Automating Detection of Drug-Related Harms on Social Media: Machine Learning Framework.

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.

Towards cross-Canada monitoring of the unregulated street drug supply.

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.

Relationship of Alexithymia Ratings to Dopamine D2-type Receptors in Anterior Cingulate and Insula of Healthy Control Subjects but Not Methamphetamine-Dependent Individuals.

BACKGROUND: Individuals with substance-use disorders exhibit emotional problems, including deficits in emotion recognition and processing, and this class of disorders also has been linked to deficits in dopaminergic markers in the brain. Because associations between these phenomena have not been explored, we compared a group of recently abstinent methamphetamine-dependent individuals (n=23) with a healthy-control group (n=17) on dopamine D2-type receptor availability, measured using positron emission tomography with [(18)F]fallypride. METHODS: The anterior cingulate and anterior insular cortices were selected as the brain regions of interest, because they receive dopaminergic innervation and are thought to be involved in emotion awareness and processing. The Toronto Alexithymia Scale, which includes items that assess difficulty in identifying and describing feelings as well as externally oriented thinking, was administered, and the scores were tested for association with D2-type receptor availability. RESULTS: Relative to controls, methamphetamine-dependent individuals showed higher alexithymia scores, reporting difficulty in identifying feelings. The groups did not differ in D2-type receptor availability in the anterior cingulate or anterior insular cortices, but a significant interaction between group and D2-type receptor availability in both regions, on self-report score, reflected significant positive correlations in the control group (higher receptor availability linked to higher alexithymia) but nonsignificant, negative correlations (lower receptor availability linked to higher alexithymia) in methamphetamine-dependent subjects. CONCLUSIONS: The results suggest that neurotransmission through D2-type receptors in the anterior cingulate and anterior insular cortices influences capacity of emotion processing in healthy people but that this association is absent in individuals with methamphetamine dependence.

[¹¹C]-(+)-PHNO PET imaging of dopamine D(2/3) receptors in Parkinson's disease with impulse control disorders.

Dopamine agonist medications with high affinity for the D3 dopamine receptor are commonly used to treat Parkinson's disease, and have been associated with pathological behaviors categorized under the umbrella of impulse control disorders (ICD). The aim of this study was to investigate whether ICD in Parkinson's patients are associated with greater D3 dopamine receptor availability. We used positron emission tomography (PET) radioligand imaging with the D3 dopamine receptor preferring agonist [¹¹C]-(+)-propyl-hexahydro-naphtho-oxazin (PHNO) in Parkinson's patients with (n = 11) and without (n = 21) ICD, and age-, sex-, and education-matched healthy control subjects (n = 18). Contrary to hypotheses, [¹¹C]-(+)-PHNO binding in D3 -rich brain areas was not elevated in Parkinson's patients with ICD compared with those without; instead, [¹¹C]-(+)-PHNO binding in ventral striatum was 20% lower (P = 0.011), correlating with two measures of ICD severity (r = -0.8 and -0.9), which may reflect higher dopamine tone in ventral striatum. In dorsal striatum, where [¹¹C]-(+)-PHNO binding is associated with D2 receptor levels, [¹¹C]-(+)-PHNO binding was elevated across patients compared with controls. We conclude that although D3 dopamine receptors have been linked to the occurrence of ICD in Parkinson's patients. Our findings do not support the hypothesis that D3 receptor levels are elevated in Parkinson's patients with ICD. We also did not find ICD-related abnormalities in D2 receptor levels. Our findings argue against the possibility that differences in D2/3 receptor levels can account for the development of ICD in PD; however, we cannot rule out that differences in dopamine levels (particularly in ventral striatum) may be involved.

Pathological choice: the neuroscience of gambling and gambling addiction.

Gambling is pertinent to neuroscience research for at least two reasons. First, gambling is a naturalistic and pervasive example of risky decision making, and thus gambling games can provide a paradigm for the investigation of human choice behavior and "irrationality." Second, excessive gambling involvement (i.e., pathological gambling) is currently conceptualized as a behavioral addiction, and research on this condition may provide insights into addictive mechanisms in the absence of exogenous drug effects. This article is a summary of topics covered in a Society for Neuroscience minisymposium, focusing on recent advances in understanding the neural basis of gambling behavior, including translational findings in rodents and nonhuman primates, which have begun to delineate neural circuitry and neurochemistry involved.

