Dopamine mediates a directionally opposite correlation between empathy and the reinforcing effects of amphetamine and gambling in people with gambling disorder vs. healthy controls.

Understanding the relationship between empathy, subjective effects of addictive reinforcers and dopamine function in people with gambling disorder (PGD) vs. healthy controls (HCs) may inform GD treatment. The current investigation addressed this issue via retrospective analysis of data from three studies using amphetamine and a slot machine (SLOTS) as reinforcers in PGD and HCs.

First-in-Human PET Imaging of [F]SDM-4MP3: A Cautionary Tale.

[F]SynVesT-1 is a PET radiopharmaceutical that binds to the synaptic vesicle protein 2A (SV2A) and serves as a biomarker of synaptic density with widespread clinical research applications in psychiatry and neurodegeneration. The initial goal of this study was to concurrently conduct PET imaging studies with [F]SynVesT-1 at our laboratories. However, the data in the first two human PET studies had anomalous biodistribution despite the injected product meeting all specifications during the prerelease quality control protocols.

Preliminary Assessment of Reference Region Quantification and Reduced Scanning Times for [F]SynVesT-1 PET in Parkinson's Disease.

Synaptic density in the central nervous system can be measured using PET with [F]SynVesT-1. While [F]SynVesT-1 has been proven to be a powerful radiopharmaceutical for PET imaging of neurodegenerative disorders such as Parkinson's disease (PD), its currently validated acquisition and quantification protocols are invasive and technically challenging in these populations due to the arterial sampling and relatively long scanning times. The objectives of this work were to evaluate a noninvasive (reference tissue) quantification method for [F]SynVesT-1 in PD patients and to determine the minimum scan time necessary for accurate quantification.

In Vivo Imaging and Kinetic Modeling of Novel Glycogen Synthase Kinase-3 Radiotracers [C]OCM-44 and [F]OCM-50 in Non-Human Primates.

Glycogen synthase kinase 3 (GSK-3) is a potential therapeutic target for a range of neurodegenerative and psychiatric disorders. The goal of this work was to evaluate two leading GSK-3 positron emission tomography (PET) radioligands, [C]OCM-44 and [F]OCM-50, in non-human primates to assess their potential for clinical translation. A total of nine PET scans were performed with the two radiotracers using arterial blood sampling in adult rhesus macaques.

Priming effects of a slot machine game and amphetamine on probabilistic risk-taking in people with gambling disorder and healthy controls.

Introduction: The Game of Dice Task (GDT) captures probabilistic risk-taking, which is an important feature of addictions and integral to gambling disorder (GD). No research appears to have assessed effects of gambling-specific priming manipulations or the pharmacological basis of such effects on the GDT.

Aims: To investigate effects of slot machine gambling (Slots) and d-amphetamine (AMPH; 20 mg) on risk-taking in people with GD and healthy controls (HCs) (n = 30/group).

Local molecular and global connectomic contributions to cross-disorder cortical abnormalities.

Numerous brain disorders demonstrate structural brain abnormalities, which are thought to arise from molecular perturbations or connectome miswiring. The unique and shared contributions of these molecular and connectomic vulnerabilities to brain disorders remain unknown, and has yet to be studied in a single multi-disorder framework. Using MRI morphometry from the ENIGMA consortium, we construct maps of cortical abnormalities for thirteen neurodevelopmental, neurological, and psychiatric disorders from N = 21,000 participants and N = 26,000 controls, collected using a harmonised processing protocol.

Evaluation of ()-, ()-, and ()-F-OF-NB1 for Imaging GluN2B Subunit-Containing -Methyl-d-Aspartate Receptors in Nonhuman Primates.

Despite 2 decades of research, no -methyl-d-aspartate (NMDA) glutamate receptor (GluN) subtype 2B (GluN1/2B) radioligand is yet clinically validated. Previously, we reported on ()-F-OF-NB1 as a promising GluN1/2B PET probe in rodents and its successful application for the visualization of GluN2B-containing NMDA receptors in postmortem brain tissues of patients with amyotrophic lateral sclerosis. In the current work, we report on the characterization of ()-, ()-, and ()-F-OF-NB1 in nonhuman primates.

Multimodal neuroimaging of metabotropic glutamate 5 receptors and functional connectivity in alcohol use disorder.

