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Drug addiction has been associated with deficits in mesostriatal dopamine (DA) function, but whether this state extends to behavioral addictions such as pathological gambling (PG) is unclear. Here we used positron emission tomography and the D3 receptor-preferring radioligand [11C]-(+)-PHNO during a dual-scan protocol to investigate DA release in response to oral amphetamine in pathological gamblers (n=12) and healthy controls (n=11). In contrast with human neuroimaging findings in drug addiction, we report the first evidence that PG is associated with greater DA release in dorsal striatum (54-63% greater [11C]-(+)-PHNO displacement) than controls. Importantly, dopaminergic response to amphetamine in gamblers was positively predicted by D3 receptor levels (measured in substantia nigra), and related to gambling severity, allowing for construction of a mechanistic model that could help explain DA contributions to PG. Our results are consistent with a hyperdopaminergic state in PG, and support the hypothesis that dopaminergic sensitization involving D3-related mechanisms might contribute to the pathophysiology of behavioral addictions. [ABSTRACT FROM AUTHOR]

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. The Empathy scale of Eysenck's Impulsiveness Questionnaire assessed trait Empathy. The Gamblers Beliefs Questionnaire assessed cognitive distortions. The Eysenck Lie scale assessed socially desirable responding. PET scans quantified dopamine receptor expression and amphetamine-induced dopamine release in Study 1. Pre-treatment with the D2-receptor (D2R)-preferring antagonist, haloperidol or D1R-D2R antagonist, fluphenazine before SLOTS tested the role of D2 autoreceptors and post-synaptic D2R in Study 2. Pre-treatment with the multi-system indirect dopamine agonist, modafinil before SLOTS assessed the reliability of correlations in PGD. Striatal D2R expression predicted greater Empathy and lower amphetamine 'Liking' in HCs, and predicted greater symptom severity in PGD. Empathy predicted lower 'Exciting' effects of SLOTS under placebo in HCs; no correlation emerged under either antagonist. Relative to placebo, haloperidol decreased, whereas fluphenazine increased, the positive correlation between Empathy and Exciting effects of SLOTS in PGD. Modafinil markedly reduced the positive correlation between Empathy and Exciting effects of SLOTS seen under placebo in PGD. Empathy predicted greater cognitive distortions in PGD in all studies. Lie scale variance influenced several primary effects. Prior research linking the insula with Empathy, reactivity to interoceptive signals for risky rewards (uncertainty), and cognitive distortions, provides a parsimonious account for these results., Competing Interests: Declaration of competing interest None of the authors declares a conflict of interest in the report of the findings in this manuscript. There was no use of Artificial Intelligence or any AI application in the preparation of this manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: Thomas Babor, Brian Rush, and Doris Payer declare that they have no conflicts of interest. Dominique Morisano owns stock in Numinus. She is currently in paid contract educational roles (re: psychedelic-assisted psychotherapy) with Journey Clinical, Fluence, Psychedelics Today, California Institute of Integral Studies (nonprofit), Naropa University (nonprofit), and The MIND Foundation (nonprofit). She is also a paid part-time contract facilitator with Beckley Retreats.

