Cocaine Abuse Research Articles

Challenge of Managing the Cocktail of Cardiac Arrhythmias Induced by Cocaine and Cannabis Poly-Drug Addiction: A Case Report.

Challenge of Managing the Cocktail of Cardiac Arrhythmias Induced by Cocaine and Cannabis Poly-Drug Addiction: A Case Report.

A new role for astrocytes in the story of cocaine abuse

In this issue of Neuron, Yang etal.1 highlight a hitherto unknown action of cocaine in VTA circuitry. They found that chronic cocaine use increased tonic inhibition selectively onto GABA neurons through Swell1 channel-dependent GABA release from astrocytes, leading to disinhibition-mediated hyperactivity in DA neurons and addictive behavior.

MicroRNA-423-5p Mediates Cocaine-Induced Smooth Muscle Cell Contraction by Targeting Cacna2d2.

Cocaine abuse increases the risk of atherosclerotic cardiovascular disease (CVD) and causes acute coronary syndromes (ACS) and hypertension (HTN). Significant research has explored the role of the sympathetic nervous system mediating the cocaine effects on the cardiovascular (CV) system. However, the response of the sympathetic nervous system alone is insufficient to completely account for the CV consequences seen in cocaine users. In this study, we examined the role of microRNAs (miRNAs) in mediating the effect of cocaine on the CV system. MiRNAs regulate many important biological processes and have been associated with both response to cocaine and CV disease development. Multiple miRNAs have altered expression in the CV system (CVS) upon cocaine exposure. To understand the molecular mechanisms underlying the cocaine response in the CV system, we studied the role of miRNA-423-5p and its target Cacna2d2 in the regulation of intracellular calcium concentration and SMC contractility, a critical factor in the modulation of blood pressure (BP). We used in vivo models to evaluate BP and aortic stiffness. In vitro, cocaine treatment decreased miR-423-5p expression and increased Cacna2d2 expression, which led to elevated intracellular calcium concentrations and increased SMC contractility. Overexpression of miR-423-5p, silencing of its target Cacna2d2, and treatment with a calcium channel blocker reversed the elevated SMC contractility caused by cocaine. In contrast, suppression of miR-423-5p increased the intracellular calcium concentration and SMC contractibility. In vivo, smooth muscle-specific overexpression of miR-423-5p ameliorated the increase in BP and aortic stiffness associated with cocaine use. Thus, miR-423-5p regulates SMC contraction by modulating Cacna2d2 expression increasing intracellular calcium concentrations. Modulation of the miR-423-5p-Cacna2d2-Calcium transport pathway may represent a novel therapeutic strategy to improve cocaine-induced HTN and aortic stiffness.

Delay discounting as a behavioral phenotype associated with social rank in female and male cynomolgus monkeys: Correlation with kappa opioid receptor availability

Cocaine use disorder (CUD) is a significant problem worldwide, with no FDA-approved treatments. Epidemiological data indicate that only about 17 % of people that use cocaine will meet DSM criteria for CUD. Thus, the identification of biomarkers predictive of eventual cocaine use may be of great value. Two potentially useful predictors of CUD are social hierarchies in nonhuman primates and delay discounting. Both social rank and preference for a smaller, immediate reinforcer relative to a larger, delayed reinforcer have been predictive of CUD. Therefore, we wanted to determine if there was also a relationship between these two predictors of CUD. In the present study, monkeys cocaine-naive responded under a concurrent schedule of 1- vs. 3-food pellets and delivery of the 3-pellet option was delayed. The primary dependent variable was the indifference point (IP), which is the delay that results in 50 % choice for both options. In the initial determination of IP, there were no differences based on sex or social rank of the monkeys. When the delays were redetermined after ~25 baseline sessions (range 5–128 sessions), dominant females and subordinate males showed the largest increases in IP scores from the first determination to the second. Because 13 of these monkeys had prior PET scans of the kappa opioid receptor (KOR), we examined the relationship between KOR availability and IP values and found that the change in IP scores from the first to the second determination significantly negatively predicted average KOR availability in most brain regions. Future studies will examine acquisition to cocaine self-administration in these same monkeys, to determine if IP values are predictive of vulnerability to cocaine reinforcement.

