Structural brain changes associated with cocaine use and digital cognitive behavioral therapy in cocaine use disorder treatment.

Background: Few studies have investigated changes in brain structure and function associated with recovery from cocaine use disorder (CUD), and fewer still have identified brain changes associated with specific CUD treatments, which could inform treatment development and optimization. Methods: In this longitudinal study, T1-weighted magnetic resonance imaging scans were acquired from 41 methadone-maintained individuals with CUD (15 women) at the beginning of and after 12 weeks of outpatient treatment. As part of a larger randomized controlled trial, these participants were randomly assigned to receive (or not) computer-based training for cognitive behavioral therapy (CBT4CBT), and galantamine (or placebo). Results: Irrespective of treatment condition, whole-brain voxel-based morphometry analyses revealed a significant decrease in right caudate body, bilateral cerebellum, and right middle temporal gyrus gray matter volume (GMV) at post-treatment relative to the start of treatment. Subsequent region of interest analyses found that greater reductions in right caudate and bilateral cerebellar GMV were associated with higher relative and absolute levels of cocaine use during treatment, respectively. Participants who completed more CBT4CBT modules had a greater reduction in right middle temporal gyrus GMV. Conclusions: These results extend previous findings regarding changes in caudate and cerebellar GMV as a function of cocaine use and provide the first evidence of a change in brain structure as a function of engagement in digital CBT for addiction. These data suggest a novel potential mechanism underlying how CBT4CBT and CBT more broadly may exert therapeutic effects on substance-use-related behaviors through brain regions implicated in semantic knowledge.

The ReCoDe addiction research consortium: Losing and regaining control over drug intake-Findings and future perspectives.

Substance use disorders (SUDs) are seen as a continuum ranging from goal-directed and hedonic drug use to loss of control over drug intake with aversive consequences for mental and physical health and social functioning. The main goals of our interdisciplinary German collaborative research centre on Losing and Regaining Control over Drug Intake (ReCoDe) are (i) to study triggers (drug cues, stressors, drug priming) and modifying factors (age, gender, physical activity, cognitive functions, childhood adversity, social factors, such as loneliness and social contact/interaction) that longitudinally modulate the trajectories of losing and regaining control over drug consumption under real-life conditions. (ii) To study underlying behavioural, cognitive and neurobiological mechanisms of disease trajectories and drug-related behaviours and (iii) to provide non-invasive mechanism-based interventions. These goals are achieved by: (A) using innovative mHealth (mobile health) tools to longitudinally monitor the effects of triggers and modifying factors on drug consumption patterns in real life in a cohort of 900 patients with alcohol use disorder. This approach will be complemented by animal models of addiction with 24/7 automated behavioural monitoring across an entire disease trajectory; i.e. from a naïve state to a drug-taking state to an addiction or resilience-like state. (B) The identification and, if applicable, computational modelling of key molecular, neurobiological and psychological mechanisms (e.g., reduced cognitive flexibility) mediating the effects of such triggers and modifying factors on disease trajectories. (C) Developing and testing non-invasive interventions (e.g., Just-In-Time-Adaptive-Interventions (JITAIs), various non-invasive brain stimulations (NIBS), individualized physical activity) that specifically target the underlying mechanisms for regaining control over drug intake. Here, we will report on the most important results of the first funding period and outline our future research strategy.

Assessing daily patterns in stimulant use during the COVID-19 pandemic in Melbourne, Australia using wastewater analysis.