Background: People recovering from alcohol use disorder (AUD) show altered resting brain connectivity. The metabotropic glutamate 5 (mGlu5) receptor is an important regulator of synaptic plasticity potentially linked with synchronized brain activity and a target of interest in treating AUD. The goal of this work was to assess potential relationships of brain connectivity at rest with mGlu5 receptor availability in people with AUD at two time points early in abstinence.

Comparison of three novel radiotracers for GluN2B-containing NMDA receptors in non-human primates: -[C]NR2B-Me, -[F]of-Me-NB1, and -[F]of-NB1.

The NMDA receptor GluN2B subunit is a target of interest in neuropsychiatric disorders but to date there is no selective radiotracer available to quantify its availability . Here we report direct comparisons in non-human primates of three GluN2B-targeting radioligands: -[C]NR2B-Me, -[F]OF-Me-NB1, and -[F]OF-NB1. Plasma free fraction, metabolism, tissue distribution and kinetics, and quantitative kinetic modeling methods and parameters were evaluated in two adult rhesus macaques.

Characterization in nonhuman primates of (R)-[F]OF-Me-NB1 and (S)-[F]OF-Me-NB1 for imaging the GluN2B subunits of the NMDA receptor.

Purpose: GluN2B containing N-methyl-D-aspartate receptors (NMDARs) play an essential role in neurotransmission and are a potential treatment target for multiple neurological and neurodegenerative diseases, including stroke, Alzheimer's disease, and Parkinson's disease. (R)-[F]OF-Me-NB1 was reported to be more specific and selective than (S)-[F]OF-Me-NB1 for the GluN2B subunits of the NMDAR based on their binding affinity to GluN2B and sigma-1 receptors. Here we report a comprehensive evaluation of (R)-[F]OF-Me-NB1 and (S)-[F]OF-Me-NB1 in nonhuman primates.

Data-driven analysis of kappa opioid receptor binding in major depressive disorder measured by positron emission tomography.

Preclinical studies have implicated kappa opioid receptors (KORs) in stress responses and depression-related behaviors, but evidence from human studies is limited. Here we present results of a secondary analysis of data acquired using positron emission tomography (PET) with the KOR radiotracer [C]GR103545 in 10 unmedicated, currently depressed individuals with major depressive disorder (MDD; 32.6 ± 6.

PET Imaging Estimates of Regional Acetylcholine Concentration Variation in Living Human Brain.

Acetylcholine (ACh) has distinct functional roles in striatum compared with cortex, and imbalance between these systems may contribute to neuropsychiatric disease. Preclinical studies indicate markedly higher ACh concentrations in the striatum. The goal of this work was to leverage positron emission tomography (PET) imaging estimates of drug occupancy at cholinergic receptors to explore ACh variation across the human brain, because these measures can be influenced by competition with endogenous neurotransmitter.

Binding of the synaptic vesicle radiotracer [C]UCB-J is unchanged during functional brain activation using a visual stimulation task.

The positron emission tomography radioligand [C]UCB-J binds to synaptic vesicle glycoprotein 2 A (SV2A), a regulator of vesicle release. Increased neuronal firing could potentially affect tracer concentrations if binding site availability is altered during vesicle exocytosis. This study assessed whether physiological brain activation induces changes in [C]UCB-J tissue influx (), volume of distribution (), or binding potential ().

Metabotropic glutamate type 5 receptor binding availability during dextroamphetamine sensitization in mice and humans.

Background: Glutamate transmission is implicated in drug-induced behavioural sensitization and the associated long-lasting increases in mesolimbic output. Metabotropic glutamate type 5 (mGlu5) receptors might be particularly important, but most details are poorly understood.

Methods: We first assessed in mice (n = 51, all male) the effects of repeated dextroamphetamine administration (2.

mGlu5 receptor availability in youth at risk for addictions: effects of vulnerability traits and cannabis use.

The excitatory neurotransmitter glutamate has been implicated in experience-dependent neuroplasticity and drug-seeking behaviors. Type 5 metabotropic glutamate (mGlu5) receptors might be particularly important. They are critically involved in synaptic plasticity and their availability has been reported to be lower in people with alcohol, tobacco, and cocaine use disorders.

Dopaminergic Plasticity in the Bilateral Hippocampus Following Threat Reversal in Humans.