Integrative genomics analysis highlights functionally relevant genes for equine behaviour.

Behavioural plasticity enables horses entering an exercise training programme to adapt with reduced stress. We characterised SNPs associated with behaviour in yearling Thoroughbred horses using genomics analyses for two phenotypes: (1) handler-assessed coping with early training events [coping] (n=96); and (2) variation in salivary cortisol concentration at the first backing event [cortisol] (n=34). Using RNA-seq derived gene expression data for amygdala and hippocampus tissues from n=2 Thoroughbred stallions, we refined the SNPs to those with functional relevance to behaviour by cross-referencing to the 500 most highly expressed genes in each tissue. The SNPs of high significance (q < 0.01) were in proximity to genes (coping - GABARAP, NDM, OAZ1, RPS15A, SPARCL1, VAMP2; cortisol - CEBPA, COA3, DUSP1, HNRNPH1, RACK1) with biological functions in social behaviour, autism spectrum disorder, suicide, stress-induced anxiety and depression, Alzheimer's disease, neurodevelopmental disorders, neuroinflammatory disease, fear-induced behaviours and alcohol and cocaine addiction. The strongest association (q=0.0002) was with NDN, a gene previously associated with temperament in cattle. This approach highlights functionally relevant genes in the behavioural adaptation of Thoroughbred horses that will contribute to the development of genetic markers to improve racehorse welfare.

A network-based analysis detects cocaine-induced changes in social interactions in Drosophila melanogaster.

Addiction is a multifactorial biological and behavioral disorder that is studied using animal models, based on simple behavioral responses in isolated individuals. A couple of decades ago it was shown that Drosophila melanogaster can serve as a model organism for behaviors related to alcohol, nicotine and cocaine (COC) addiction. Scoring of COC-induced behaviors in a large group of flies has been technologically challenging, so we have applied a local, middle and global level of network-based analyses to study social interaction networks (SINs) among a group of 30 untreated males compared to those that have been orally administered with 0.50 mg/mL of COC for 24 hours. In this study, we have confirmed the previously described increase in locomotion upon COC feeding. We have isolated new network-based measures associated with COC, and influenced by group on the individual behavior. COC fed flies showed a longer duration of interactions on the local level, and formed larger, more densely populated and compact, communities at the middle level. Untreated flies have a higher number of interactions with other flies in a group at the local level, and at the middle level, these interactions led to the formation of separated communities. Although the network density at the global level is higher in COC fed flies, at the middle level the modularity is higher in untreated flies. One COC specific behavior that we have isolated was an increase in the proportion of individuals that do not interact with the rest of the group, considered as the individual difference in COC induced behavior and/or consequence of group influence on individual behavior. Our approach can be expanded on different classes of drugs with the same acute response as COC to determine drug specific network-based measures and could serve as a tool to determinate genetic and environmental factors that influence both drug addiction and social interaction.

Cocaine induces locomotor sensitization through a dopamine-dependent VTA-mPFC-FrA cortico-cortical pathway in male mice

As a central part of the mammalian brain, the prefrontal cortex (PFC) has been implicated in regulating cocaine-induced behaviors including compulsive seeking and reinstatement. Although dysfunction of the PFC has been reported in animal and human users with chronic cocaine abuse, less is known about how the PFC is involved in cocaine-induced behaviors. By using two-photon Ca2+ imaging to simultaneously record tens of intact individual networking neurons in the frontal association cortex (FrA) in awake male mice, here we report that a systematic acute cocaine exposure decreased the FrA neural activity in mice, while the chemogenetic intervention blocked the cocaine-induced locomotor sensitization. The hypoactivity of FrA neurons was critically dependent on both dopamine transporters and dopamine transmission in the ventromedial PFC (vmPFC). Both dopamine D1R and D2R neurons in the vmPFC projected to and innervated FrA neurons, the manipulation of which changed the cocaine-induced hypoactivity of the FrA and locomotor sensitization. Together, this work demonstrates acute cocaine-induced hypoactivity of FrA neurons in awake mice, which defines a cortico-cortical projection bridging dopamine transmission and cocaine sensitization.