During the COVID-19 pandemic, one of Australia's biggest cities, Melbourne, experienced three major isolation ("lockdown") periods in 2020 (160 days) and in 2021 (111 days) which makes it one of the most locked down cities world-wide. This study assessed how the pandemic affected temporal trends in methamphetamine, MDMA and cocaine consumption using wastewater-based epidemiology. Daily samples were collected for most of 2020 and 2021 (n = 660 days). Concentrations were measured using direct-injection LC-MS/MS and back-calculated to consumption estimates. Results indicate that methamphetamine use was increasing before the first lockdown and decreased after the end of the first lockdown in 2020. Methamphetamine trends appeared to have remained steady throughout the second lockdown period before increasing steeply after it ended. For most of 2020, cocaine use remained steady, with an increase after the second lockdown. MDMA use decreased after the start of the first lockdown and remained steady throughout most of 2020 and 2021. In comparison to 2020, trends in 2021 were less variable and stimulant use did not appear to be as associated with COVID-19 restrictions. Overall, this study was able to show the impact of lockdown periods and the related social restrictions on illicit stimulant use. ENVIRONMENTAL IMPLICATION: Illicit drugs are hazardous chemicals, of concern both to humans and the environment. While studies have been undertaken to understand their temporal trends, this work utilizes wastewater-based epidemiology and daily sampling to provide a comprehensive understanding of the impact of the COVID-19 pandemic on the use of methamphetamine, MDMA and cocaine on one of the most locked-down cities in the world. Understanding the consequences of this significant intervention on illicit drug use could provide valuable insights into its potential environmental impact.

Conditional deletion of the AMPA-GluA1 and NMDA-GluN1 receptor subunit genes in midbrain D1 neurons does not alter cocaine reward in mice.

Synaptic plasticity in the mesolimbic dopamine (DA) system contributes to the neural adaptations underlying addictive behaviors and relapse. However, the specific behavioral relevance of glutamatergic excitatory drive onto dopamine D1 receptor (D1R)-expressing neurons in mediating the reinforcing effect of cocaine remains unclear. Here, we investigated how midbrain AMPAR and NMDAR function modulate cocaine reward-related behavior using mutant mouse lines lacking the glutamate receptor genes Gria1 or Grin1 in D1R-expressing neurons (GluA1D1CreERT2 or GluN1D1CreERT2, respectively). We found that conditional genetic deletion of either GluA1 or GluN1 within this neuronal sub-population did not impact the ability of acute cocaine injection to increase intracranial self-stimulation (ICSS) ratio or reduced brain reward threshold compared to littermate controls. Additionally, our data demonstrate that deletion of GluA1 and GluN1 receptor subunits within D1R-expressing neurons did not affect cocaine reinforcement in an operant self-administration paradigm, as mutant mice showed comparable cocaine responses and intake to controls. Given the pivotal role of glutamate receptors in mediating relapse behavior, we further explored the impact of genetic deletion of AMPAR and NMDAR onto D1R-expressing neurons on cue-induced reinstatement following extinction. Surprisingly, deletion of AMPAR and NMDAR onto these neurons did not impair cue-induced reinstatement of cocaine-seeking behavior. These findings suggest that glutamatergic activity via NMDAR and AMPAR in D1R-expressing neurons may not exclusively mediate the reinforcing effects of cocaine and cue-induced reinstatement.

Application of European Society of Cardiology guidelines for evaluating acute coronary syndrome risk in low-risk patients with cocaine-associated chest pain: Findings from the RISK study - An observational analysis.

Background: Cocaine was the drug of choice in 4.7 % of all recreational drug-related emergency department visits. Of these patients, 40 % present with cocaine-associated chest pain, of whom 4.7 % develop an acute coronary syndrome. The American Heart Association recommends a 12-hour observation period for these patients. Objective: This study primarily aimed to ascertain whether the European Society of Cardiology non-ST-elevation myocardial infarction guidelines can be safely applied to rule-out acute coronary syndrome in low-risk patients with cocaine-associated chest pain. Methods: For this prospective observational cohort study, patients, aged 18-45 years old, who presented with cocaine-associated chest pain and were risk stratified as low risk according to the European Society of Cardiology non-ST-elevation myocardial infarction guidelines and therefore discharged home without prolonged observation period, were included. They were followed to assess major adverse cardiac events four weeks after presentation to the emergency department or chest pain unit. Cocaine use was confirmed with urine toxicology screening. Results: A total of 107 patients were included and analysed. The accuracy of the self-reported history of recent cocaine use was 94 %. Post-discharge cocaine use persisted among 32 % of patients. None of the included 107 patients died and major adverse cardiac event within four weeks did not occur among 97 patients with available data regarding MACE. Conclusion: Ruling out an acute coronary syndrome using the European Society of Cardiology non-ST-elevation myocardial infarction guidelines is likely to be safe for patients with cocaine-associated chest pain, however this study was underpowered to reach definitive conclusions.

