BACKGROUND: Dopaminergic tone and phasic release have transdiagnostic relevance. Preclinical research suggests that the active form of vitamin D, calcitriol, increases subcortical tyrosine hydroxylase, D2/D3 receptors, and amphetamine-stimulated dopamine release in rodents. Comparable studies have not been conducted in humans. METHODS: Healthy, vitamin D-sufficient adults (N = 18, 32.8 6 6.6 years; 33% female) participated in a randomized, double-blind, placebo-controlled within-subjects study involving 4 total scans over 2 visits consisting of same-day preamphetamine and postamphetamine (0.3 mg/kg) [11C]-PHNO positron emission tomography scanning to examine D2/D3 receptor availability (nondisplaceable binding potential [BPND]) following active calcitriol (1.5 mg night before experimental day and 1.5 mg morning of experimental day) or placebo at least 6 days apart. Parametric images of [11C]-PHNO positron emission tomography BPND were computed using a simplified reference tissue model with the cerebellum as reference. Blood samples were acquired to measure serum calcitriol, amphetamine, and calcium levels. Regions of interest examined were the dorsal caudate, dorsal putamen, ventral striatum, globus pallidus, and substantia nigra. RESULTS: For preamphetamine scans, there was a medication 3 region of interest interaction (F4,153 = 2.59, p = .039) and a main effect of medication (F1,153 = 4.88, p = .029) on BPND, with higher BPND values on calcitriol in the ventral striatum (t153 = 2.89, p = .004) and dorsal putamen (t153 = 2.15, p = .033). There was a main effect of medication on postamphetamine change in BPND (F4,153 = 5.93, p = .016), with greater decreases in calcitriol in the ventral striatum (t153 = 3.00, p = .003), substantia nigra (t153 = 2.49, p = .014), and dorsal caudate (t153 = 2.29, p = .023). CONCLUSIONS: Results provide translational support for vitamin D to target dopaminergic tone, with implications for clinical disorders that involve dysregulated dopamine function.

Objectives: Our group has previously established how remote on-body electrocardiogram (ECG) sensors may discriminate cocaine use from other sympathomimetic conditions. The current analyses assess whether discriminatory power is mainly driven by differences in heart rate between conditions. Methods: Individuals who use cocaine (N = 11) wore ECG sensors during (1) cocaine self-administration, (2) methylphenidate administration, (3) aerobic exercise, and (4) tobacco use (N = 9). Primary outcomes included: (1) time elapsed between 2 successive R waves (ie, RR interval), (2) ECG interval proxies, and (3) waveforms. ECG traces were matched for heart rate between conditions for all discriminations. Results: ECG interval proxies and waveforms exhibited high discriminatory power in distinguishing cocaine use from methylphenidate, exercise, and tobacco use, with mean areas under the receiver operating characteristics ranging from 0.87 to 0.99, while RR-related measures ranged from 0.49 to 0.5, reflecting low discriminatory power. Conclusion: Our results suggest that the ECG sensors’ discriminatory power is based on nuances in ECG data beyond mere changes in heart rate.

BACKGROUND:Genetic research on nicotine dependence has utilized multiple assessments that are in weak agreement. METHODS:We conducted a genome-wide association study (GWAS) of nicotine dependence defined using the Diagnostic and Statistical Manual of Mental Disorders (DSM-NicDep) in 61,861 individuals (47,884 of European ancestry [EUR], 10,231 of African ancestry, and 3,746 of East Asian ancestry) and compared the results to other nicotine-related phenotypes. RESULTS:We replicated the well-known association at the CHRNA5 locus (lead single-nucleotide polymorphism [SNP]: rs147144681, p = 1.27E-11 in EUR; lead SNP = rs2036527, p = 6.49e-13 in cross-ancestry analysis). DSM-NicDep showed strong positive genetic correlations with cannabis use disorder, opioid use disorder, problematic alcohol use, lung cancer, material deprivation, and several psychiatric disorders, and negative correlations with respiratory function and educational attainment. A polygenic score of DSM-NicDep predicted DSM-5 tobacco use disorder criterion count and all 11 individual diagnostic criteria in the independent National Epidemiologic Survey on Alcohol and Related Conditions-III sample. In genomic structural equation models, DSM-NicDep loaded more strongly on a previously identified factor of general addiction liability than a "problematic tobacco use" factor (a combination of cigarettes per day and nicotine dependence defined by the Fagerström Test for Nicotine Dependence). Finally, DSM-NicDep showed a strong genetic correlation with a GWAS of tobacco use disorder as defined in electronic health records (EHRs). CONCLUSIONS:Our results suggest that combining the wide availability of diagnostic EHR data with nuanced criterion-level analyses of DSM tobacco use disorder may produce new insights into the genetics of this disorder.