When a cue no longer predicts a threat, a diminished ability to extinguish or reverse this association is thought to increase risk for stress-related disorders. Despite the clear clinical relevance, the mediating neurochemical mechanisms of threat reversal have received relatively little study. One neurotransmitter implicated in rodent research of changing associations with threat is dopamine.

Separating dopamine D and D receptor sources of [C]-(+)-PHNO binding potential: Independent component analysis of competitive binding.

Development of medications selective for dopamine D or D receptors is an active area of research in numerous neuropsychiatric disorders including addiction and Parkinson's disease. The positron emission tomography (PET) radiotracer [C]-(+)-PHNO, an agonist that binds with high affinity to both D and D receptors, has been used to estimate relative receptor subtype occupancy by drugs based on a priori knowledge of regional variation in the expression of D and D receptors. The objective of this work was to use a data-driven independent component analysis (ICA) of receptor blocking scans to separate D-and D-related signal in [C]-(+)-PHNO binding data in order to improve the precision of subtype specific measurements of binding and occupancy.

Radiosynthesis of the diastereomerically pure (E)-[ C]ABP688.

We report an efficient protocol for the radiosynthesis of diastereomerically pure (E)-[ C]ABP688, a positron emission tomography (PET) tracer for metabotropic glutamate type 5 (mGlu5) receptor imaging. The protocol reliably provides sterile and pyrogen-free formulation of (E)-[ C]ABP688 suitable for preclinical and clinical PET imaging with >99% diastereomeric excess (d.e.

Impulsivity moderates the effects of dopamine D2 and mixed D1-D2 antagonists in individuals with gambling disorder.

Background: The functional role of dopamine D1 and D2 receptors in gambling disorder (GD) remains unclear.

Aims: This study aimed to investigate the role of D1 activation and the moderating effects of impulsivity, a trait linked with weaker D2-mediated inhibition of dopamine release, in GD subjects.

Methods: Thirty (nine female) non-comorbid GD subjects with low (LI), moderate (MI), or high impulsivity (HI) received the preferential D2 antagonist haloperidol (HAL; 3 mg) or the mixed D1-D2 antagonist fluphenazine (FLU; 3 mg), on separate sessions before a 15-minute slot machine game or amphetamine (AMPH; 20 mg), in a placebo-controlled, double-blind, counterbalanced design.

Why Is Aging a Risk Factor for Cognitive Impairment in Parkinson's Disease?-A Resting State fMRI Study.

Using resting-state functional MRI (rsfMRI) data of younger and older healthy volunteers and patients with Parkinson's disease (PD) with and without mild cognitive impairment (MCI) and applying two different analytic approaches, we investigated the effects of age, pathology, and cognition on brain connectivity. When comparing rsfMRI connectivity strength of PD patients and older healthy volunteers, reduction between multiple brain regions in PD patients with MCI (PD-MCI) compared with PD patients without MCI (PD-non-MCI) was observed. This group difference was not affected by the number and location of clusters but was reduced when age was included as a covariate.

Sex differences in [C]ABP688 binding: a positron emission tomography study of mGlu5 receptors.

Purpose: The purpose of this study was to assess, in a large sample of healthy young adults, sex differences in the binding potential of [C]ABP688, a positron emission tomography (PET) tracer selective for the metabotropic glutamate type 5 (mGlu5) receptor.

Methods: High resolution [C]ABP688 PET scans were acquired in 74 healthy volunteers (25 male, 49 female, mean age 20 ± 3.0).

Effect of (Z)-isomer content on [C]ABP688 binding potential in humans.

Purpose: To determine how the low-affinity (Z)-isomer of the radiotracer [C]ABP688 affects binding potential values in vivo in humans.

Methods: High-resolution [C]ABP688 PET scans were acquired on 74 healthy volunteers (25 male, 49 female, mean age 20 ± 3.0).

Test-retest variability of [ C]ABP688 estimates of metabotropic glutamate receptor subtype 5 availability in humans.

[ C]ABP688 is a positron emission tomography (PET) radioligand that binds selectively to metabotropic glutamate type 5 receptors (mGluR5). The use of this tracer has identified receptor binding changes in clinical populations, and has been informative in drug occupancy studies. However, previous studies have found significant increases in [ C]ABP688 binding in the later scan of same-day comparisons, and estimates of test-retest reliability under consistent scanning conditions are not available.