Changes in dorsomedial striatum activity during expression of goal-directed vs. habit-like cue-induced cocaine seeking.

A preclinical model of cue exposure therapy, cue extinction, reduces cue-induced cocaine seeking that is goal-directed but not habit-like. Goal-directed and habitual behaviors differentially rely on the dorsomedial striatum (DMS) and dorsolateral striatum (DLS), but the effects of cue extinction on dorsal striatal responses to cue-induced drug seeking are unknown. We used fiber photometry in rats trained to self-administer cocaine paired with an audiovisual cue to examine how dorsal striatal intracellular calcium and extracellular dopamine activity differs between goal-directed and habit-like cue-induced cocaine seeking and how it is impacted by cue extinction. After minimal fixed-ratio training, rats showed enhanced DMS and DLS calcium responses to cue-reinforced compared to unreinforced lever presses. After rats were trained on goal-promoting fixed ratio schedules or habit-promoting second-order schedules of reinforcement, different patterns of dorsal striatal calcium and dopamine responses to cue-reinforced lever presses emerged. Rats trained on habit-promoting second-order schedules showed reduced DMS calcium responses and enhanced DLS dopamine responses to cue-reinforced lever presses. Cue extinction reduced calcium responses during subsequent drug seeking in the DMS, but not in the DLS. Therefore, cue extinction may reduce goal-directed behavior through its effects on the DMS, whereas habit-like behavior and the DLS are unaffected.

[Screening of the lncRNA SNHG3 regulating CART expression in the bovine hypothalamus].

This study aimed to screen for the long non-coding RNA (lncRNA) small nucleolar RNA host gene 3 (SNHG3) capable of regulating the expression of cocaine- and amphetamine-regulated transcriptional peptide (CART) in the bovine hypothalamus and elucidate the underlying mechanism. StarBase v2.0, NCBI, and DIANA tools were used to predict the lncRNAs targeting miR-381 and miR-491, which were responsible for inhibiting CART expression. The binding sites were analyzed, and the endogenous expression of the selected lncRNAs was determined by semi-quantitative RT-PCR of the hypothalamus tissue from three healthy adult Simmental cows. The dual-luciferase reporter gene assay was employed to detect the targeted binding relationship between miR-381/491 and lncRNAs. The over-expression vectors of lncRNAs, CART, and miR-381/491 mimics were constructed and transfected into 293T cells to reveal the mechanism of lncRNAs in regulating the CART expression. Animal experiments were conducted to analyze the regulatory function of the strongest lncRNA at the cellular level. The results showed that lncRNAs TUG1, SNHG3, H19, SNHG12, and DANCR were expressed in the bovine hypothalamus. The lncRNAs TUG1 and SNHG3 had binding sites for miR-381, and H19, SNHG12, and DANCR had binding sites for miR-491. The dual-luciferase reporter gene assay showed that miR-381 inhibited the relative luciferase activities of TUG1-WT (P < 0.05) and SNHG3-WT (P < 0.01), and miR-491 inhibited the luciferase activities of DANCR-WT (P < 0.05), H19-WT (P < 0.05), and SNHG12-WT (P < 0.01). SNHG3 and SNHG12 up-regulated the CART expression by specifically binding to miR-381 (P < 0.001) and miR-491 (P < 0.01), respectively, and SNHG3 had the strongest effect of regulating CART expression. The results from animal experiments showed that SNHG3 significantly up-regulated the mRNA and protein levels of CART by specifically binding to miR-381. This study confirmed that the lncRNA SNHG3, acting as a competing endogenous RNA of miR-381, significantly up-regulated CART expression at the transcriptional and post-transcriptional levels, laying a foundation for deciphering the mechanism of the molecular network regulation of CART in the bovine hypothalamus.