Interaction between maternal immune activation and peripubertal stress in rats: impact on cocaine addiction-like behaviour, morphofunctional brain parameters and striatal transcriptome

Substance use disorders are more prevalent in schizophrenia, but the causal links between both conditions remain unclear. Maternal immune activation (MIA) is associated with schizophrenia which may be triggered by stressful experiences during adolescence. Therefore, we used a double-hit rat model, combining MIA and peripubertal stress (PUS), to study cocaine addiction and the underlying neurobehavioural alterations. We injected lipopolysaccharide or saline on gestational days 15 and 16 to Sprague-Dawley dams. Their male offspring underwent five episodes of unpredictable stress every other day from postnatal day 28 to 38. When animals reached adulthood, we studied cocaine addiction-like behaviour, impulsivity, Pavlovian and instrumental conditioning, and several aspects of brain structure and function by MRI, PET and RNAseq. MIA facilitated the acquisition of cocaine self-administration and increased the motivation for the drug; however, PUS reduced cocaine intake, an effect that was reversed in MIA + PUS rats. We found concomitant brain alterations: MIA + PUS altered the structure and function of the dorsal striatum, increasing its volume and interfering with glutamatergic dynamics (PUS decreased the levels of NAA + NAAG but only in LPS animals) and modulated specific genes that could account for the restoration of cocaine intake such as the pentraxin family. On its own, PUS reduced hippocampal volume and hyperactivated the dorsal subiculum, also having a profound effect on the dorsal striatal transcriptome. However, these effects were obliterated when PUS occurred in animals with MIA experience. Our results describe an unprecedented interplay between MIA and stress on neurodevelopment and the susceptibility to cocaine addiction.

CBT4CBT web-based add-on treatment for cocaine use disorder: Study protocol for a randomized controlled trial.

Cocaine use disorder (CUD) is a chronic condition that presents high relapse rates and treatment dropouts. Web-based interventions have proven to be effective when optimizing face-to-face treatments in different mental health conditions and have the potential to optimize current CUD treatments. However, web-based interventions in addictive behaviors are still limited. The aim of this study is to evaluate whether adding a web-based cognitive behavioral therapy (i.e., CBT4CBT) to standard CUD treatment, improves treatment outcomes in a Spanish sample of patients with severe CUD (which requires inpatient treatment). Additionally, we aim to explore predictive factors of treatment response and treatment gender-related differences. All individuals coming for inpatient cocaine detoxification who meet the inclusion criteria will have the possibility to be part of the study. The participants of this open-label randomized controlled clinical trial (RCT) will be allocated to treatment as usual (TAU) or TAU+CBT4CBT after the hospitalization for cocaine detoxification. During the inpatient treatment they will all receive an individualized psychological intervention. There will be six time point assessments: at 48-72 h of starting inpatient treatment, at the end of inpatient treatment and before starting day care and outpatient treatment, at the end of the 8 weeks CTB4CBT / TAU arm treatment and at three follow-up time points (1-, 3-, and 6-months post-treatment). To the best of our knowledge, this is the first RCT that explores the efficacy of adding a web-based cognitive behavioral therapy to usual CUD treatment with patients of a clinical sample in Europe. IIBSP-CTB-2020-116, NCT05207228. Submitted 8th of April 2021, posted 26 st of January 2022. https://clinicaltrials.gov/ct2/show/NCT05207228?cond=Cocaine+Use+Disorder&draw=2&rank=1.

Prescription psychostimulants for cocaine use disorder: A review from molecular basis to clinical approach.

Cocaine use is a public health concern in many countries worldwide, particularly in the Americas and Oceania. Overdose deaths involving stimulants, such as cocaine, have been increasing markedly in North America, especially with concurrent opioid involvement. To date, no pharmacological treatment is available to treat stimulant (including cocaine) use disorders. Prescription psychostimulants (PPs) could be useful to treat cocaine use disorder (CUD) as they share the pharmacological effects with cocaine, as evidenced by a recent meta-analysis that assessed 38 randomized clinical trials (RCTs). PPs were found to promote sustained abstinence and reduce drug use in patients with CUD. The aim of this paper is to provide a narrative review of the clinical pharmacology of PPs and comment on the current stage of evidence supporting PPs to treat CUD. We also propose a model of care that integrates PPs with evidence-based psychosocial interventions (such as cognitive-behavioural therapy [CBT] and contingency management [CM]), a harm reduction approach and case management with social support.