Background: A hallmark of unregulated drug markets is their unpredictability and constant evolution with newly introduced substances. People who use drugs and the public health workforce are often unaware of the appearance of new drugs on the unregulated market and their type, safe dosage, and potential adverse effects. This increases risks to people who use drugs, including the risk of unknown consumption and unintentional drug poisoning. Early warning systems (EWSs) can help monitor the landscape of emerging drugs in a given community by collecting and tracking up-to-date information and determining trends. However, there are currently few ways to systematically monitor the appearance and harms of new drugs on the unregulated market in Canada., Objective: The goal of this work is to examine how artificial intelligence can assist in identifying patterns of drug-related risks and harms, by monitoring the social media activity of public health and law enforcement groups. This information is beneficial in the form of an EWS as it can be used to identify new and emerging drug trends in various communities., Methods: To collect data for this study, 145 relevant Twitter accounts throughout Quebec (n=33), Ontario (n=78), and British Columbia (n=34) were manually identified. Tweets posted between August 23 and December 21, 2021, were collected via the application programming interface developed by Twitter for a total of 40,393 tweets. Next, subject matter experts (1) developed keyword filters that reduced the data set to 3746 tweets and (2) manually identified relevant tweets for monitoring and early warning efforts for a total of 464 tweets. Using this information, a zero-shot classifier was applied to tweets from step 1 with a set of keep (drug arrest, drug discovery, and drug report) and not-keep (drug addiction support, public safety report, and others) labels to see how accurately it could extract the tweets identified in step 2., Results: When looking at the accuracy in identifying relevant posts, the system extracted a total of 584 tweets and had an overlap of 392 out of 477 (specificity of ~84.5%) with the subject matter experts. Conversely, the system identified a total of 3162 irrelevant tweets and had an overlap of 3090 (sensitivity of ~94.1%) with the subject matter experts., Conclusions: This study demonstrates the benefits of using artificial intelligence to assist in finding relevant tweets for an EWS. The results showed that it can be quite accurate in filtering out irrelevant information, which greatly reduces the amount of manual work required. Although the accuracy in retaining relevant information was observed to be lower, an analysis showed that the label definitions can impact the results significantly and would therefore be suitable for future work to refine. Nonetheless, the performance is promising and demonstrates the usefulness of artificial intelligence in this domain., (©Andrew Fisher, Matthew Maclaren Young, Doris Payer, Karen Pacheco, Chad Dubeau, Vijay Mago. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 19.09.2023.)

Background: The well-being of people who use drugs (PWUD) continues to be threatened by substances of unknown type or quantity in the unregulated street drug supply. Current efforts to monitor the drug supply are limited in population reach and comparability. This restricts capacity to identify and develop measures that safeguard the health of PWUD. This study describes the development of a low-barrier system for monitoring the contents of drugs in the unregulated street supply. Early results for pilot sites are presented and compared across regions., Methods: The drug content monitoring system integrates a low-barrier survey and broad spectrum urine toxicology screening to compare substances expected to be consumed and those actually in the drug supply. The system prototype was developed by harm reduction pilot projects in British Columbia (BC) and Montreal with participation of PWUD. Data were collected from harm reduction supply distribution site clients in BC, Edmonton and Montreal between May 2018-March 2019. Survey and urine toxicology data were linked via anonymous codes and analyzed descriptively by region for trends in self-reported and detected use., Results: The sample consisted of 878 participants from 40 sites across 3 regions. Reported use of substances, their detection, and concordance between the two varied across regions. Methamphetamine use was reported and detected most frequently in BC (reported: 62.8%; detected: 72.2%) and Edmonton (58.3%; 68.8%). In Montreal, high concordance was also observed between reported (74.5%) and detected (86.5%) cocaine/crack use. Among those with fentanyl detected, the percentage of participants who used fentanyl unintentionally ranged from 36.1% in BC, 78.6% in Edmonton and 90.9% in Montreal., Conclusions: This study is the first to describe a feasible, scalable monitoring system for the unregulated drug supply that can contrast expected and actual drug use and compare trends across regions. The system used principles of flexibility, capacity-building and community participation in its design. Results are well-suited to meet the needs of PWUD and inform the local harm reduction services they rely on. Further standardization of the survey tool and knowledge mobilization is needed to expand the system to new jurisdictions., (© 2021. The Author(s).)

