Dopamine-driven increase in IL-1β in myeloid cells is mediated by differential dopamine receptor expression and exacerbated by HIV

Journal of Neuroinflammation, Год журнала: 2025, Номер 22(1)

Опубликована: Март 23, 2025

The catecholamine neurotransmitter dopamine is classically known for regulation of central nervous system (CNS) functions such as reward, movement, and cognition. Increasing evidence also indicates that regulates critical in peripheral organs an important immunoregulatory factor. We have previously shown increases NF-κB activity, inflammasome activation, the production inflammatory cytokines IL-1β human macrophages. As myeloid lineage cells are to initiation resolution acute responses, dopamine-mediated dysregulation these could both impair innate immune response exacerbate chronic inflammation. However, exact pathways by which drives inflammation not well defined, studies rodent systems indicate can impact mediators through D1-like receptors (DRD1, DRD5) D2-like (DRD2, DRD3, DRD4). Therefore, we hypothesized regulated ratio different activated. Our data primary monocyte-derived macrophages (hMDM) DRD1 expression necessary IL-1β, changes DRD2 other alter magnitude increase IL-1β. Mature hMDM a high receptor ratio, relative monocytes blood mononuclear (PBMCs). further confirm microglia cell lines promotes dopamine-induced gene protein using pharmacological inhibition or overexpression receptors. RNA-sequencing dopamine-treated shows genes encoding signaling pathways, neurotransmission increased with treatment. Finally, HIV example disease substantively worsened comorbid substance use disorders (SUDs) dopaminergic signaling, show effects on activation presence microglia. These suggest addictive substances dopamine-modulating therapeutics dysregulate neuroimmunological conditions like HIV. Thus, detailed understanding inflammation, particular regulating will be effectively tailor medication regimens.

Язык: Английский

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Development of a Fluorescently Labeled Ligand for Rapid Detection of DAT in Human and Mouse Peripheral Blood Monocytes

JACS Au, Год журнала: 2024, Номер 4(2), С. 657 - 665

Опубликована: Янв. 24, 2024

The dopamine transporter (DAT) is one of the key regulators (DA) signaling in central nervous system (CNS) and periphery. Recent reports a model Parkinson's disease (PD) have shown that neuronal loss CNS impacts expression DAT peripheral immune cells. mechanism underlying this connection still unclear but could be illuminated with sensitive high-throughput detection DAT-expressing cells circulation. Herein, we developed fluorescently labeled ligands (FLL) bind to surface-expressing high affinity selectivity. diSulfoCy5-FLL (

Язык: Английский

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Leaky lessons learned: Efflux prone dopamine transporter variant reveals sex and circuit specific contributions of D2 receptor signalling to neuropsychiatric disease

Basic & Clinical Pharmacology & Toxicology, Год журнала: 2023, Номер 134(2), С. 206 - 218

Опубликована: Ноя. 21, 2023

Aberrant dopamine (DA) signalling has been implicated in various neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum (ASD), schizophrenia, bipolar (BPD) and addiction. The availability of extracellular DA is sculpted by the exocytotic release vesicular subsequent transporter-mediated clearance, rendering presynaptic transporter (DAT) a crucial regulator neurotransmission. D2-type autoreceptors (D2ARs) regulate multiple aspects homeostasis, (i) synthesis, (ii) release, (iii) neuron firing (iv) surface expression DAT DAT-mediated clearance. Val559 variant, identified boys with ADHD or ASD, as well girl BPD, supports anomalous efflux (ADE), which we have shown drives tonic activation D2ARs. Through ex vivo studies variant using transgenic knock-in mice, uncovered circuit sex-specific capacity D2ARs to DAT, consequently disrupts behaviour differently males females. Our reveal ability construct-valid model elucidate endogenous mechanisms that support signalling, findings may be translational and/or therapeutic importance.

Язык: Английский

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The Effects of Chronic Psychostimulant Administration on Bone Health: A Review

Biomedicines, Год журнала: 2024, Номер 12(8), С. 1914 - 1914

Опубликована: Авг. 21, 2024

(1) Background: Methylphenidate (MP) and amphetamine (AMP) are psychostimulants that widely prescribed to treat Attention Deficit Hyperactivity Disorder (ADHD) narcolepsy. In recent years, 6.1 million children received an ADHD diagnosis, nearly 2/3 of these were for treatment. The purpose this review is summarize the current literature on psychostimulant use resulting effects bone homeostasis, biomechanical properties, functional integrity. (2) Methods: Literature searches conducted from Medline/PubMed electronic databases utilizing search terms “methylphenidate” OR “amphetamine” AND “bone health” remodeling” “osteoclast” “osteoblast” “dopamine” 01/1985 04/2023. (3) Results: Of 550 publications found, 44 met inclusion criteria. Data identified studies demonstrate MP AMP results in decreases specific properties integrity via downstream osteoblasts osteoclast-related genes. (4) Conclusions: chronic negatively affects strength as a result increased osteoclast activity. These data support need take into consideration when planning treatment type duration fractures.

