TABLE 2.
Effects of dopaminergic immunomodulation associated with disease
| Species | Cell type/region | Dopamine receptors/proteins involved | Dopamine/dopamine modifying agent or method | Immunologic finding | Method of detection | Reference |
|---|---|---|---|---|---|---|
| NeuroHIV | ||||||
| Human | Macrophage (HIV-infected monocyte-derived) | D1-like | Meth (1–250 μM) SCH23390 (10 μM) |
↑ HIV replication and ↑ CCR5 with Meth (effect blocked by SCH23390) | RT-PCR ELISA Western blot |
Liang et al., 2008 |
| Human | Macrophage (HIV-infected ART-treated monocyte-derived macrophage) | N/A | Dopamine (1 nM–1μM) | ↑ IL-1β, IL-6, IL-18, CCL2, CXCL8, CXCL9, CXCL10 | AlphaLISA | Nolan et al., 2019 |
| Human | Macrophage (monocyte-derived macrophages) | D1-like D2-like |
Dopamine (1 nM–1μM) | ↑ HIV entry by increasing calcium release with dopamine | Viral entry assay Immunofluorescence |
Nickoloff-Bybel et al., 2019 |
| Mouse | Macrophage (bone marrow–derived macrophages from transgenic nef mice) Brain (striatum) |
DAT | N/A | ↓ Striatal dopamine and DAT levels in HIV nef mice ↑ ccl2 gene expression in striatum and cortex ↑ ccl2 and ↓ ifn-α gene expression in BMDM ↑ ccl2 gene expression in striatum |
qPCR IHC Western blot HPLC |
Acharjee et al., 2014 |
| Human | Monocyte (CD14+CD16+ Peripheral blood mononuclear cells) | D1-like | Dopamine (1–50 μM) SKF38393 (1–50 μM) |
↑ Monocyte migration across the blood–brain barrier from HIV infected individuals with dopamine and SKF38393 | Flow cytometry | Calderon et al., 2017 |
| Primate | Brain (SIV infected frontal cortex, basal ganglia and SbN) | MAO D1-like D2-like |
Selegiline (0.01–2 mg/kg intramuscularly) L-DOPA (50 mg/kg orally) |
↑ SIV expression and TNF-α with selegiline and L-DOPA | In situ hybridization | Czub et al., 2004 |
| Human | Dendritic cell (HIV-infected human PBMC-derived dendritic cells) | D2 | Meth (10–100 μM) Sulpiride (100 μM) |
↑ HIV replication and phospho-p38-MAPK with Meth ↑ CCR5 and CXCR4 with Meth ↓ Viral replication and CCR5 with drd1 KD and sulpiride |
MAGI assay ELISA RT-PCR Western blot |
Nair et al., 2009 |
| Human | Macrophage (primary monocyte-derived macrophages) | D1-like D2-like |
Dopamine (0.01–10 μM) Flupentixol (1 μM) |
↑ HIV entry in the presence of dopamine (blocked by flupentixol) | Viral entry assay | Gaskill et al., 2014 |
| Human | Macrophage (primary monocyte-derived macrophages) | D1-like D2-like |
Dopamine (1 μM) | ↑ HIV replication with dopamine Dopamine alters effectiveness of maraviroc on HIV infection |
AlphaLISA | Matt et al., 2021 |
| Human | Microglia (C06 microglia and iPSC-derived microglia) | D1-like D2-like |
Dopamine (1 μM) | ↑ HIV replication with dopamine | AlphaLISA | Matt et al., 2021 |
| Human | T-lymphoblast (ACH-2 cell line) | Dopamine dependent oxidative stress | Dopamine (20–100 μM) Glutathione (1–2 mM) |
↑ HIV in chronically infected T lymphoblasts in the presence of dopamine (effects attenuated by Gluthiatione) | Flow cytometry | Scheller et al., 2000 |
| Human | Monocyte (CD14+CD16+ peripheral blood mononuclear cells) | D1-like | Dopamine (100 nM–1 μM) SKF38393 (1 nM–100 nM) |
↑ Monocyte migration (chemokinesis) with dopamine and SKF38393 ↑ monocyte adherence with dopamine |
Migration assay Spreading and adhesion assay |
Coley et al., 2015 |
| Human | T-cell (Jurkat cell line) | N/A | Dopamine (10–300 μM) | ↑ HIV-1 gene transcription in presence of dopamine | Chloramphenicol acetyltransferase assay | Rohr, Sawaya et al., 1999 |