Corticotropin-releasing hormone (CRH) is a key component of the neuroendocrine response to stress. In animal models, CRH has been shown to modulate dopamine release, and this interaction is believed to contribute to stress-induced relapse in neuropsychiatric disorders. Here we investigated whether CRH administration induces dopamine release in humans, using positron emission tomography (PET). Eight healthy volunteers (5 female, 22-48 years old) completed two PET scans with the dopamine D 2/3 receptor radioligand [ 11 C]-(+)-PHNO: once after saline injection, and once after injection of corticorelin (synthetic human CRH). We also assessed subjective reports and measured plasma levels of endocrine hormones (adrenocorticotropic hormone and cortisol). Relative to saline, corticorelin administration decreased binding of the D 2/3 PET probe [ 11 C]-(+)-PHNO, suggesting dopamine release. Endocrine stress markers were also elevated, in line with activation of the hypothalamic-pituitary-adrenal axis, but we detected no changes in subjective ratings. Preliminary results from this proof-of-concept study suggests that CRH challenge in combination with [ 11 C]-(+)-PHNO PET may serve as an assay of dopamine release, presenting a potential platform for evaluating CRH/dopamine interactions in neuropsychiatric disorders and CRH antagonists as potential treatment avenues., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Neuroimaging studies in stimulant use (eg, cocaine, methamphetamine) disorders show that diminished dopamine release by dopamine-elevating drugs is a potential marker of relapse and suggest that increasing dopamine at the D 2/3 receptors may be therapeutically beneficial. In contrast, recent investigations indicate heightened D 3 receptor levels in stimulant users prompting the view that D 3 antagonism may help prevent relapse. Here we tested whether a 'blunted' response to amphetamine in methamphetamine (MA) users extends to D 3 -rich brain areas. Fourteen MA users and 15 healthy controls completed two positron emission tomographic scans with a D 3 -preferring probe [ 11 C]-(+)-PHNO at baseline and after amphetamine (0.4 mg/kg). Relative to healthy controls, MA users had greater decreases in [ 11 C]-(+)-PHNO binding (increased dopamine release) after amphetamine in D 3 -rich substantia nigra (36 vs 20%, p=0.03) and globus pallidus (30 vs 17%, p=0.06), which correlated with self-reported 'drug wanting'. We did not observe a 'blunted' dopamine response to amphetamine in D 2 -rich striatum; however, drug use severity was negatively associated with amphetamine-induced striatal changes in [ 11 C]-(+)-PHNO binding. Our study provides evidence that dopamine transmission in extrastriatal 'D 3 -areas' is not blunted but rather increased in MA users. Together with our previous finding of elevated D 3 receptor level in MA users, the current observation suggests that greater dopaminergic transmission at the D 3 dopamine receptor may contribute to motivation to use drugs and argues in favor of D 3 antagonism as a possible therapeutic tool to reduce craving and relapse in MA addiction.

There is considerable interest in blocking the dopamine D3 receptor (DRD3) versus the D2 receptor (DRD2) to treat drug addiction. However, there are currently no selective DRD3 antagonists available in the clinic. The anxiolytic drug buspirone has been proposed as a potential strategy as findings suggest that this drug has high in vitro affinity for DRD3, binds to DRD3 in brain of living non-human primate, and also disrupts psychostimulant self-administration in preclinical models. No study has explored the occupancy of DRD3 by buspirone in humans. Here, we used positron emission tomography (PET) and the D3-preferring probe, [(11)C]-(+)-PHNO, to test the hypothesis that buspirone will occupy (decreases [(11)C]-(+)-PHNO binding) the DRD3 more readily than the DRD2. Eight healthy participants underwent [(11)C]-(+)-PHNO scans after single oral dose administration of placebo and 30, 60, and 120 mg of buspirone in a single-blind within-subjects design. [(11)C]-(+)-PHNO binding in DRD2- and DRD3-rich areas was decreased by the highest (60-120 mg), but not the lowest (30 mg), doses of buspirone. The maximal occupancy obtained was ~25% in both areas. Plasma levels of prolactin (a DRD2 marker) correlated with percentage occupancy after orally administered buspirone. Self-reported dizziness and drowsiness increased after buspirone but that did not correlate with receptor occupancy in any region. Overall, the modest occupancy of DRD2 and DRD3 even at high acute doses of buspirone, yielding high levels of metabolites, suggests that buspirone may not be a good drug to preferentially block DRD3 in humans.