Detecting univariate, bivariate, and overall effects of drug mixtures using Bayesian kernel machine regression.

Background: Innovative analytic approaches to drug studies are needed to understand better the co-use of opioids with non-opioids among people using illicit drugs. One approach is the Bayesian kernel machine regression (BKMR), widely applied in environmental epidemiology to study exposure mixtures but has received far less attention in substance use research.Objective: To describe the utility of the BKMR approach to study the effects of drug substance mixtures on health outcomes.Methods: We simulated data for 200 individuals. Using the Vale and Maurelli method, we simulated multivariate non-normal drug exposure data: xylazine (mean = 300 ng/mL, SD = 100 ng/mL), fentanyl (mean = 200 ng/mL, SD = 71 ng/mL), benzodiazepine (mean = 300 ng/mL, SD = 55 ng/mL), and nitazene (mean = 200 ng/mL, SD = 141 ng/mL) concentrations. We performed 10,000 MCMC sampling iterations with three Markov chains. Model diagnostics included trace plots, r-hat values, and effective sample sizes. We also provided visual relationships of the univariate and bivariate exposure-response and the overall mixture effect.Results: Higher levels of fentanyl and nitazene concentrations were associated with higher levels of the simulated health outcome, controlling for age. Trace plots, r-hat values, and effective sample size statistics demonstrated BKMR stability across multiple Markov chains.Conclusions: Our understanding of drug mixtures tends to be limited to studies of single-drug models. BKMR offers an innovative way to discern which substances pose a greater health risk than other substances and can be applied to assess univariate, bivariate, and cumulative drug effects on health outcomes.

Co-stimulation of muscarinic M1 and M4 acetylcholine receptors prevents later cocaine reinforcement in male and female mice, but not place-conditioning.

Acute stimulation of M1 or M4 muscarinic cholinergic receptors reduces cocaine abuse-related effects in mice and rats. The combined activation of these receptor subtypes produces synergistic effects on some behavioural endpoints in mice. M1 and M1 + M4 receptor stimulation in a cocaine vs. food choice assay in rats and microdialysis in rats showed delayed and lasting "anticocaine effects". Here, we tested whether these putative lasting neuroplastic changes are sufficient to occlude the reinforcing effects of cocaine at the behavioural level in mice. Mice were pre-treated with the M1 receptor partial agonist VU0364572, M4 receptor positive allosteric modulator VU0152100, or VU0364572 + VU0152100 two weeks prior to acquisition of cocaine intravenous self-administration (IVSA). Male C57BL/6JRj mice received vehicle, VU0364572, VU0152100, or VU0364572 + VU0152100. Female mice were tested with two VU0364572 + VU0152100 dose combinations or vehicle. To attribute potential effects to either reduced rewarding effects or increased aversion to cocaine, we tested VU0364572 alone and VU0364572 + VU0152100 in acquisition of cocaine-conditioned place preference (CPP) in male mice using an unbiased design. The acquisition of cocaine IVSA was drastically reduced and/or slowed in male and female mice receiving VU0364572 + VU0152100, but not either drug alone. Food-maintained operant behaviour was unaffected, indicating that the treatment effects were cocaine-specific. No treatment altered the acquisition of cocaine-CPP, neither in the post-test, nor in a challenge 14 days later. The cocaine IVSA findings confirm unusual long-lasting "anticocaine" effects of muscarinic M1 + M4 receptor stimulation. Thus, in mice, simultaneous stimulation of both receptor subtypes seems to produce potential neuroplastic changes that yield lasting effects.

CREB-Binding Protein Regulates Cocaine- and Amphetamine-Regulated Transcript Peptide Expression in the Lateral Hypothalamus: Implication in Reward and Reinforcement.