Rates of opioid use disorder (OUD) and overdose deaths have increased dramatically in recent years. Currently approved medications for OUD include the opioid agonists methadone and buprenorphine, and the opioid antagonist naltrexone. However, relapse rates are high due to an impaired ability for addicts to control their urge to consume due to strong cravings, and the extreme severity of withdrawal symptoms. Additionally, the nature of the agonists can lead to abuse of those compounds as well. Non-opioid targets, such as glutamate receptors, are potentially ideal for developing intervention strategies with the goal of reducing OUD, relapse, and overdose death. NYX-783 is a small molecule positive allosteric modulator for the glutamate receptor NMDA. It has been shown to modulate learning and memory, both of which are impaired in drug addicts, and known play a role in relapse. Using mice, we have conducted preclinical studies to evaluate the potential for NYX-783 as a therapeutic for OUD with assessment of several outcomes: 1) respiratory depression, 2) consumption during maintenance of regular consumption as well as post-abstinence reinstatement, 3) motivation for consumption, 4) somatic withdrawals, and 5) the development of aversion to withdrawal symptoms. For respiratory depression studies, mice were pretreated 1h prior with NYX-783 and respiratory rates were monitored for 15min after each escalating dose of oxycodone. No effects were seen for any dose of NYX-783. To test for effects on drug consumption, mice were trained to orally self-administer oxycodone and then treated every two days with different doses of NYX-783 or entering an abstinence phase prior to testing with NYX-783. No effect on intake at clinically-relevant doses was observed during regular maintenance or post-abstinence intake. Additionally, we used a progressive ratio to assess the motivation self-administering mice had for reward acquisition, and no effect of NYX-783 was observed on rewards earned. We next evaluated withdrawal using two separate paradigms to test for effects of NYX-783 on, 1) for somatic withdrawal symptoms, 2) aversion to the state of withdrawal. For somatic withdrawal, using higher doses of naloxone (1 mg/kg), NYX-783 did not attenuate jumping behavior. For aversion to withdrawal, three aversion pairings were completed that consisted of oxycodone treatment, followed by NYX-783 preceding a low dose of naloxone (0.1mg/kg ip) immediately before pairing in a specific context. These alternated with neutral (saline) pairings daily. We observed a significant improvement in aversion scores in female mice treated with NYX-783, and a trending significant improvement in males. This suggests a potential therapeutic use for NYX-783 in reducing the negative state of withdrawal that can drive relapse in OUD.

Postmortem analyses of deceased opioid users show elevated glial markers and disrupted neuroinflammatory pathways. To date, evidence of neuroinflammation among living persons with opioid use disorder (OUD) is lacking. To address this question, OUD patients and control subjects underwent Positron Emission Tomography (PET) imaging with [11C]PBR28, a widely-used in vivo neuroimmune system marker.

Background: Our group has established the feasibility of using on-body electrocardiographic (ECG) sensors to detect cocaine use in the human laboratory. The purpose of the current study was to test whether ECG sensors and features are capable of discriminating cocaine use from other non-cocaine sympathomimetics.Methods: Eleven subjects with cocaine use disorder wore the Zephyr BioHarnessTM 3 chest band under six experimental (drug and non-drug) conditions, including 1) laboratory, intravenous cocaine self-administration, 2) after a single oral dose of methylphenidate, 3) during aerobic exercise, 4) during tobacco use (N=7 who smoked tobacco), and 5) during routine activities of daily inpatient living (unit activity). Three ECG-derived feature sets served as primary outcome measures, including 1) the RR interval (i.e., heart rate), 2) a group of ECG interval proxies (i.e., PR, QS, QT and QTc intervals), and 3) the full ECG waveform. Discriminatory power between cocaine and non-cocaine conditions for each of the three outcomes measures was expressed as the area under the receiver operating characteristics (AUROC) curve.Results: All three outcomes successfully discriminated cocaine use from unit activity, exercise, tobacco, and methylphenidate conditions with a mean AUROC values ranging from 0.66 to 0.99 and with least squares means values all statistically different/higher than 0.5 among all subjects [F(3, 99) = 3.38, p =0.02] and among those with tobacco use [F(4, 84) = 5.39, p = 0.0007].Conclusions: These preliminary results support discriminatory power of wearable ECG sensors for detecting cocaine use.