Cardiovascular and hypothalamic pituitary axis (HPA) disturbances have been observed in individuals who are pathological gamblers (PGs). These may partly derive from chronic exposure to gambling. Response to amphetamine (AMPH) may reveal such disturbances while controlling for differential conditioned responses to gambling in PGs vs healthy controls (HCs). This study assessed heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP) and plasma cortisol following oral AMPH (0.4 mg/kg) in male PGs (n=12) and HCs (n=11) who underwent a positron emission tomography (PET) scan. The Stop Signal Task enabled assessment of the link between physiological and behavioral dysregulation. Trait moderating effects were explored. The responses of PGs to AMPH differed from those of HCs on every index. PGs displayed persistent elevation in DBP and concomitant reduction in HR (i.e. baroreflex) compared to HCs beyond 90 min post-dose. PGs displayed deficits in cortisol compared to HCs that were partially reversed by AMPH. Impairment on the Stop Signal Task correlated positively with HR in controls, but negatively with HR in PGs, suggesting that strong initial and compensatory cardiac responses to a stimulant may each predict disinhibition. Extraversion predicted greater disinhibition in PGs. Noradrenergic disturbances may contribute to sensitized responses to stimulant challenge and disinhibition in PGs., (© The Author(s) 2015.)

Chronic drug use has been associated with dopaminergic abnormalities, detectable in humans with positron emission tomography (PET). Among these, a hallmark feature is low D2 dopamine receptor availability, which has been linked to clinical outcomes, but has not yet translated into a therapeutic strategy. The D3 dopamine receptor on the other hand has gained increasing attention, as, in contrast to D2, chronic exposure to drugs has been shown to up-regulate this receptor subtype in preclinical models of addiction-a phenomenon linked to dopamine system sensitization and drug-seeking. The present article summarizes the literature to date in humans, suggesting that the D3 receptor may indeed contribute to core features of addiction such as impulsiveness and cognitive impairment. A particularly useful tool in investigating this question is the PET imaging probe [(11)C]-(+)-PHNO, which binds to D2/3 dopamine receptors but has preferential affinity for D3. This technique has been used to demonstrate D3 up-regulation in humans, and can be applied to assess pharmacological interventions for development of D3-targeted strategies in addiction treatment., (Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.)

The chronic use of drugs, including psychostimulants such as cocaine and amphetamine, has been associated with low D2/3 dopamine receptor availability, which in turn has been linked to poor clinical outcome. In contrast, recent studies focused on the D3 receptor (a member of the D2-like receptor family) suggest that chronic exposure to stimulant drugs can up-regulate this receptor subtype, which, in preclinical models, is linked to dopamine system sensitization - a process hypothesized to contribute to relapse in addiction. In this mini review we present recent human data suggesting that the D3 receptor may contribute to core features of addiction, and discuss the usefulness of the PET imaging probe [(11)C]-(+)-PHNO in investigating this question., (© 2013.)

Aims: Pathological gambling (PG) shares diagnostic features with substance use disorder (SUD), but the neurochemical mechanisms underlying PG are poorly understood. Because dopamine (DA), a neurotransmitter implicated in reward and reinforcement, is probably involved, we used positron emission tomography (PET) to test whether PG is associated with abnormalities in D2 and D3 receptor levels, as observed in SUD., Design: Case-control study comparing PG to healthy control (HC) subjects., Setting: Academic research imaging centre., Participants: Thirteen non-treatment-seeking males meeting DSM-IV criteria for PG, and 12 matched HC (11 of whom completed PET)., Measurements: Two PET scans (one with the D3 receptor preferring agonist [11C]-(+)-propyl-hexahydro-naphtho-oxazin (PHNO) and the other with [11C]raclopride) to assess D(2/3) DA receptor availability, and behavioural measures (self-report questionnaires and slot-machine game) to assess subjective effects and relationships to PET measures., Findings: Binding of both radiotracers did not differ between groups in striatum or substantia nigra (SN) (all P > 0.1). Across PG, [11C]-(+)-PHNO binding in SN, where the signal is attributable primarily to D3 receptors, correlated with gambling severity (r = 0.57, P = 0.04) and impulsiveness (r = 0.65, P = 0.03). In HC, [11C]raclopride binding in dorsal striatum correlated inversely with subjective effects of gambling (r = -0.70, P = 0.03) and impulsiveness (r = -0.70, P = 0.03)., Conclusions: Unlike with substance use disorder, there appear to be no marked differences in D2 /D3 levels between healthy subjects and pathological gamblers, suggesting that low receptor availability may not be a necessary feature of addiction. However, relationships between [11C]-(+)-PHNO binding and gambling severity/impulsiveness suggests involvement of the D3 receptor in impulsive/compulsive behaviours., (© 2012 The Authors, Addiction © 2012 Society for the Study of Addiction.)