Safety and immunogenicity of the anti-cocaine vaccine UFMG-VAC-V4N2 in a non-human primate model.

A promising strategy for cocaine addiction treatment is the anti-drug vaccine. These vaccines induce the production of anticocaine antibodies, capable of linking to cocaine, and decrease the passage of cocaine throughout the blood-brain barrier, decreasing drug activity in the brain. Our research group developed a new vaccine candidate, the UFMG-V4N2, to treat cocaine use disorders (CUD) using an innovative carrier based on calixarenes. This study assessed the safety and immunogenicity of the anti-cocaine vaccine UFMG-VAC-V4N2 in a non-human primate toxicity study using single and multiple vaccine doses. The UFMG-VAC-V4N2 yielded only mild effects in the injection site and did not influence the general health, feeding behavior, or hematological, renal, hepatic, or metabolic parameters in the vaccinated marmosets. The anti-cocaine vaccine UFMG-VAC-V4N2 presented a favorable safety profile and induced the expected immune response in a non-human primate model of Callithrix penicillata. This preclinical UFMG-VAC-V4N2 study responds to the criteria required by international regulatory agencies contributing to future anticocaine clinical trials of this anti-cocaine vaccine.

Toxic encephalopathy after an overdose of cocaine : a case serie

Introductioncocaine is a widely used illegal drug, known for its fast ability to induce euphoria and arousal. However, cocaine exposure can contribute to several mental and physical effects. Cocaine induced brain damage can be divided into 3 mechanisms: direct effect leading to toxic encephalopathy, secondary to vascular damage causing vasculitis, stroke and vasospasm, and tertiary effect due to hypoxia through a cardiovascular collapse.ObjectivesHere, we report 2 young men who developed a subacute encephalopathy with different clinical and radiological presentation after a cocaine overdoseMethodsa case serieResultswe present two men aged respectively of 28 (P1) and 42 years-old (P2). Both had a history of alcohol consumption and toxicomania (mainly cocaine) during the past year. They manifested, 2 weeks following a cocaine overdose, with gait disorder and confusion. On examination, P1 was apathic and confused. He had a subcortical frontal syndrome with gait apraxia and grasping reflex, along with a quadri-pyramidal syndrome. While patient P2 developed a cognitive decline, parkinsonism with dystonic posture of the trunk and the right limbs, and a pseudobulbar syndrome. Brain MRI was performed in both patients and showed a bilateral multifocal leukoencephalopathy (P1) and the presence of bilateral hyper T2 and FLAIR weighted images affecting basal ganglia, the mesencephalon and the periventricular cerebral white matter. Cerebrospinal fluid (CSF) analysis showed no pleocytosis and normal proteinorrachia. Electroencephalogram was also normal. Infectious differential diagnosis including Human Immunodeficiency Virus (HIV) and syphilis were excluded and metabolic screening including copper analysis, serum and CSF lactate were normal. The urine toxic screening, performed 20 days following the drug overdose, was negative. Both patients were treated with benzodiazepine and fluids without significative improvement. They were discharged with major cognitive and motor impairment.Conclusionscocaine toxicity is associated with high morbidity and mortality. Usually, cocaine abuse can lead to cardio-vascular, pulmonary and nervous complication. Neuropsychiatric sequelae are uncommon with less recovery potential. To date, there is no drug to prevent or cure cocaine addiction. The key is to educate the patient when he or she presents to the emergency department. Patients should be urged to seek drug counseling.Disclosure of InterestNone Declared