Neuropeptide cocaine- and amphetamine-regulated transcript peptide (CARTp) is known to play an important role in reward processing. The rats conditioned to intra-cranial self-stimulation (ICSS) showed massive upregulation of CART protein and mRNA in the vicinity of the electrode implanted to deliver the electric current directly at the lateral hypothalamus (LH)-medial forebrain bundle (MFB) area. However, the underlying mechanisms leading to the upregulation of CART in ICSS animals remain elusive. We tested the putative role of CREB-binding protein (CBP), an epigenetic enzyme with intrinsic histone acetyltransferase (HAT) activity, in regulating CART expression during ICSS. An electrode was implanted in LH-MFB and the rats were conditioned to self-stimulation in an operant chamber. CBP siRNA was delivered ipsilaterally in the LH-MFB to knock-down CBP and the effects on lever press activity were monitored. While ICSS-conditioned rats showed distinct increase in CART, CBP and pCREB levels, enhanced CBP binding and histone acetylation (H3K9ac) were noticed on the CART promoter in chromatin immunoprecipitation assay. Direct infusion of CBP siRNA in the LH-MFB lowered lever press activity, CBP levels, histone acetylation at the CART promoter, and CART mRNA and peptide expression. Co-infusion of CARTp in LH-MFB rescued the waning effects of CBP siRNA on self-stimulation. We suggest that CBP-mediated histone acetylation may play a causal role in CART expression in LH, which in turn may drive the positive reinforcement of lever press activity.

Chronic trophic disorders in cocaine and heroin injectors: A multicenter retrospective observational descriptive study.

AIMS: To describe the demographic characteristics of heroin and cocaine injectors with chronic injection-related trophic disorders, as well as the clinical and progressive characteristics of these disorders. METHODS: A descriptive, observational, multicenter and retrospective study over the last 15 years. Patients were recruited via a call for cases and by consulting the health data warehouse of the university hospital center. RESULTS: The population comprised 39 injection drug users, of whom 79.5% were male, with a median age of 41 years. Subjects had numerous co-addictions and 70.5% were infected with hepatitis C virus. Trophic disorders were multiple in some cases: 43.5% of patients had lymphoedema, 87% had ulcers, and 56.5% had injection-related scars. Ulcers were multiple, large, and present for a median of 3 years. They were located on the upper limbs in 32.5% of cases. Ulcers constituted a source of complications in 64.5% of cases and these were infectious in 91% of cases (local, osteoarticular or systemic). During follow-up, 8 patients died and 21.5% of patients requiring ulcer care were lost to follow-up. CONCLUSIONS: This study showed a high rate of complications, particularly infections, of ulcers in injection drug users. Localization of these ulcers to the upper limbs, although rare in the general population, is relatively frequent in this population. Follow-up is difficult and cooperation between dermatologist and addictologist is essential to improve patient care.

Electrochemical and statistical study of Nickel ion assessment in daily children intake samples relying on magnesium aluminate spinel nanoparticles.

Lately, children's daily consumption of some products, such as cereals and candies, has been rising, which provides a compelling rationale for determining any metallic substances that may be present. Monitoring the concentration of certain metals, like nickel, in these products is necessary due to medical issues in humans when consumed regularly. So, in this work, a novel and highly selective carbon paste as a Ni(II) ion-selective sensor was prepared and investigated using ceramic magnesium aluminum spinel nanoparticles as the ionophore and tritolyl phosphate (TOCP) as a plasticizer. A modified co-precipitation method was used to synthesize the spinel nanoparticles. X-ray diffraction, scanning electron microscope with EDAX, transmission electron microscope, and BET surface area were used to determine the phase composition, microstructure, pores size, particle size, and surface area of the synthesized nanoparticles. The spinel nanoparticle was found to have a nano crystallite size with a cubic crystal system, a particle size ranging from 17.2 to 51.52 nm, mesoporous nature (average pore size = 8.72 nm), and a large surface area (61.75 m2/g). The composition ratio of graphite carbon as a base: TOCP as binder: spinal as ionophore was 67.3:30.0:2.7 (wt%) based on potentiometric detections over concentrations from 5.0 × 10-8 to 1.0 × 10-2 mol L-1 with LOD of 5.0 × 10-8 mol L-1. A measurement of 29.22 ± 0.12 mV decade-1 over pH 2.0-7.0 was made for the Nernstian slope. This sensor demonstrated good repeatability over nine weeks and a rapid response of 8 s. A good selectivity was shown for Ni(II) ions across many interferents, tri-, di-, and monovalent cations. The Ni(II) content in spiked real samples, including cocaine, sweets, coca, chocolate, carbonated drinks, cereals, and packages, were measured. The results obtained indicated no significant difference between the proposed potentiometric method and the officially reported ICP method according to the F- and t-test data. In addition to utilizing ANOVA statistical analysis, validation procedures have been implemented, and the results exceed the ICP-MS methodology.