Alcohol use disorder (AUD) is a leading cause of death and disability worldwide. Genome-wide association studies (GWAS) have identified ~30 AUD risk genes in European populations, but many fewer in East Asians. We conducted GWAS and genome-wide meta-analysis of AUD in 13,551 subjects with East Asian ancestry, using published summary data and newly genotyped data from five cohorts: (1) electronic health record (EHR)-diagnosed AUD in the Million Veteran Program (MVP) sample; (2) DSM-IV diagnosed alcohol dependence (AD) in a Han Chinese–GSA (array) cohort; (3) AD in a Han Chinese–Cyto (array) cohort; and (4) two AD Thai cohorts. The MVP and Thai samples included newly genotyped subjects from ongoing recruitment. In total, 2254 cases and 11,297 controls were analyzed. An AUD polygenic risk score was analyzed in an independent sample with 4464 East Asians (Genetic Epidemiology Research in Adult Health and Aging (GERA)). Phenotypes from survey data and ICD-9-CM diagnoses were tested for association with the AUD PRS. Two risk loci were detected: the well-known functional variant rs1229984 in ADH1B and rs3782886 in BRAP (near the ALDH2 gene locus) are the lead variants. AUD PRS was significantly associated with days per week of alcohol consumption (beta = 0.43, SE = 0.067, p = 2.47 × 10−10) and nominally associated with pack years of smoking (beta = 0.09, SE = 0.05, p = 4.52 × 10−2) and ever vs. never smoking (beta = 0.06, SE = 0.02, p = 1.14 × 10−2). This is the largest GWAS of AUD in East Asians to date. Building on previous findings, we were able to analyze pleiotropy, but did not identify any new risk regions, underscoring the importance of recruiting additional East Asian subjects for alcohol GWAS.

Aims: To describe and compare methamphetamine (MA) users with and without a family history of alcohol or drug () use in the household. Design: A total of 1144 Thai-speaking MA users in Thailand were recruited for a cohort study. Cross-sectional baseline data were analyzed according to their exposure to FAOD use (FAOD+/FAOD-). The Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA) was utilized to collect baseline socio-demographic information and variables known to be associated with the impact of FAOD use. Findings: FAOD+ participants had lower average years of education (p<0.01), fewer average months of employment in the past year (p<0.01) and reported higher rates of self-harm experience (p<0.001), gambling (p=0.018) and antisocial personality disorder (p=0.015). FAOD+ participants had more severe clinical, adverse consequences. FAOD+ significantly predicted episodes of lifetime MA use (R2 =0.004, p=0.032), the largest number of drinks ever had in a 24-hour period (R2 =0.01, p=0.001), paranoid experiences ([OR]=1.090, p=0.004), alcohol dependence ([OR]=1.112, p=0.001) and antisocial personality disorder ([OR]=1.139, p=0.015). FAOD+ participants who were exposed to alcohol only were more likely to report a significantly higher number of drinks ever had in a 24-hour periods (p<0.005). Similarly, FAOD+ participants who were exposed to MA use only were significantly more likely to report more frequent use of MA (p<0.005). Conclusions: FAOD+ participants were characterized by a generally more severe clinical presentation than FAOD- participants. Moreover, we show the specificity of drug type mattered, with family exposure of alcohol and MA associated with greater subsequent use of the respective drugs.