Higher binding of the dopamine D3 receptor-preferring ligand [11C]-(+)-propyl-hexahydro-naphtho-oxazin in methamphetamine polydrug users: a positron emission tomography study.

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.

Differences in cortical activity between methamphetamine-dependent and healthy individuals performing a facial affect matching task.

As individuals who abuse methamphetamine (MA) often exhibit socially maladaptive behaviors such as violence and aggression, it is possible that they respond abnormally to social cues. To investigate this issue, we exposed 12 MA-dependent participants (abstinent 5-16 days) and 12 healthy comparison participants to fearful and angry faces while they performed an affect matching task during functional magnetic resonance imaging (fMRI). Although the groups did not differ in task performance, the healthy participants showed more task-related activity than the MA-dependent participants in a set of cortical regions consisting of the ventrolateral prefrontal cortex (VLPFC), temporoparietal junction (TPJ), anterior and posterior temporal cortex, and fusiform gyrus in the right hemisphere, and the cuneus in the left hemisphere. In contrast, the MA-dependent participants showed more task-related activity than the healthy participants in the dorsal anterior cingulate cortex (dACC). As expected, the task elicited activation of the amygdala in both groups; however, contrary to expectation, we found no difference between groups in this activation. Dorsal ACC hyperactivity, along with high self-ratings of hostility and interpersonal sensitivity in the MA-dependent group, suggest a hyper-sensitivity to socially threatening cues in the MA-dependent participants, while lower VLPFC activation could point to a deficit in integrating socio-emotional information and/or regulating this limbic hyperactivity. Additional activation differences in neural circuitry related to social cognition (TPJ, anterior, and posterior temporal cortex) suggest further socio-emotional deficits. Together, the results point to cortical abnormalities that could underlie the socially inappropriate behaviors often shown by individuals who abuse MA.

Corticotropin-releasing hormone and dopamine release in healthy individuals.

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 D2/3 receptor radioligand [11C]-(+)-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 D2/3 PET probe [11C]-(+)-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 [11C]-(+)-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.

Decreased neural specialization in old adults on a working memory task.

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.

Heightened Dopaminergic Response to Amphetamine at the D3 Dopamine Receptor in Methamphetamine Users.

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 D2/3 receptors may be therapeutically beneficial. In contrast, recent investigations indicate heightened D3 receptor levels in stimulant users prompting the view that D3 antagonism may help prevent relapse. Here we tested whether a 'blunted' response to amphetamine in methamphetamine (MA) users extends to D3-rich brain areas. Fourteen MA users and 15 healthy controls completed two positron emission tomographic scans with a D3-preferring probe [11C]-(+)-PHNO at baseline and after amphetamine (0.4 mg/kg). Relative to healthy controls, MA users had greater decreases in [11C]-(+)-PHNO binding (increased dopamine release) after amphetamine in D3-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 D2-rich striatum; however, drug use severity was negatively associated with amphetamine-induced striatal changes in [11C]-(+)-PHNO binding. Our study provides evidence that dopamine transmission in extrastriatal 'D3-areas' is not blunted but rather increased in MA users. Together with our previous finding of elevated D3 receptor level in MA users, the current observation suggests that greater dopaminergic transmission at the D3 dopamine receptor may contribute to motivation to use drugs and argues in favor of D3 antagonism as a possible therapeutic tool to reduce craving and relapse in MA addiction.

Emotion dysregulation and amygdala dopamine D2-type receptor availability in methamphetamine users.

BACKGROUND: Individuals who use methamphetamine chronically exhibit emotional and dopaminergic neurochemical deficits. Although the amygdala has an important role in emotion processing and receives dopaminergic innervation, little is known about how dopamine transmission in this region contributes to emotion regulation. This investigation aimed to evaluate emotion regulation in subjects who met DSM-IV criteria for methamphetamine dependence, and to test for a relationship between self-reports of difficulty in emotion regulation and D2-type dopamine receptor availability in the amygdala. METHOD: Ninety-four methamphetamine-using and 102 healthy-control subjects completed the Difficulties in Emotion Regulation Scale (DERS); 33 of those who used methamphetamine completed the Addiction Severity Index (ASI). A subset of 27 methamphetamine-group and 20 control-group subjects completed positron emission tomography with [(18)F]fallypride to assay amygdala D2-type dopamine receptor availability, measured as binding potential (BPND). RESULTS: The methamphetamine group scored higher than the control group on the DERS total score (p<0.001), with DERS total score positively correlated with the Drug Composite Score on the ASI (p=0.02) in the methamphetamine group. The DERS total score was positively correlated with amygdala BPND in both groups and the combined group of participants (combined: r=0.331, p=0.02), and the groups did not differ in this relationship. CONCLUSION: These findings highlight problems with emotion regulation linked to methamphetamine use, possibly contributing to personal and interpersonal behavioral problems. They also suggest that D2-type dopamine receptors in the amygdala contribute to emotion regulation in both healthy and methamphetamine-using subjects.

