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Nature Communications Jun 2024HIV-1 Vpr promotes efficient spread of HIV-1 from macrophages to T cells by transcriptionally downmodulating restriction factors that target HIV-1 Envelope protein...
HIV-1 Vpr promotes efficient spread of HIV-1 from macrophages to T cells by transcriptionally downmodulating restriction factors that target HIV-1 Envelope protein (Env). Here we find that Vpr induces broad transcriptomic changes by targeting PU.1, a transcription factor necessary for expression of host innate immune response genes, including those that target Env. Consistent with this, we find silencing PU.1 in infected macrophages lacking Vpr rescues Env. Vpr downmodulates PU.1 through a proteasomal degradation pathway that depends on physical interactions with PU.1 and DCAF1, a component of the Cul4A E3 ubiquitin ligase. The capacity for Vpr to target PU.1 is highly conserved across primate lentiviruses. In addition to impacting infected cells, we find that Vpr suppresses expression of innate immune response genes in uninfected bystander cells, and that virion-associated Vpr can degrade PU.1. Together, we demonstrate Vpr counteracts PU.1 in macrophages to blunt antiviral immune responses and promote viral spread.
Topics: Humans; Macrophages; vpr Gene Products, Human Immunodeficiency Virus; HIV-1; Trans-Activators; Proto-Oncogene Proteins; Immunity, Innate; Ubiquitin-Protein Ligases; HIV Infections; HEK293 Cells; Virion; Protein Serine-Threonine Kinases
PubMed: 38951492
DOI: 10.1038/s41467-024-49635-w -
Progress in Neuro-psychopharmacology &... Jun 2024Acute stimulation of M or M muscarinic cholinergic receptors reduces cocaine abuse-related effects in mice and rats. The combined activation of these receptor subtypes...
Acute stimulation of M or M 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. M and M + M 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 M receptor partial agonist VU0364572, M 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 M + M receptor stimulation. Thus, in mice, simultaneous stimulation of both receptor subtypes seems to produce potential neuroplastic changes that yield lasting effects.
PubMed: 38950842
DOI: 10.1016/j.pnpbp.2024.111079 -
Health Affairs (Project Hope) Jul 2024
Topics: Humans; Residential Treatment; Adolescent; Substance-Related Disorders; Substance Abuse Treatment Centers
PubMed: 38950304
DOI: 10.1377/hlthaff.2024.00497 -
Health Affairs (Project Hope) Jul 2024
Topics: Humans; Adolescent; Residential Treatment; Substance-Related Disorders; Male; Female; Substance Abuse Treatment Centers; United States
PubMed: 38950297
DOI: 10.1377/hlthaff.2024.00108 -
Health Affairs (Project Hope) Jul 2024Managed care plans, which contract with states to cover three-quarters of Medicaid enrollees, play a crucial role in addressing the drug epidemic in the United States....
Managed care plans, which contract with states to cover three-quarters of Medicaid enrollees, play a crucial role in addressing the drug epidemic in the United States. However, substance use disorder benefits vary across Medicaid managed care plans, and it is unclear what role states play in regulating their activities. To address this question, we surveyed thirty-three states and Washington, D.C., regarding their substance use disorder treatment coverage and utilization management requirements for Medicaid managed care plans in 2021. Most states mandated coverage of common forms of substance use disorder treatment and prohibited annual maximums and enrollee cost sharing in managed care. Fewer than one-third of states forbade managed care plans from imposing prior authorization for each treatment service. For most treatment medications, fewer than two-thirds of states prohibited prior authorization, drug testing, "fail first," or psychosocial therapy requirements in managed care. Our findings suggest that many states give managed care plans broad discretion to impose requirements on covered substance use disorder treatments, which may affect access to lifesaving care.
Topics: United States; Managed Care Programs; Medicaid; Substance-Related Disorders; Humans; Insurance Coverage; Cost Sharing; Prior Authorization
PubMed: 38950296
DOI: 10.1377/hlthaff.2023.01023 -
Addiction Biology Jul 2024Substance 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... (Review)
Review
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.
Topics: Humans; Substance-Related Disorders; Animals; Germany; Behavior, Addictive; Alcoholism
PubMed: 38949209
DOI: 10.1111/adb.13419 -
Addiction Biology Jul 2024Opioid use disorder (OUD) is a multifaceted condition influenced by sex, genetic and environmental factors that could be linked with epigenetic changes. Understanding...