Positron emission tomography (PET) findings suggesting lower D2-type dopamine receptors and dopamine concentration in brains of stimulant users have prompted speculation that increasing dopamine signaling might help in drug treatment. However, this strategy needs to consider the possibility, based on animal and postmortem human data, that dopaminergic activity at the related D3 receptor might, in contrast, be elevated and thereby contribute to drug-taking behavior. We tested the hypothesis that D3 receptor binding is above normal in methamphetamine (MA) polydrug users, using PET and the D3-preferring ligand [11C]-(+)-propyl-hexahydro-naphtho-oxazin ([11C]-(+)-PHNO). Sixteen control subjects and 16 polydrug users reporting MA as their primary drug of abuse underwent PET scanning after [11C]-(+)-PHNO. Compared with control subjects, drug users had higher [11C]-(+)-PHNO binding in the D3-rich midbrain substantia nigra (SN; +46%; p<0.02) and in the globus pallidus (+9%; p=0.06) and ventral pallidum (+11%; p=0.1), whereas binding was slightly lower in the D2-rich dorsal striatum (approximately -4%, NS; -12% in heavy users, p=0.01) and related to drug-use severity. The [11C]-(+)-PHNO binding ratio in D3-rich SN versus D2-rich dorsal striatum was 55% higher in MA users (p=0.004), with heavy but not moderate users having ratios significantly different from controls. [11C]-(+)-PHNO binding in SN was related to self-reported "drug wanting." We conclude that the dopamine D3 receptor, unlike the D2 receptor, might be upregulated in brains of MA polydrug users, although lower dopamine levels in MA users could have contributed to the finding. Pharmacological studies are needed to establish whether normalization of D3 receptor function could reduce vulnerability to relapse in stimulant abuse.

Prior research suggests that abrupt initiation of abstinence from cigarette smoking reduces neural cognitive efficiency. When cognitive efficiency is high, processing speed and accuracy are maximized with minimal allocation of cognitive resources. The study presented here tested the effects of resumption of smoking on cognitive response conflict after overnight abstinence from smoking, hypothesizing that smoking would enhance cognitive efficiency. Twenty paid research volunteers who were chronic cigarette smokers abstained from smoking overnight (>12 h) before undergoing fMRI while performing a color-word Stroop task during two separate test sessions: one that did not include smoking before testing and another one that did. Statistical analyses were performed by modeling the Stroop effect (incongruent >congruent) BOLD response within a collection of a priori regions of interest that have consistently been associated with cognitive control. Behavioral assessment alone did not reveal any significant differences in the Stroop effect between the two sessions. BOLD activations, however, indicated that in the right anterior cingulate cortex (ACC), smokers had significantly less task-related activity following smoking (p<0.02). In contrast, the right middle frontal gyrus exhibited significantly greater activity after smoking as compared to the no-smoking session (p<0.003). Exaggerated neural activity in the ACC during nicotine withdrawal may reflect a compensatory mechanism by which cognitive control networks expend excessive energy to support selective attention processes. Resumption of smoking may enhance cognitive control in smokers, involving a reduction in ACC response conflict activity together with improvement in conflict resolution involving the dorsolateral prefrontal cortex.