| Human | Peripheral blood mononuclear cells | N/A | Dopamine (100 μM) | ↑ HIV-1 gene transcription in presence of dopamine | Chloramphenicol acetyltransferase assay | Rohr, Sawaya et al., 1999 |
| Human | Macrophage (monocyte-derived macrophages) | D2-like | Dopamine (20 μM) Quinpirole (1 μM) |
↑ HIV-1 replication via ERK1 phosphorylation with dopamine ↑ Number of virally infected macrophages with dopamine ↑ HIV replication with quinpirole |
ELISA Immunofluorescence Western blot |
Gaskill et al., 2009 |
| PD | ||||||
| Mouse | T-cell (CD4+ T-cells from MPTP-treated mice) | D2 | Sumanirole (1 μM) L-741,226 (1 μM) |
↑ MPTP-induced neuropathology and motor impairment in drd2-KO ↑ Th1/Th17 phenotype with drd2-KO ↓ Th1/Th17 phenotype with Sumanirole in vitro (reversed by L-741,226) ↑ CD11b, TNF-α, IL-1β, IFN-γ, IL-17A in drd2-KO MPTP-treated mice |
Flow cytometry Western blot RT-PCR |
Liu, Zhai et al., 2021 |
| Mouse | Microglia (MPTP-treated mice) Brain (substantia nigra) |
D3 | N/A | drd3-KO is neuroprotective in SbN of MPTP-treated mice and ↓ microglia activation | Flow cytometry | González et al., 2013 |
| Mouse | T-cell (CD3+ T-cells from MPTP-treated mice) | D3 | PD 128907 (50 nM in vitro) | ↑ Percentage of Foxp3+ in drd3-KO cells ↓ IL-2, TNF-α, and IFN-γ in drd3-KO cells ↑IL-2 with PD 128907 |
ELISA Flow cytometry |
González et al., 2013 |
| Human | Lymphocyte (peripheral blood of untreated early PD patients) | D3 | N/A | ↓ drd3 gene expression | qPCR | Kim, Nigmatullina et al., 2019 |
| Mouse | Lymphocyte (MPTP-treated mice) | D3 | N/A | ↑ drd3 gene expression | qPCR | Kim, Nigmatullina et al., 2019 |
| Human | T-cell (peripheral blood mononuclear cells from PD patients and healthy donors) | D3 | N/A | ↓ D3 receptor expression levels in CD4+ T-cells from PD patients and higher frequency of Th1 polarization | Flow cytometry | Elgueta et al., 2019 |
| Mouse | T-cell (CD4+ T-cells from MPTP-treated mice) | D3 | PG01037 (30 mg/kg) | ↓ Microglial activation, motor impairment and neurodegeneration in MPTP-treated mice given PG01037 Transference of CD4+ T-cells that were treated ex vivo with PG01037 led to ↓ microglial activation and motor impairment |
Flow cytometry | Elgueta et al., 2019 |
| Human | Lymphocyte (peripheral blood mononuclear cells of PD patients) | D3 | [3H]7-OH-DPAT | ↓ drd3 gene expression and inversely correlated with disease severity ↓ D3 receptor binding sites on lymphocytes of PD patients |
qRT-PCR Receptor binding assay |
Nagai et al., 1996 |
| Human | Lymphocyte (peripheral blood lymphocytes from PD patients) | D2 | [3H]spiroperidol (0.1–7nM) | 73% ↓ in [3H]spiroperidol binding sites in PD patients | Receptor binding assay | Le Fur et al., 1980 |
| Human | Lymphocyte (peripheral blood lymphocytes from PD patients and healthy controls) | D1-like D2-like |
[3H] SCH 23390 [3H] 7OH-DPAT |
↑ Density of D1-like and D2-like receptors on PBLs of PD patients prior to treatment (reversed following L-DOPA or bromocriptine therapy) | Receptor binding assay | Barbanti et al., 1999 |
| Human | Lymphocyte (peripheral blood lymphocytes from PD patients and healthy controls) | TH | N/A | ↓ TH immunoreactivity in PD patients ↓ intracellular DA concentration in PD patients |
Tyrosine hydroxylase immunoreactivity assay HPLC |
Caronti et al., 1999 |