Opioid use disorder (OUD) is a multifaceted condition influenced by sex, genetic and environmental factors that could be linked with epigenetic changes. Understanding how these factors interact is crucial to understand and address the development and progression of this disorder. Our aim was to elucidate different potential epigenetic and genetic mechanisms between women and men that correlate with OUD under real-world pain unit conditions. Associations between analgesic response and the DNA methylation level of the opioid mu receptor (OPRM1) gene (CpG sites 1-5 selected in the promoter region) were evaluated in 345 long opioid-treated chronic non cancer pain: cases with OUD (n = 67) and controls (without OUD, n = 278). Cases showed younger ages, low employment status and quality of life, but higher morphine equivalent daily dose and psychotropic use, compared to the controls. The patients with OUD showed a significant decrease in OPRM1 DNA methylation, which correlated with clinical outcomes like pain relief, depression and different adverse events. Significant differences were found at the five CpG sites studied for men, and exclusively in women for CpG site 3, in relation to OUD diagnosis. These findings support the importance of epigenetics and sex as biological variables to be considered toward efficient OUD understanding and therapy development.
Topics: Humans; Receptors, Opioid, mu; DNA Methylation; Male; Female; Epigenesis, Genetic; Chronic Pain; Opioid-Related Disorders; Middle Aged; Adult; Sex Factors; Analgesics, Opioid; Case-Control Studies; CpG Islands; Quality of Life
PubMed: 38949208
DOI: 10.1111/adb.13422 -
Drug Testing and Analysis Jul 2024External contamination is a well-recognized limitation of hair analysis for drugs of abuse like methylamphetamine (MA), and there are no guidelines regarding the...
External contamination is a well-recognized limitation of hair analysis for drugs of abuse like methylamphetamine (MA), and there are no guidelines regarding the analysis of specific metabolites of MA to assist interpretation. We developed an analytical method to detect MA, amphetamine (AMP), and para-hydroxy-methylamphetamine (p-OH-MA) in hair and present their concentrations among a cohort of deceased persons positive for MA in blood (n = 63). Hair samples (≤ 3 cm) were washed with dichloromethane and water prior to extraction using a methanolic micro-pulverization. The reconstituted hair extracts were separated on a UCT Selectra® Aqueous C18 HPLC Column (100 × 2.1 mm, 3 μm) by gradient elution and detected using a Sciex Triple Quad 6500+ system. Validation was satisfactory, and the lower limits of quantitation were 0.01 ng/mg for MA and AMP and 0.001 ng/mg for p-OH-MA. The median hair concentrations of MA, AMP, and p-OH-MA were 13 ng/mg (range = 0.015-49; n = 51), 1.1 ng/mg (range = 0.018-44; n = 60), and 0.020 ng/mg (range = 0.0012-0.38, n = 62), respectively. These concentrations in hair were strongly positively correlated (r = .7202 to .8641, p < .001), suggesting similar modes of incorporation. Moreover, the wash/hair ratios were indicative of external contamination, especially among the soiled group of hair samples. Therefore, further studies are necessary to determine concentrations of p-OH-MA in living MA users and confirm if this metabolite constitutes a potential marker of MA consumption.
PubMed: 38949034
DOI: 10.1002/dta.3765 -
JPMA. the Journal of the Pakistan... Jun 2024
Topics: Humans; Zolpidem; Young Adult; Recreational Drug Use; Pakistan; Male; Hypnotics and Sedatives; Female; Adult; Substance-Related Disorders; Sleep Aids, Pharmaceutical
PubMed: 38949014
DOI: 10.47391/JPMA.10844 -
BioRxiv : the Preprint Server For... Jun 2024Drugs of abuse activate defined neuronal ensembles in brain reward structures such as the nucleus accumbens (NAc), which are thought to promote the enduring synaptic,...
Drugs of abuse activate defined neuronal ensembles in brain reward structures such as the nucleus accumbens (NAc), which are thought to promote the enduring synaptic, circuit, and behavioral consequences of drug exposure. While the molecular and cellular effects arising from experience with drugs like cocaine are increasingly well understood, the mechanisms that sculpt NAc ensemble participation are largely unknown. Here, we leveraged unbiased single-nucleus transcriptional profiling to identify expression of the secreted glycoprotein Reelin (encoded by the gene) as a marker of cocaine-activated neuronal ensembles within the rat NAc. Multiplexed in situ detection confirmed selective expression of the immediate early gene in neurons after cocaine experience, and also revealed enrichment of mRNA in + medium spiny neurons (MSNs) in both the rat and human brain. Using a novel CRISPR interference strategy enabling selective knockdown in the adult NAc, we observed altered expression of genes linked to calcium signaling, emergence of a transcriptional trajectory consistent with loss of cocaine sensitivity, and a striking decrease in MSN intrinsic excitability. At the behavioral level, loss of prevented cocaine locomotor sensitization, abolished cocaine place preference memory, and decreased cocaine self-administration behavior. Together, these results identify Reelin as a critical mechanistic link between ensemble participation and cocaine-induced behavioral adaptations.
PubMed: 38948801
DOI: 10.1101/2024.06.17.599348