Trends in peripheral artery disease and critical limb ischemia hospitalizations among cocaine and methamphetamine users in the United States: a nationwide study.

Background: Peripheral artery disease (PAD) is on the rise worldwide, ranking as the third leading cause of atherosclerosis-related morbidity; much less is known about its trends in hospitalizations among methamphetamine and cocaine users. Objectives: We aim to evaluate the overall trend in the prevalence of hospital admission for PAD with or without the use of stimulant abuse (methamphetamine and cocaine) across the United States. Additionally, we evaluated the PAD-related hospitalizations trend stratified by age, race, sex, and geographic location. Methods: We used the National Inpatient Sample (NIS) database from 2008 to 2020. The Cochran Armitage trend test was used to compare the trend between groups. Multivariate logistic regression was used to examine adjusted odds for PAD and CLI hospitalizations among methamphetamine and cocaine users. Results: Between 2008 and 2020, PAD-related hospitalizations showed an increasing trend in Hispanics, African Americans, and western states, while a decreasing trend in southern and Midwestern states (p-trend <0.05). Among methamphetamine users, an overall increasing trend was observed in men, women, western, southern, and midwestern states (p-trend <0.05). However, among cocaine users, PAD-related hospitalization increased significantly for White, African American, age group >64 years, southern and western states (p-trend <0.05). Overall, CLI-related hospitalizations showed an encouraging decreasing trend in men and women, age group >64 years, and CLI-related amputations declined for women, White patient population, age group >40, and all regions (p-trend <0.05). However, among methamphetamine users, a significantly increasing trend in CLI-related hospitalization was seen in men, women, White & Hispanic population, age group 26-45, western, southern, and midwestern regions. Conclusions: There was an increasing trend in PAD-related hospitalizations among methamphetamine and cocaine users for both males and females. Although an overall decreasing trend in CLI-related hospitalization was observed for both genders, an up-trend in CLI was seen among methamphetamine users. The upward trends were more prominent for White, Hispanic & African Americans, and southern and western states, highlighting racial and geographic variations over the study period.

Clavulanic Acid-Mediated Increases in Anterior Cingulate Glutamate Levels are Associated With Decreased Cocaine Craving and Brain Network Functional Connectivity Changes.

Background: There is an urgent need for pharmacological treatment for cocaine (COC) use disorder (CUD). Glutamatergic transmission in the prefrontal cortex is affected by addictive behaviors. Clavulanic acid (CLAV), a glutamate transporter GLT-1 (excitatory amino acid transporter) activator, is a clinical-stage medication that has potential for treating CUD. Methods: In a pilot study, nine participants with CUD received 500 mg CLAV with dose escalations to 750 mg and 1000 mg over 10 days. In 5 separate magnetic resonance imaging (MRI) sessions, brain anterior cingulate cortex (ACC) glutamate level and resting state network (RSN) functional connectivity (FC) were assessed using MR spectroscopy and functional MRI. Craving was assessed at the same time points, between baseline (before CLAV), 6 days, and 10 days of CLAV. Independent component analysis with dual regression was used to identify RSN FC changes from baseline to Days 6 and 10. Relationships among glutamate, craving, and resting state FC values were analyzed. Results: Participants who achieved high ACC glutamate levels after CLAV treatment had robust decreases in COC craving (r = -0.90, P = 0.0009, n = 9). The salience network (SN) and executive control network (ECN) demonstrated an association between increased FC after CLAV treatment and low baseline ACC Glu levels (SN CLAV 750 mg, r = -0.82, P = 0.007) (ECN CLAV 1000 mg, r = -0.667, P = 0.050; n = 9). Conclusions: Glutamate associated changes in craving and FC of the salience and executive control brain networks support CLAV as a potentially efficacious pharmacological treatment for CUD.