| Human | Lymphocyte (peripheral blood lymphocytes from PD patients and healthy control) | DAT | N/A | ↓ DAT immunoreactivity in lymphocytes of early PD patients | Immunohistochemistry | Caronti et al., 2001 |
| Human | Lymphocyte (peripheral blood lymphocytes from PD patients and healthy control) | DAT | N/A | ↓ DAT immunoreactivity in lymphocytes of early PD patients | Densitometric analysis | Pellicano et al., 2007 |
| Mouse | Striatum (MPTP-treated mice) | N/A | Rotigotine-loaded microspheres (10 mg/kg) or rotigotine (0.7 mg/kg) | ↓ TNF-α, IL-1β, IL-6 | Immunohistochemistry ELISA |
Yu et al., 2015 |
| Human | T-cells (CD4+ naïve T-cells and memory T-cells of PD patients and healthy controls) | D1-like D2-like |
N/A | ↓ D1-like receptors on naïve CD4+ T-cells of PD patients ↑ D2-like receptors on memory T-cells of PD patients |
qPCR Flow cytometry |
Kustrimovic et al., 2016 |
| Schizophrenia | ||||||
| Human | Peripheral blood mononuclear cells (patients diagnosed with schizophrenia /schizophreniform disorder) | D2 D3 |
N/A | ↑drd3 gene expression compared with controls drd2 gene expression correlated with positive symptom scores |
qPCR | Cui et al., 2015 |
| Human | T-cell (peripheral blood mononuclear cells from patients diagnosed with schizophrenia) | D3 D4 |
N/A | ↑ drd3 and ↓ drd4 gene expression on T-cells | RT-PCR | Boneberg et al., 2006 |
| Human | T-cell (CD4+ peripheral blood mononuclear cells from patients diagnosed with schizophrenia) | D3 | N/A | ↑ D3 receptor expression in CD4+ T-cells of clozapine-treated schizophrenia patients | Flow cytometry | Fernandez-Egea et al., 2016 |
| Human | T-cell (peripheral blood mononuclear cells from patients diagnosed with schizophrenia) | D2 D4 |
N/A | ↑ D2 receptor expression on CD8+ T-cells and correlated positively with symptom scores ↓ D2 receptor expression on CD4+ T-cells ↑ D4 receptor expression on CD4+ T-cells and inversely correlated to symptom scores |
Flow cytometry | Brito-Melo et al., 2012 |
| Human | T-cell (peripheral blood T lymphocytes from patients diagnosed with schizophrenia) | D3 D5 |
N/A | ↑ drd3 and drd5 gene expression in lymphocytes of drug naïve patients with schizophrenia compared with treated patients | RT-PCR | Kwak et al., 2001 |
| Human | Serum (children with first episode of psychosis) | D2 | N/A | IgG and IgM DRD2 antibodies were present in children with first episode of psychosis | Flow cytometry | Pathmanandavel et al., 2015 |
| Human | Lymphocyte (peripheral blood lymphocytes from patients diagnosed with schizophrenia) | D2 | N/A | ↑ D2 receptor expression | Receptor binding assay | Bondy et al., 1985 |
| Human | Lymphocyte (peripheral blood lymphocytes from patients diagnosed with schizophrenia) | D3 | N/A | ↑ drd3 gene expression | RT-PCR | Ilani et al., 2001 |
| Human | Lymphocyte (peripheral blood lymphocytes from patients diagnosed with schizophrenia) | D3 | N/A | ↓ drd3 gene expression | RT-PCR | Vogel et al., 2004 |
| Human | Lymphocyte (peripheral blood lymphocytes from patients diagnosed with schizophrenia) | DAT | N/A | ↓ DAT receptor expression | Receptor binding assay | Marazziti et al., 2010 |
| Bipolar disorder | ||||||
| Mouse | Brain (striatum, PFC, and hippocampus) | DAT | GBR12909 | ↑ IL-2, ↓ IL-6, and ↑ BDNF in PFC ↑ IL-2 and IL-4, ↓ IL-6, ↑ IL-10 and IFN-γ in striatum ↑ IL-4 and IFN-γ, ↓ IL-10 in hippocampus |
Cytokine binding assay ELISA |
Bastos et al., 2018 |