Late diagnosis of attention deficit hyperactivity disorder and cocaine abuse

IntroductionAdult ADHD diagnosis sometimes represents a challenge for the clinician, due to the comorbid psychiatric diseases that are often associated and which complicate de recognition of the primary symptoms of ADHD. The prevalence of ADHD in adult populations is 2’5% and it is a relevant cause of functional impairment.ObjectivesPresentation of a clinical case of a male cocaine user diagnosed with adult ADHD.MethodsLiterature review on adult ADHD and comorbid substance abuse.ResultsA 43-year-old male who consulted in the Emergency Department due to auditory hallucinosis in the context of an increase in his daily cocaine use. There were not delusional symptoms associated and judgment of reality was preserved. Treatment with olanzapine was started and the patient was referred for consultation. In psychiatry consultations, he did not refer sensory-perceptual alterations anymore, nor appeared any signals to suspect so, and he was willing to abandon cocaine use after a few appointments. He expressed some work concerns, highlighting that in recent months, in the context of a greater workload, he had been given several traffic tickets for “distractions.” His wife explained that he had always been a inattentive person (he forgets important dates or appointments) and impulsive, sometimes interrupting conversations. In the Barkley Adult ADHD Rating Scale he scored 32 points.He was diagnosed with adult ADHD and treatment with extended-release methylphenidate was started with good tolerance and evolution, with improvement in adaptation to his job and social environment. Since then, the patient has moderately reduced the consumption of drugs, although he continues to use cocaine very sporadically.ConclusionsEarly detection of ADHD and its comorbidities has the potential to change the course of the disorder and the morbidity that will occur later in adults. Comorbidity in adult ADHD is rather the norm than the exception, and it renders diagnosis more difficult. The most frequent comorbidities are usually mood disorders, substance use disorders, and personality disorders. Treatment of adult ADHD consists mainly of pharmacotherapy supported by behavioral interventions. When ADHD coexists with another disorder, the one that most compromises functionality will be treated first and they can be treated simultaneously. The individual characteristics of each patient must be taken into account to choose the optimal treatment.Disclosure of InterestNone Declared

First psychotic episode due to inmunosupresor medication

Introduction48-year-old man from Spain who lived with his wife until he got divorced 4 months before starting the follow up in Mental Health. The debut was in September 2021 with a hospitalization in the Brief-acute hospitalization unit due to florid psychotic clinic-He consumed several drugs in his twenties (cocaine, marihuana and heroin IV) and was diagnosed of HIV at the age of 29. He abandoned the use of drugs after the diagnoses and keep good adherence to the antiretroviral treatment (Abacavir + Lamivudine +Efavirenz).At the age of 46 (January 2020), he was successfully transplanted a kidney. Afterwards, he started taking inmunosupresor medication to avoid transplant rejectionAt the few months of the transplant and the beginning of the inmusosupresor medication, the patient became more irascible with moments of remarkable disinhibition and progressive abandon of the work obligations.In January of 2021, he got divorced after months of difficulties with his wife, married 28 years before, due to the mentioned problems as well as moments of bizarre and disorganized conducts and suspicion towards his wife with probable delusional jealousy. He, therefore, lost his job, hose and marriage and started taking drugs again after 17 years of abstinence.He was hospitalized in e Brief Acute Inpatient Unit in September 2021 with distrustful and hypervigilant attitude- He was suffering from delusional ideation of harm and persecution with high distress and emotional repercussion. He also presented disorganized conduct and probable auditory hallucinations. He was positive to amphetamines and cocaine After 3 days without consuming; there was no remission of the clinic.ObjectivesDiscussing the association between the initiation of inmunsupresor medication and the beggining of psychotic clinicMethodsFirst psychotic episode (FEP) has a likely consequence of the initiation and maintenance of Tacrolimus -due to a kidney transplant- with the concomitant abuse of amphetamines and cocaine as a trigger factor.The psychotic clinic progressively remitted in one week after the administration of 3 mg/day of risperidone.The antiretroviral treatment was changed due to the poor adherence during the disorganization period. The tacrolimus was not removed because of the good response to the neuroleptic and the risk of transplant rejectionResultsThe patient started with prodromic symptoms of psychosis at the time he began with the inmunosupresor medication. Progresively, the psychotic clinic worsen wit the consequence of a biographical break with the consequence of a divorce, therlost of work and home and a drug relapse.ConclusionsThere is evidence of the association between psychotic episodes in people with no psychiatric history and the inmunosupresor medication for the kidney transplant (Above all, tracolimus). This case remarks the need of an exhaustive medical anamnesis in the diagnosis of psychiatric pathologies.Disclosure of InterestNone Declared