Case report: Tremor in the placebo condition of a blinded clinical trial of intermittent theta-burst stimulation for cocaine use disorder.

We report a case of a new-onset, persistent tremor that developed during a clinical trial (NCT02927236) of intermittent theta burst stimulation [iTBS, a form of repetitive magnetic transcranial magnetic stimulation (rTMS)] for cocaine use disorder. Although the participant exhibited an exceptionally strong clinical response, subsequent unblinding revealed that they received sham iTBS. This case highlights the potential for strong functional neurological placebo responses in rTMS trials, and functional disorders might be a marker of a placebo response. Additionally, we note the possibility that the weak e-fields produced by some sham rTMS systems may induce clinically relevant effects.

Disrupted dynamic brain functional connectivity in male cocaine use disorder: Hyperconnectivity, strongly-connected state tendency, and links to impulsivity and borderline traits.

Cocaine use is a major public health problem with serious negative consequences at both the individual and societal levels. Cocaine use disorder (CUD) is associated with cognitive and emotional impairments, often manifesting as alterations in brain functional connectivity (FC). This study employed resting-state functional magnetic resonance imaging (rs-fMRI) to examine dynamic FC in 38 male participants with CUD and 31 matched healthy controls. Using group spatial independent component analysis (group ICA) combined with sliding window approach, we identified two recurring distinct connectivity states: the strongly-connected state (state 1) and weakly-connected state (state 2). CUD patients exhibited significant increased mean dwell and fraction time in state 1, and increased transitions from state 2 to state 1, demonstrated significant strongly-connected state tendency. Our analysis revealed abnormal FC patterns that are state-dependent and state-shared in CUD patients. This study observed hyperconnectivity within the default mode network (DMN) and between DMN and other networks, which varied depending on the state. Furthermore, after adjustment for multiple comparisons, we found significant correlations between these altered dynamic FCs and clinical measures of impulsivity and borderline personality disorder. The disrupted FC and repetitive effects of precuneus and angular gyrus across correlations suggested that they might be the important hub of neural circuits related behaviorally and mentally in CUD. In summary, our study highlighted the potential of these disrupted FC as neuroimaging biomarkers and therapeutic targets, and provided new insights into the understanding of the neurophysiologic mechanisms of CUD.

How omics is revealing new roles for glia in addiction.

Experiments to study the biology of addiction have historically focused on the mechanisms through which drugs of abuse drive changes in the functioning of neurons and neural circuits. Glia have often been ignored in these studies, however, and this has left many questions in the field unanswered, particularly, surrounding how glia contribute to changes in synaptic plasticity, regulation of neuroinflammation, and functioning of neural ensembles given massive changes in signaling across the CNS. Omics methods (transcriptomics, translatomics, epigenomics, proteomics, metabolomics, and others) have expanded researchers' abilities to generate hypotheses and carry out mechanistic studies of glial cells during acquisition of drug taking, intoxication, withdrawal, and relapse to drug seeking. Here, we present a survey of how omics technological advances are revising our understanding of astrocytes, microglia, oligodendrocytes, and ependymal cells in addiction biology.

Presynaptic and Postsynaptic Mesolimbic Dopamine D3 Receptors Play Distinct Roles in Cocaine Versus Opioid Reward in Mice.