D3 dopamine receptor-preferring [11C]PHNO PET imaging in Parkinson patients with dyskinesia.

OBJECTIVE: To investigate whether levodopa-induced dyskinesias (LID) are associated with D3 overexpression in levodopa-treated humans with Parkinson disease (PD). METHODS: In this case-control study, we used PET with the D3-preferring radioligand [(11)C]-(+)-PHNO to estimate D2/3 receptor binding in patients with levodopa-treated PD with LID (n = 12) and without LID (n = 12), and healthy control subjects matched for age, sex, education, and mental status (n = 18). RESULTS: Compared to nondyskinetic patients, those with LID showed heightened [(11)C]-(+)-PHNO binding in the D3-rich globus pallidus. Both PD groups also showed higher binding than controls in the sensorimotor division of the striatum. In contrast, D2/3 binding in the ventral striatum was lower in patients with LID than without, possibly reflecting higher dopamine levels. CONCLUSIONS: Dopaminergic abnormalities contributing to LID may include elevated D2/3 binding in globus pallidus, perhaps reflecting D3 receptor upregulation. The findings support therapeutic strategies that target and diminish activity at D3 to prevent LID.

Fatty Acid Amide Hydrolase Binding in Brain of Cannabis Users: Imaging With the Novel Radiotracer [11C]CURB.

BACKGROUND: One of the major mechanisms for terminating the actions of the endocannabinoid anandamide is hydrolysis by fatty acid amide hydrolase (FAAH), and inhibitors of the enzyme were suggested as potential treatment for human cannabis dependence. However, the status of brain FAAH in cannabis use disorder is unknown. METHODS: Brain FAAH binding was measured with positron emission tomography and [11C]CURB in 22 healthy control subjects and ten chronic cannabis users during early abstinence. The FAAH genetic polymorphism (rs324420) and blood, urine, and hair levels of cannabinoids and metabolites were determined. RESULTS: In cannabis users, FAAH binding was significantly lower by 14%-20% across the brain regions examined than in matched control subjects (overall Cohen's d = 0.96). Lower binding was negatively correlated with cannabinoid concentrations in blood and urine and was associated with higher trait impulsiveness. CONCLUSIONS: Lower FAAH binding levels in the brain may be a consequence of chronic and recent cannabis exposure and could contribute to cannabis withdrawal. This effect should be considered in the development of novel treatment strategies for cannabis use disorder that target FAAH and endocannabinoids. Further studies are needed to examine possible changes in FAAH binding during prolonged cannabis abstinence and whether lower FAAH binding predates drug use.

Occupancy of Dopamine D3 and D2 Receptors by Buspirone: A [11C]-(+)-PHNO PET Study in Humans.

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.

Imaging the D3 dopamine receptor across behavioral and drug addictions: Positron emission tomography studies with [(11)C]-(+)-PHNO.

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.

Measuring cigarette smoking-induced cortical dopamine release: A [¹¹C]FLB-457 PET study.

Striatal dopamine (DA) is thought to have a fundamental role in the reinforcing effects of tobacco smoking and nicotine. Microdialysis studies indicate that nicotine also increases DA in extrastriatal brain areas, but much less is known about its role in addiction. High-affinity D2/3 receptor radiotracers permit the measurement of cortical DA in humans using positron emission tomography (PET). [(11)C]FLB-457 PET scans were conducted in 10 nicotine-dependent daily smokers after overnight abstinence and reinstatement of smoking. Voxel-wise [(11)C]-FLB-457-binding potential (BPND) in the frontal lobe, insula, and limbic regions was estimated in the two conditions. Paired t-tests showed BPND values were reduced following smoking (an indirect index of DA release). The overall peak t was located in the cingulate gyrus, which was part of a larger medial cluster (BPND change -12.1±9.4%) and this survived false discovery rate correction for multiple comparisons. Clusters were also identified in the left anterior cingulate cortex/medial frontal gyrus, bilateral prefrontal cortex (PFC), bilateral amygdala, and the left insula. This is the first demonstration of tobacco smoking-induced cortical DA release in humans; it may be the result of both pharmacological (nicotine) and non-pharmacological factors (tobacco cues). Abstinence increased craving but had minimal cognitive effects, thus limiting correlation analyses. However, given that the cingulate cortex, PFC, insula, and amygdala are thought to have important roles in tobacco craving, cognition, and relapse, these associations warrant investigation in a larger sample. [(11)C]FLB-457 PET imaging may represent a useful tool to investigate individual differences in tobacco addiction severity and treatment response.