Mental Health Services Utilization among Suicidal Patients: Comparing the Impact of Co-Occurring Opioid or Other Substance Use Disorders

IntroductionPrior literature establishes bidirectional associations between suicide and substance use disorders (SUDs), particularly opioid use disorder (OUD). However, the context of mental health services utilization remains under-investigated. This analysis examined patterns of mental health services utilization in patients with SUDs and suicidality, identified associated risk factors, and evaluated the impact of patient engagement on subsequent mental health outcomesObjectivesSee above.MethodsElectronic health records (EHRs) derived from 7 health systems across New York City between 2010-2019 were analyzed. Suicidality was identified as any ICD-9/10 diagnosis of suicide attempt, suicidal ideation, or self-harm injury. SUDs were identified as any opioid, cannabis, cocaine, hallucinogen, inhalant, sedative/hypnotic/anxiolytic, amphetamine, or other substance abuse or dependence. Quasi-Poisson regression adjusted for age, gender, and chronic diseases was used to model associations between OUD exposure and the frequency of encounters and estimate the relative risk (RR) of significant covariates.ResultsA total of 6977 adults with suicidality and any comorbid SUD were selected, including 2203 (31.6%) with a diagnosis of OUD and 4774 (68.4%) without a diagnosis of OUD. Most patients were male (54.8%) and aged between 25-64 years (79.3%). Many (61.3%) had over 3 chronic diseases, including depression (80.8%), hypertension (60.6%), anemia (43.0%), and hyperlipidemia (41.9%). Compared to patients with other SUDs, those with OUD had higher odds of self-harm injury [OR: 1.26 (95% CI: 1.13-1.41)], depressive disorders [1.47 (1.29-1.67)], anxiety disorders [1.65 (1.48-1.84)], psychotic disorders [1.23 (1.11-1.37)], personality disorders [1.30 (1.16-1.48)], and post-traumatic stress disorder [1.37 (1.20-1.57)]. Patients with OUD were more likely to utilize all-cause outpatient (RR: 1.16), emergency department (ED) (RR: 1.43), and inpatient (RR: 1.60) services (p&lt;0.001). Among OUD patients, males were less likely to have outpatient visits (RR: 0.79) and inpatient hospitalizations (RR: 0.88), and older age was protective against ED admissions (RR range: 0.62-0.71). Additionally, individuals with OUD were more likely than those with other SUDs to have SUD-related encounters, as well as suicide-related ED admissions and inpatient hospitalizations (p&lt;0.0001). Those who had more mental health outpatient visits were less likely to have suicide-related ED admissions (RR: 0.85), however this association was weaker among younger or male patients with comorbid OUD.ConclusionsAmong suicidal adults with comorbid SUDs, those with a diagnosis of OUD were more likely to utilize mental health services and have psychiatric comorbidity. Males and older adults were less likely to utilize services.Disclosure of InterestNone Declared

Abstract Number: LBA23 Endovascular treatment of large vessel occlusion stroke caused by infective endocarditis

Introduction Infective endocarditis (IE) often presents as an acute ischemic stroke (AIS) secondary to a thromboembolic event leading to large vessel occlusion (LVO). These patients are at significant risk for intracerebral hemorrhage when given intravenous thrombolytics (IT) and are therefore better candidates for mechanical thrombectomy (MT). Current reports in the literature are divided on the safety of MT in this setting and no randomized control studies exist. With the advent of modern thrombectomy devices, we believe MT might be safe in this patient population. Methods Here we report a patient with IE who presented with LVO stroke (MCA syndrome) and underwent MT leading to first‐pass Thrombolysis inCerebral Infarction (TICI) score of 3 revascularization. In addition to presenting our case, we did a comprehensive review of the current literature on this topic. Results A thirty‐year‐old female with a history of cocaine abuse presented with acute onset left hemiplegia, dysarthria, and rightward gaze deviation. NIHSS was 19 and she presented 90 minutes from her last known well time . Computed Tomography (CT) head and CT perfusion imaging demonstrated a large MCA distribution stroke, an AlbertaStrokeProgram Early CT Score (ASPECTS) of 10, with significant perfusion mismatch of right MCA territory. CT angiography (CTA) confirmed a proximal large vessel occlusion (LVO) at the proximal M1. On initial assessment, the patient was febrile with a temperature of 40 degrees Celsius with a high clinical suspicion for IE; therefore, intravenous thrombolytic was not administered. MT was performed with one pull of stent retrieval under aspiration led to a successful opening of the vessel with TICI score of 3. Positive cocaine on urine toxicology was noted as well as, two sets of gram‐positive blood cultures which later resulted in Staph Aureus, oxacillin susceptible, unremarkable transthoracic echo, but with TEE demonstrating vegetative thickening within atrial aspects of both anterior andposterior mitral valve leaflets(Figure1). On hospital day two, magnetic resonance imaging of the brain shows small acute infarct with no bleed. The patient underwent a mitral valve replacement on hospital day nine. The patient was discharged to rehabilitation facilities with an NIHSS of two for mild left facial droop and mild left arm weakness; her degree of disability was measured as a modified Rankin Scale (mRS) one at 3 months. Conclusions In case IE is suspected, giving IV tPA (tissue‐type plasminogen activator) is contraindicated as it increases the chance of hemorrhagic complications and when LVO is confirmed in the setting of AIS, MT might be safe and effective to be considered .