Язык: Английский

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Illuminating the monoamine transporters: Fluorescently labelled ligands to study dopamine, serotonin and norepinephrine transporters

Basic & Clinical Pharmacology & Toxicology, Год журнала: 2022, Номер 133(5), С. 473 - 484

Опубликована: Дек. 17, 2022

Fluorescence microscopy has revolutionized the visualization of physiological processes in live-cell systems. With recent innovations super resolution microscopy, these events can be examined with high precision and accuracy. The development fluorescently labelled small molecules provided a significant advance understanding relevance targeted proteins that now visualized at cellular level. One set physiologically important target are monoamine transporters (MATs) play an instrumental role maintaining signalling homeostasis. Understanding mechanisms underlying their regulation dysregulation is fundamental to treating several neuropsychiatric conditions such as attention deficit hyperactivity disorder (ADHD), anxiety, depression substance use disorders. Herein, we describe rationale behind molecule design ligands (FLL) either MAT substrates or inhibitors well applications our this class health disease.

Язык: Английский

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Immunity on ice: The impact of methamphetamine on peripheral immunity

Advances in pharmacology, Год журнала: 2023, Номер unknown, С. 217 - 250

Опубликована: Окт. 24, 2023

Язык: Английский

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Longitudinal immunophenotyping to track motor progression in Parkinson’s Associated with a TH mutation

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Янв. 4, 2024

Abstract Background and Objectives: PD is the second most common neurodegenerative disorder fastest growing. Genetic factors account for ∼15% of cases. Despite some consistency in symptoms across idiopathic genetic cases, tracking progression treatment response remains an important challenge especially development new therapies. There have been many traditional approaches to including DaTscan imaging, cardiac 123I-MIBG scintigraphy, MRI, CSF analysis, following clinical symptom progression. Methods: Our previous work showed that peripheral blood mononuclear cells (PBMCs) expressing dopamine transporter (DAT) tyrosine hydroxylase (TH) patients may correlate with disease levodopa. We describe a single case longitudinal follow up 40-45-year-old woman who carried heterozygous TH mutation. assessed her features over 18 months DaT scans immunophenotyping PBMCs. Her data were compared (n=130 subjects, both sexes) healthy controls (n=80, age/sex matched). Results: The results revealed rise DAT+ immune which occurred coincident documented worsening UPDRS-III motor scores. Unlike patients, levodopa therapy, TH+ cell levels remained elevated, despite score improvement. Discussion: this patient mutation suggested PBMCs could be candidate biomarkers possibly effectiveness. This study provides proof concept explore approach investigate

Язык: Английский

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Post-translational mechanisms in psychostimulant-induced neurotransmitter efflux

Advances in pharmacology, Год журнала: 2024, Номер unknown, С. 1 - 33

Опубликована: Янв. 1, 2024

Язык: Английский

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Dopamine-driven Increase in IL-1β in Myeloid Cells is Mediated by Differential Dopamine Receptor Expression and Exacerbated by HIV

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 10, 2024

The catecholamine neurotransmitter dopamine is classically known for regulation of central nervous system (CNS) functions such as reward, movement, and cognition. Increasing evidence also indicates that regulates critical in peripheral organs an important immunoregulatory factor. We have previously shown increases NF-κB activity, inflammasome activation, the production inflammatory cytokines IL-1β human macrophages. As myeloid lineage cells are to initiation resolution acute responses, dopamine-mediated dysregulation these could both impair innate immune response exacerbate chronic inflammation. However, exact pathways by which drives inflammation not well defined, studies rodent systems indicate can impact mediators through D1-like receptors (DRD1, DRD5) D2-like (DRD2, DRD3, DRD4). Therefore, we hypothesized regulated ratio different activated. Our data primary monocyte-derived macrophages (hMDM) DRD1 expression necessary IL-1β, changes DRD2 other alter magnitude increase IL-1β. Mature hMDM a high receptor ratio, relative monocytes blood mononuclear (PBMCs). further confirm microglia cell lines promotes dopamine-induced gene protein using pharmacological inhibition or overexpression receptors. RNA-sequencing dopamine-treated shows genes encoding signaling pathways, neurotransmission increased with treatment. Finally, HIV example disease substantively worsened comorbid substance use disorders (SUDs) dopaminergic signaling, show effects on activation presence microglia. These suggest addictive substances dopamine-modulating therapeutics dysregulate neuroimmunological conditions like HIV. Thus, detailed understanding inflammation, particular regulating will be effectively tailor medication regimens.

Язык: Английский

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A novel fluorescently labelled ligand for the detection of DAT in immune cells by flow cytometry

Neuropsychopharmacology, Год журнала: 2024, Номер 50(1), С. 349 - 350

Опубликована: Июль 24, 2024

Язык: Английский

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