Personality disorder symptomatology is associated with anomalies in striatal and prefrontal morphology.

Personality disorder symptomatology (PD-Sx) can result in personal distress and impaired interpersonal functioning, even in the absence of a clinical diagnosis, and is frequently comorbid with psychiatric disorders such as substance use, mood, and anxiety disorders; however, they often remain untreated, and are not taken into account in clinical studies. To investigate brain morphological correlates of PD-Sx, we measured subcortical volume and shape, and cortical thickness/surface area, based on structural magnetic resonance images. We investigated 37 subjects who reported PD-Sx exceeding DSM-IV Axis-II screening thresholds, and 35 age, sex, and smoking status-matched control subjects. Subjects reporting PD-Sx were then grouped into symptom-based clusters: N = 20 into Cluster B (reporting Antisocial, Borderline, Histrionic, or Narcissistic PD-Sx) and N = 28 into Cluster C (reporting Obsessive-Compulsive, Avoidant, or Dependent PD-Sx); N = 11 subjects reported PD-Sx from both clusters, and none reported Cluster A (Paranoid, Schizoid, or Schizotypal) PD-Sx. Compared to control, Cluster C PD-Sx was associated with greater striatal surface area localized to the caudate tail, smaller ventral striatum volumes, and greater cortical thickness in right prefrontal cortex. Both Cluster B and C PD-Sx groups also showed trends toward greater posterior caudate volumes and orbitofrontal surface area anomalies, but these findings did not survive correction for multiple comparisons. The results point to morphological abnormalities that could contribute to Cluster C PD-Sx. In addition, the observations parallel those in substance use disorders, pointing to the importance of considering PD-Sx when interpreting findings in often-comorbid psychiatric disorders.

Differential cardiovascular and hypothalamic pituitary response to amphetamine in male pathological gamblers versus healthy controls.

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.

What is the role of the D3 receptor in addiction? A mini review of PET studies with [(11)C]-(+)-PHNO.

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.

Heightened D3 dopamine receptor levels in cocaine dependence and contributions to the addiction behavioral phenotype: a positron emission tomography study with [11C]-+-PHNO.

The dopamine system is a primary treatment target for cocaine dependence (CD), but research on dopaminergic abnormalities (eg, D2 receptor system deficiencies) has so far failed to translate into effective treatment strategies. The D3 receptor system has recently attracted considerable clinical interest, and D3 antagonism is now under investigation as a novel avenue for addiction treatment. The objective here was to evaluate the status and behavioral relevance of the D3 receptor system in CD, using the positron emission tomography (PET) radiotracer [(11)C]-(+)-PHNO. Fifteen CD subjects (many actively using, but all abstinent 7-240 days on scan day) and fifteen matched healthy control (HC) subjects completed two PET scans: one with [(11)C]-(+)-PHNO to assess D3 receptor binding (BPND; calculated regionally using the simplified reference tissue model), and for comparison, a second scan with [(11)C]raclopride to assess D2/3 binding. CD subjects also completed a behavioral battery to characterize the addiction behavioral phenotype. CD subjects showed higher [(11)C]-(+)-PHNO BPND than HC in the substantia nigra, which correlated with behavioral impulsiveness and risky decision making. In contrast, [(11)C]raclopride BPND was lower across the striatum in CD, consistent with previous literature in 2 week abstinence. The data suggest that in contrast to a D2 deficiency, CD individuals may have heightened D3 receptor levels, which could contribute to addiction-relevant traits. D3 upregulation is emerging as a biomarker in preclinical models of addiction, and human PET studies of this receptor system can help guide novel pharmacological strategies for treatment.