Terephthalic acid (TPA) deposited on Si(111)-7 x 7, Si(111)-square root 3 x square root 3-Ag and Ag(111) has been studied as a model system to understand how much passivated semiconductor surfaces differ from semiconductor and metal surfaces in respect of supramolecular self assembly. By scanning tunneling microscopy it is found that TPA molecules do not form any ordered supramolecular structure on the pristine semiconductor surface, due to a strong molecule-substrate interaction. On the contrary, TPA has a weaker interaction with Si(111)-square root 3 x square root 3-Ag, leading to the formation of an ordered supramolecular layer stabilized by carboxyl hydrogen bonds. These structures are very similar to the supramolecular layer of TPA formed on Ag(111), indicating that the two substrates behave similarly for what concerns the adsorption of functional organic molecules. However, the deposition of Fe on the TPA layers on Si(111)-square root 3 x square root 3-Ag does not induce the formation of two-dimensional metal-organic frameworks which, on the contrary, readily develop on Ag(111). Possible origins of this difference are discussed.

Using scanning tunneling microscopy (STM), electrospray ionization mass spectrometry (ESI-MS), and X-ray photoelectron spectroscopy (XPS), we demonstrate that a free [2]catenane consisting of two interlocking 30-membered rings (cat-30) can be deposited on a Ag(111) surface by vacuum sublimation without decomposition. The deposited cat-30 molecules self-organize as ordered dimer chain structures at the surface, presumably via intermolecular pi-pi stacking. An in situ addition of Cu atoms to the surface-adsorbed catenanes induces a drastic change in the molecular organization, i.e., from the dimer chain structure to isolated species. The nitrogen core level spectra suggest that the cat-30 phenanthroline units coordinate with Cu, indicating that the free catenane has been transformed into a Cu-complexed [2]catenane. Since it is known that the two interlocked macrocyclic rings of the free ligand cat-30 completely rearrange, i.e., circumrotate, upon complexation to copper, our results reveal that when adsorbed on the silver surface, the two macrocyclic rings of the free [2]catenane can glide within one another so as to generate the corresponding copper complex by in situ Cu complexation.

Hydrogen-bond formation between ionic adsorbates on an Ag(111) surface under ultrahigh vacuum was studied by scanning tunneling microscopy/spectroscopy (STM/STS), X-ray photoelectron spectroscopy (XPS), near-edge X-ray absorption fine structure (NEXAFS), and molecular dynamics calculations. The adsorbate, 1,3,5-benzenetricarboxylic acid (trimesic acid, TMA), self-assembles at low temperatures (250-300 K) into the known open honeycomb motif through neutral hydrogen bonds formed between carboxyl groups, whereas annealing at 420 K leads to a densely packed quartet structure consisting of flat-lying molecules with one deprotonated carboxyl group per molecule. The resulting charged carboxylate groups form intermolecular ionic hydrogen bonds with enhanced strength compared to the neutral hydrogen bonds; this represents an alternative supramolecular bonding motif in 2D supramolecular organization.

Two-dimensional supramolecular honeycomb networks with cavities of an internal diameter of 2.95 nm were formed by the self-assembly of 4,4',4' '-benzene-1,3,5-triyl-tribenzoic acid (BTA) on a Ag(111) surface at room temperature. Annealing to higher temperatures resulted in two sequential phase transformations into closer-packed supramolecular arrangements. The phase transformations are associated with stepwise deprotonation of the carboxylic acid groups. The voids of the honeycomb network of BTA have a suitable size for the construction of hierarchical structures with guest molecules. Single molecules of the macrocyclic compound mt-33 were successfully confined inside 2D nanocavities of the honeycomb networks and released when the phase was transformed to the close-packed structure.

Compelling evidence shows that there is decreased neural specialization in the ventral visual cortex in older adults under passive viewing conditions. We assessed whether such specialization would be maintained on a working memory task and whether decreased specialization co-occurred with increased prefrontal activations. Participants encoded three faces or houses and maintained the set across an 8-s interval. Results provided evidence for less specialization of faces and houses in older adults than in younger adults, while the middle and inferior frontal cortex showed increased activation in elders compared with the young.