BACKGROUND:Positron emission tomography (PET) work with the dopamine D3 receptor (D3R) preferring ligand [11C]PHNO in obese individuals has demonstrated higher binding and positive correlations with body mass index (BMI) in otherwise healthy individuals. These findings implicated brain reward areas including the substantia nigra/ventral tegmental area (SN/VTA) and pallidum. In cocaine use disorder (CUD), similar SN/VTA binding profiles have been found compared to healthy control subjects. This study investigates whether BMI-[11C]PHNO relationships are similar in individuals with CUD. METHODS:Non-obese CUD subjects (N = 12) were compared to age-matched obese CUD subjects (N = 14). All subjects underwent [11C]PHNO acquisition using a High Resolution Research Tomograph PET scanner. Parametric images were computed using the simplified reference tissue model with cerebellum as the reference region. [11C]PHNO measures of receptor availability were calculated and expressed as non-displaceable binding potential (BPND). RESULTS:In between-group analyses, D2/3R availability in non-obese and obese CUD groups was not significantly different overall. BMI was inversely correlated withBPND in the SN/VTA (r = -0.45, p = 0.02 uncorrected) in all subjects. CONCLUSION:These data suggest that obesity in CUD was not associated with significant differences in D2/3R availability. This in contrast to previous findings in non-CUD individuals that found increased availability of D3Rs in the SN/VTA associated with obesity. These findings could potentially reflect dysregulation of D3R in CUD, impacting how affected individuals respond to natural stimuli such as food.

C-11-UCB-J ((R)-1-((3-(C-11-methyl-C-11)pyridin-4-yl)-methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one) is a PET tracer for synaptic vesicle glycoprotein 2A, which may be a marker of synaptic density. To simplify the scan protocol, SUV ratios (SUVRs) were compared with model-based nondisplaceable binding potential (BPND) to select the optimal time window in healthy and neuropsychiatric subjects. Methods: In total, 141 scans were acquired for 90 min. Arterial blood sampling and metabolite analysis were conducted. SUVR-1 (centrum semiovale reference region) was computed for six 30-min windows and compared with 1-tissue-compartment model BPND. Simulations were performed to assess the time dependency of SUVR-1. Results: Greater correlation and less bias were observed for SUVR-1 at later time windows for all subjects. Simulations showed that the agreement between SUVR-1 and BPND is time-dependent. Conclusion: The 60- to 90-min period provided the best match between SUVR-1 and BPND (-1% +/- 7%); thus, a short scan is sufficient for accurate quantification of C-11-UCB-J-specific binding.

Beyond its established role in calcium homeostasis, vitamin D acts as a neuroactive steroid. Our group has shown important effects of its physiologically active form, calcitriol, on mesolimbic dopamine (DA) systems in rodents, including increases in subcortical tyrosine hydroxylase, D2/3 receptors, and amphetamine-stimulated DA release and locomotion. However, calcitriol’s effects on midbrain DA function in humans are untested. We explored whether calcitriol enhances D2/3 receptors/subcortical DA release in healthy humans as measured by 11C-PHNO PET.

Background: Preclinical rodent studies have demonstrated reduced cocaine taking after administration of glucagon-like peptide 1 (GLP-1) analogues. We investigated effects of a GLP-1 analogue (exenatide) on behavioral and subjective effects of cocaine in individuals with cocaine use disorder (CUD). Methods: Non-treatment-seeking CUD subjects underwent two human laboratory cocaine self-administration test sessions following an acute 3 -h pre-treatment with exenatide (5 mcg; subcutaneously) or placebo. Primary outcomes consisted of infusions of cocaine and visual analog scale self-ratings of euphoria and wanting cocaine. Secondary outcomes consisted of pertinent hormone levels (GLP-1, insulin, and amylin). Results: Thirteen individuals completed the study. Acute pretreatment with exenatide versus placebo did not change cocaine infusions (8.5 ? 1.2 vs. 9.1 ? 1.2; p = 0.39), self-reported euphoria (4.4 ? 0.8 vs. 4.1 ? 0.8; p = 0.21), or wanting of cocaine (5.6 ? 0.9 vs. 5.4 ? 0.9; p = 0.46). Exenatide vs. placebo reduced levels of GLP-1 (p = 0.03) and insulin (p = 0.02). Self-administered cocaine also reduced levels of GLP-1 (p < 0.0001), insulin (p < 0.0001), and amylin (p < 0.0001). Conclusions: We did not find evidence that low dose exenatide alters cocaine self-administration or the subjective effects of cocaine in people with CUD. Limitations such as single acute rather than chronic pre-treatment, as well as evaluation of only one dose, preclude drawing firm conclusions about the efficacy of exenatide. Exenatide and cocaine independently reduced levels of GLP-1 and insulin, while cocaine also reduced levels of amylin.