Cocaine-use disorder and childhood maltreatment are associated with the activation of neutrophils and increased inflammation.

Cocaine-use disorder (CUD) has been associated with early life adversity and activated cellular immune responses. Women are most vulnerable to complications from chronic substance disorders, generally presenting an intense feeling of abstinence and consuming significant drug amounts. Here, we investigated neutrophil functional activities in CUD, including the formation of neutrophil extracellular traps (NETs) and related intracellular signalling. We also investigated the role of early life stress in inflammatory profiles. Blood samples, clinical data, and history of childhood abuse or neglect were collected at the onset of detoxification treatment of 41 female individuals with CUD and 31 healthy controls (HCs). Plasma cytokines, neutrophil phagocytosis, NETs, intracellular reactive oxygen species (ROS) generation, and phosphorylated protein kinase B (Akt) and mitogen-activated protein kinases (MAPK)s were assessed by flow cytometry. CUD subjects had higher scores of childhood trauma than controls. Increased plasma cytokines (TNF-α, IL-1β, IL-6, IL-8, IL-12, and IL-10), neutrophil phagocytosis, and production of NETs were reported in CUD subjects as compared to HC. Neutrophils of CUD subjects also produced high levels of intracellular ROS and had more activated Akt and MAPKs (p38/ERK), which are essential signalling pathways involved in cell survival and NETs production. Childhood trauma scores were significantly associated with neutrophil activation and peripheral inflammation. Our study reinforces that smoked cocaine and early life stress activate neutrophils in an inflammatory environment.

Inducible CRISPR Epigenome Systems Mimic Cocaine Induced Bidirectional Regulation of Nab2 and Egr3.

Substance use disorder is a chronic disease and a leading cause of disability around the world. The NAc is a major brain hub mediating reward behavior. Studies demonstrate exposure to cocaine is associated with molecular and functional imbalance in NAc medium spiny neuron subtypes (MSNs), dopamine receptor 1 and 2 enriched D1-MSNs and D2-MSNs. We previously reported repeated cocaine exposure induced transcription factor early growth response 3 (Egr3) mRNA in NAc D1-MSNs, and reduced it in D2-MSNs. Here, we report our findings of repeated cocaine exposure in male mice inducing MSN subtype-specific bidirectional expression of the Egr3 corepressor NGFI-A-binding protein 2 (Nab2). Using CRISPR activation and interference (CRISPRa and CRISPRi) tools combined with Nab2 or Egr3-targeted sgRNAs, we mimicked these bidirectional changes in Neuro2a cells. Furthermore, we investigated D1-MSN- and D2-MSN-specific expressional changes of histone lysine demethylases Kdm1a, Kdm6a, and Kdm5c in NAc after repeated cocaine exposure in male mice. Since Kdm1a showed bidirectional expression patterns in D1-MSNs and D2-MSNs, like Egr3, we developed a light-inducible Opto-CRISPR-KDM1a system. We were able to downregulate Egr3 and Nab2 transcripts in Neuro2A cells and cause similar bidirectional expression changes we observed in D1-MSNs and D2-MSNs of mouse repeated cocaine exposure model. Contrastingly, our Opto-CRISPR-p300 activation system induced the Egr3 and Nab2 transcripts and caused opposite bidirectional transcription regulations. Our study sheds light on the expression patterns of Nab2 and Egr3 in specific NAc MSNs in cocaine action and uses CRISPR tools to further mimic these expression patterns.SIGNIFICANCE STATEMENT Substance use disorder is a major societal issue. The lack of medication to treat cocaine addiction desperately calls for a treatment development based on precise understanding of molecular mechanisms underlying cocaine addiction. In this study, we show that Egr3 and Nab2 are bidirectionally regulated in mouse NAc D1-MSNs and D2-MSNs after repeated exposure to cocaine. Furthermore, histone lysine demethylations enzymes with putative EGR3 binding sites showed bidirectional regulation in D1- and D2-MSNs after repeated exposure to cocaine. Using Cre- and light-inducible CRISPR tools, we show that we can mimic this bidirectional regulation of Egr3 and Nab2 in Neuro2a cells.

