjects who underwent whole-body PET/CT over 120 min from the cranial vertex to the mid-thigh. Volumes of interest were drawn around visually identifiable source organs to generate time-activity curves (TAC). Residence times were determined from time-activity curves. Absorbed doses to individual organs and the whole body effective dose were calculated using OLINDA/EXM 1.1 for each subject. RESULTS: The highest measured activity concentration was in the kidney and spleen. The longest residence time was in the muscle at 0.100 ± 0.023 h, followed by the liver at 0.067 ± 0.015 h and lungs at 0.052 ± 0.010 h. The highest mean organ absorbed dose was within the heart wall (0.028 ± 0.002 mGy/MBq), followed by the kidneys (0.026 ± 0.005 mGy/MBq). The critical organ was the heart wall. The total mean effective dose averaged over subjects was estimated to be 0.0056 ± 0.0004 mSv/MBq for an injection of 11C-BU99008. CONCLUSIONS: The biodistribution of 11C-BU99008 has been shown here for the first time in humans. Our dosimetry data showed the total mean effective dose over all subjects was 0.0056 ± 0.0004 mSv/MBq, which would result in a total effective dose of 1.96 mSv for a typical injection of 350 MBq of 11C-BU99008. The effective dose is not appreciably different from those obtained with other 11C tracers.

Evaluation of 11C-BU99008, a PET Ligand for the Imidazoline2 Binding Site in Human Brain.

The imidazoline2 binding site (I2BS) is thought to be expressed in glia and implicated in the regulation of glial fibrillary acidic protein. A PET ligand for this target would be important for the investigation of neurodegenerative and neuroinflammatory diseases. 11C-BU99008 has previously been identified as a putative PET radioligand. Here, we present the first in vivo characterization of this PET radioligand in humans and assess its test-retest reproducibility. Methods: Fourteen healthy male volunteers underwent dynamic PET imaging with 11C-BU99008 and arterial sampling. Six subjects were used in a test-retest assessment, and 8 were used in a pharmacologic evaluation, undergoing a second or third heterologous competition scan with the mixed I2BS/α2-adrenoceptor drug idazoxan (n = 8; 20, 40, 60, and 80 mg) and the mixed irreversible monoamine oxidase type A/B inhibitor isocarboxazid (n = 4; 50 mg). Regional time-activity data were generated from arterial plasma input functions corrected for metabolites using the most appropriate model to derive the outcome measure VT (regional distribution volume). All image processing and kinetic analyses were performed in MIAKAT. Results: Brain uptake of 11C-BU99008 was good, with reversible kinetics and a heterogeneous distribution consistent with known I2BS expression. Model selection criteria indicated that the 2-tissue-compartment model was preferred. VT estimates were high in the striatum (105 ± 21 mL⋅cm-3), medium in the cingulate cortex (62 ± 10 mL⋅cm-3), and low in the cerebellum (41 ± 7 mL⋅cm-3). Test-retest reliability was reasonable. The uptake was dose-dependently reduced throughout the brain by pretreatment with idazoxan, with an average block across all regions of about 60% (VT, ∼30 mL⋅cm-3) at the highest dose (80 mg). The median effective dose for idazoxan was 28 mg. Uptake was not blocked by pretreatment with the monoamine oxidase inhibitor isocarboxazid. Conclusion:11C-BU99008 in human PET studies demonstrates good brain delivery, reversible kinetics, heterogeneous distribution, specific binding signal consistent with I2BS distribution, and good test-retest reliability.

Development and validation of a clinical risk score to predict mortality after percutaneous coronary intervention.

OBJECTIVE: To develop and validate a contemporary clinical risk score to predict mortality after percutaneous coronary intervention (PCI). METHODS: Using data collected from patients undergoing PCI at the South Yorkshire Cardiothoracic Centre, Sheffield, UK, between January 2007 and September 2013, a risk score was developed to predict mortality. Logistic regression was used to evaluate the effect of each variable upon 30-day mortality. A backwards stepwise logistic regression model was then used to build a predictive model. The results were validated both internally and externally with data from Manchester Royal Infirmary, UK. 30-Day mortality status was determined from the UK Office of National Statistics. RESULTS: The development data set comprised 6522 patients from Sheffield. Five risk factors, including cardiogenic shock, procedural urgency, history of renal disease, diabetes mellitus and age, were statistically significant to predict 30-day mortality. The risk score was validated internally on a further 3290 patients from Sheffield and externally on 3230 patients from Manchester. The discrimination of the model was high in the development (C-statistic=0.82, 95% CI 0.79 to 0.85), internal (C-statistic=0.81, 95% CI 0.76 to 0.86) and external (C statistics=0.90, 95% CI 0.87 to 0.93) cohorts. There was no significant difference between observed and predicted mortality in any group. CONCLUSION: This contemporary risk score reliably predicts 30-day mortality after PCI using a small number of clinical variables obtainable prior to the procedure, without knowledge of the coronary anatomy.

Validated Method for the Quantification of Baclofen in Human Plasma Using Solid-Phase Extraction and Liquid Chromatography-Tandem Mass Spectrometry.

A highly sensitive and fully validated method was developed for the quantification of baclofen in human plasma. After adjusting the pH of the plasma samples using a phosphate buffer solution (pH 4), baclofen was purified using mixed mode (C8/cation exchange) solid-phase extraction (SPE) cartridges. Endogenous water-soluble compounds and lipids were removed from the cartridges before the samples were eluted and concentrated. The samples were analyzed using triple-quadrupole liquid chromatography-tandem mass spectrometry (LC-MS-MS) with triggered dynamic multiple reaction monitoring mode for simultaneous quantification and confirmation. The assay was linear from 25 to 1,000 ng/mL (r(2) > 0.999; n = 6). Intraday (n = 6) and interday (n = 15) imprecisions (% relative standard deviation) were <5%, and the average recovery was 30%. The limit of detection of the method was 5 ng/mL, and the limit of quantification was 25 ng/mL. Plasma samples from healthy male volunteers (n = 9, median age: 22) given two single oral doses of baclofen (10 and 60 mg) on nonconsecutive days were analyzed to demonstrate method applicability.