BACKGROUND: Past research has illuminated pivotal roles of dopamine D3 receptors (D3R) in the rewarding effects of cocaine and opioids. However, the cellular and neural circuit mechanisms that underlie these actions remain unclear. METHODS: We employed Cre-LoxP techniques to selectively delete D3R from presynaptic dopamine neurons or postsynaptic dopamine D1 receptor (D1R)-expressing neurons in male and female mice. We utilized RNAscope in situ hybridization, immunohistochemistry, real-time polymerase chain reaction, voltammetry, optogenetics, microdialysis, and behavioral assays (n ≥ 8 animals per group) to functionally characterize the roles of presynaptic versus postsynaptic D3R in cocaine and opioid actions. RESULTS: Our results revealed D3R expression in ∼25% of midbrain dopamine neurons and ∼70% of D1R-expressing neurons in the nucleus accumbens. While dopamine D2 receptors (D2R) were expressed in ∼80% dopamine neurons, we found no D2R and D3R colocalization among these cells. Selective deletion of D3R from dopamine neurons increased exploratory behavior in novel environments and enhanced pulse-evoked nucleus accumbens dopamine release. Conversely, deletion of D3R from D1R-expressing neurons attenuated locomotor responses to D1-like and D2-like agonists. Strikingly, deletion of D3R from either cell type reduced oxycodone self-administration and oxycodone-enhanced brain-stimulation reward. In contrast, neither of these D3R deletions impacted cocaine self-administration, cocaine-enhanced brain-stimulation reward, or cocaine-induced hyperlocomotion. Furthermore, D3R knockout in dopamine neurons reduced oxycodone-induced hyperactivity and analgesia, while deletion from D1R-expressing neurons potentiated opioid-induced hyperactivity without affecting analgesia. CONCLUSIONS: We dissected presynaptic versus postsynaptic D3R function in the mesolimbic dopamine system. D2R and D3R are expressed in different populations of midbrain dopamine neurons, regulating dopamine release. Mesolimbic D3R are critically involved in the actions of opioids but not cocaine.

The Structural Basis of the Activity Cliff in Modafinil-Based Dopamine Transporter Inhibitors.

Modafinil analogs with either a sulfoxide or sulfide moiety have improved binding affinities at the human dopamine transporter (hDAT) compared to modafinil, with lead sulfoxide-substituted analogs showing characteristics of atypical inhibition (e.g., JJC8-091). Interestingly, the only distinction between sulfoxide and sulfide substitution is the presence of one additional oxygen atom. To elucidate why such a subtle difference in ligand structure can result in different typical or atypical profiles, we investigated two pairs of analogs. Our quantum mechanical calculations revealed a more negatively charged distribution of the electrostatic potential surface of the sulfoxide substitution. Using molecular dynamics simulations, we demonstrated that sulfoxide-substituted modafinil analogs have a propensity to attract more water into the binding pocket. They also exhibited a tendency to dissociate from Asp79 and form a new interaction with Asp421, consequently promoting an inward-facing conformation of hDAT. In contrast, sulfide-substituted analogs did not display these effects. These findings elucidate the structural basis of the activity cliff observed with modafinil analogs and also enhance our understanding of the functionally relevant conformational spectrum of hDAT.

Implications of Impulsivity on Criminal Behavior in Individuals With Substance Use Disorder.

OBJECTIVE: Our aim was to analyze the association between criminal behavior and impulsivity in individuals with drug addiction and investigate whether impulsiveness mediates the relationship between drug use severity and legal problems. METHODS: This cross-sectional study included 773 men diagnosed with addiction (295 alcohol users and 478 users of crack/polysubstance) while undergoing addiction treatment. The BIS-11 and ASI-6 were applied to assess impulsivity, criminal behavior, and drug use. RESULTS: The prevalence of criminal behavior was 41.7% (n = 123) in alcohol users and 64.9% (n = 310) in users of crack/polysubstance. Earlier use of different substances and higher impulsivity scores were observed in individuals with criminal history. Mediation analyses revealed that impulsiveness acts as a mediator factor between substance use and criminal behavior, enhancing the severity of legal problems. CONCLUSION: Our findings can help in deciding on tailored treatment strategies, focusing not only on substance use, but also on the prevention of social problems, criminality, and impulsivity.