Alterations in Abundance and Compartmentalization of miRNAs in Blood Plasma Extracellular Vesicles and Extracellular Condensates during HIV/SIV Infection and Its Modulation by Antiretroviral Therapy (ART) and Delta-9-Tetrahydrocannabinol (Δ9-THC).

Alterations in Abundance and Compartmentalization of miRNAs in Blood Plasma Extracellular Vesicles and Extracellular Condensates during HIV/SIV Infection and Its Modulation by Antiretroviral Therapy (ART) and Delta-9-Tetrahydrocannabinol (Δ9-THC).

Repurposing ketamine to treat cocaine use disorder: integration of artificial intelligence-based prediction, expert evaluation, clinical corroboration and mechanism of action analyses.

Cocaine use disorder (CUD) is a significant public health issue for which there is no Food and Drug Administration (FDA) approved medication. Drug repurposing looks for new cost-effective uses of approved drugs. This study presents an integrated strategy to identify repurposed FDA-approved drugs for CUD treatment. Our drug repurposing strategy combines artificial intelligence (AI)-based drug prediction, expert panel review, clinical corroboration and mechanisms of action analysis being implemented in the National Drug Abuse Treatment Clinical Trials Network (CTN). Based on AI-based prediction and expert knowledge, ketamine was ranked as the top candidate for clinical corroboration via electronic health record (EHR) evaluation of CUD patient cohorts prescribed ketamine for anesthesia or depression compared with matched controls who received non-ketamine anesthesia or antidepressants/midazolam. Genetic and pathway enrichment analyses were performed to understand ketamine's potential mechanisms of action in the context of CUD. The study utilized TriNetX to access EHRs from more than 90 million patients world-wide. Genetic- and functional-level analyses used DisGeNet, Search Tool for Interactions of Chemicals and Kyoto Encyclopedia of Genes and Genomes databases. A total of 7742 CUD patients who received anesthesia (3871 ketamine-exposed and 3871 anesthetic-controlled) and 7910 CUD patients with depression (3955 ketamine-exposed and 3955 antidepressant-controlled) were identified after propensity score-matching. EHR analysis outcome was a CUD remission diagnosis within 1 year of drug prescription. Patients with CUD prescribed ketamine for anesthesia displayed a significantly higher rate of CUD remission compared with matched individuals prescribed other anesthetics [hazard ratio (HR) = 1.98, 95% confidence interval (CI) = 1.42-2.78]. Similarly, CUD patients prescribed ketamine for depression evidenced a significantly higher CUD remission ratio compared with matched patients prescribed antidepressants or midazolam (HR = 4.39, 95% CI = 2.89-6.68). The mechanism of action analysis revealed that ketamine directly targets multiple CUD-associated genes (BDNF, CNR1, DRD2, GABRA2, GABRB3, GAD1, OPRK1, OPRM1, SLC6A3, SLC6A4) and pathways implicated in neuroactive ligand-receptor interaction, cAMP signaling and cocaine abuse/dependence. Ketamine appears to be a potential repurposed drug for treatment of cocaine use disorder.