Preclinical studies have revealed robust and long-lasting alterations in dendritic spines in the brain following cocaine exposure. Such alterations are hypothesized to underlie enduring maladaptive behaviours observed in cocaine use disorder (CUD). The current study explored whether synaptic density is altered in CUD. Fifteen individuals with DSM-5 CUD and 15 demographically matched healthy control (HC) subjects participated in a single 11 C-UCB-J positron emission tomography scan to assess density of synaptic vesicle glycoprotein 2A (SV2A). The volume of distribution (VT ) and the plasma-free fraction-corrected form of the total volume of distribution (VT /fP ) were analysed in the anterior cingulate cortex (ACC), dorsomedial and ventromedial prefrontal cortex (PFC), lateral and medial orbitofrontal cortex (OFC) and ventral striatum. A significant diagnostic-group-by-region interaction was observed for VT and VT /fP . Post hoc analyses revealed no differences on VT , while for VT /fP showed lower values in CUD as compared with HC subjects in the ACC (-10.9%, p = 0.02), ventromedial PFC (-9.9%, p = 0.02) and medial OFC (-9.9%, p = 0.04). Regional VT /fP values in CUD, though unrelated to measures of lifetime cocaine use, were positively correlated with the frequency of recent cocaine use (p = 0.02-0.03) and negatively correlated with cocaine abstinence (p = 0.008-0.03). These findings provide initial preliminary in vivo evidence of altered (lower) synaptic density in the PFC of humans with CUD. Cross-sectional variation in SV2A availability as a function of recent cocaine use and abstinence suggests that synaptic density may be dynamically and plastically regulated by acute cocaine, an observation that merits direct testing by studies using more definitive longitudinal designs.

Background: The Semi-structured Assessment for Drug Dependence and Alcoholism (SSADDA) was developed to assess substance-use disorders and other psychiatric traits. We translated the SSADDA into Chinese and evaluated its inter-rater reliability and concurrent validity in diagnosing DSM-IV methamphetamine (MA) dependence and DSM-5 MA-use disorder (MUD). Methods: The sample comprised 231 participants who were interviewed using the Chinese SSADDA and the Mini International Neuropsychiatric Interview (Chinese MINI) for concurrent validation. Of the 231 participants, 191 were interviewed by two different interviewers two weeks apart. We evaluated the inter-rater reliability and concurrent validity of the diagnoses using percent agreement and Cohen's kappa coefficient (kappa). Cohen's linear weighted kappa was used to assess the reliability of DSM-5 MUD severity. Results: It showed good inter-rater reliability and no significant differences among the DSM-5 MUD (kappa = 0.71), DSM-IV MA abuse or dependence (kappa = 0.72), and the DSM-IV diagnoses of MA dependence (kappa = 0.66) and abuse (kappa = 0.68) tested separately. The weighted kappa was 0.67 across the three DSM-5 MUD severity levels. The reliability of each individual diagnostic criterion for DSM-5 MUD ranged from fair to excellent (kappa = 0.41-0.80), except for "repeated attempts to quit/control use" (kappa = 0.38). The concurrent validity based on MINI-derived diagnoses ranged from good to excellent (kappa = 0.65-0.78). Conclusions: This study shows that the Chinese version of SSADDA has good reliability and validity among Chinese MA users.

Stimulant-use disorders have been associated with lower availability of dopamine type-2 receptors (D2R) and greater availability of type-3 receptors (D3R). Links between D2R levels, cognitive performance, and suppression of the default mode network (DMN) during executive functioning have been observed in healthy and addicted populations; however, there is limited evidence regarding a potential role of elevated D3R in influencing cognitive control processes in groups with and without addictions. Sixteen individuals with cocaine-use disorder (CUD) and 16 healthy comparison (HC) participants completed [11C]-(+)-PHNO PET imaging of D2R and D3R availability and fMRI during a Stroop task of cognitive control. Independent component analysis was performed on fMRI data to assess DMN suppression during Stroop performance. In HC individuals, lower D2R-related binding in the dorsal putamen was associated with improved task performance and greater DMN suppression. By comparison, in individuals with CUD, greater D3R-related binding in the substantia nigra was associated with improved performance and greater DMN suppression. Exploratory moderated-mediation analyses indicated that DMN suppression was associated with Stroop performance indirectly through D2R in HC and D3R in CUD participants, and these indirect effects were different between groups. To our knowledge, this is the first evidence of a dissociative and potentially beneficial role of elevated D3R availability in executive functioning in cocaine-use disorder.