| Human | Lymphocyte (peripheral blood T lymphocytes of patients diagnosed with bipolar disorder) | D3 | N/A | ↓ drd3 gene expression in patients with bipolar disorder compared with healthy controls | RT-PCR | Vogel et al., 2004 |
| Human | Lymphocyte (peripheral blood lymphocytes from patients diagnosed with bipolar disorder) | DAT | N/A | ↓ DAT receptor expression in patients diagnosed with bipolar disorder compared with healthy controls | Receptor binding assay | Marazziti et al., 2010 |
| Depression | ||||||
| Human | Lymphocyte (peripheral blood lymphocytes from patients diagnosed with major depression) | D4 | N/A | ↓ drd4 gene expression in patients with major depression | RT-PCR | Rocc et al., 2002 |
| Primate | Brain | D2 | N/A | ↓ D2 receptor binding and striatal dopamine release with chronic interferon-alpha administration in association with anhedonia-like behavior | PET imaging | Felger et al., 2013 |
| Anxiety | ||||||
| Mouse | Myeloid cell (CD11b+CD45+ immune cells from brain tissue) | D1 | Modafinil (90 mg/kg) SCH23390 (0.1 mg/kg) |
↓ LPS-induced immune cell infiltration in the brain with Modafinil ↓ il1b gene expression in stressed mice treated with Modafinil (blocked by SCH23390) |
Flow cytometry qPCR |
Zager et al., 2018 |
| Human | T-cell (peripheral blood T lymphocytes from patients diagnosed with GAD) | N/A | Dopamine (1 μM) | ↓ IL-2 and IFN-γ in dopamine treated PHA activated T-cells ↓ IL-10 and TGF-β but ↑ IL-17 and IL-21 in dopamine treated PHA activated T-cells from patients with GAD ↑ IL-6 and TNFα in dopamine treated PHA activated T-cells from both healthy controls and patients with GAD |
ELISA | Ferreira et al., 2011 |
| ADHD | ||||||
| Human | Serum (children diagnosed with ADHD) | DAT | N/A | Individuals carrying DAT 10/10 genotype exhibited higher DAT auto-antibodies levels than healthy controls which correlated with disease severity ↓ DAT auto-antibody levels comparable to healthy controls in ADHD patients treated with methylphenidate |
ELISA qPCR |
Giana et al., 2015 |
| Mouse | Brain (prefrontal cortex, NAc, VTA of male adult mice) | D1 D2 |
N/A | Locomotor hyperactivity with alterations in D1 and D2 receptor profile in the brain of male mice exposed to ↑ early prenatal stress | qPCR | Bronson and Bale, 2014 |
| Mouse | Choroid plexus (microglia, monocyte) | DAT | Amphetamine (1.5 mg/kg) | Dopamine transporter hypofunction ↓ monocyte-macrophage infiltration into the brain and was associated with ↓ microglial activation (COX-2, TNF-α and IRF7) | Histochemistry Flow cytometry qPCR |
Castellani et al., 2019 |
| Epilepsy | ||||||
| Human | Peripheral blood immune cells from patients diagnosed with TLE | D1 D2 D4 D5 |
N/A | ↑ D2 expression in T lymphocytes of patients diagnosed with TLE ↑ D1, D2, D4, and D5 receptor expression on monocyte and granulocytes of patients with TLE |
Flow cytometry | Vieira et al., 2021 |
| Colitis and inflammatory bowel disease | ||||||
| Mouse | T-cell [splenic and lymph node T-cells from DSS-induced colitis model (drd5-KO and Rag1-KO)] | D5 | SFK81297 (10–1000 nM) | ↓ CD4+ T-cell migration into gut lamina propria without impacting survivability, proliferation, and differentiation in drd5-KO ↓ Colitis manifestations with D5 deficient T-cells or CCR9 deficient T-cells ↑ ERK1/2 phosphorylation and cAMP accumulation with SKF81297 treatment |
AlphaScreen Time-resolved fluorescence resonance energy transfer |
Osorio-Barrios et al., 2021 |
| Mouse | Macrophage [colonic macrophages from DSS-induced colitis model (drd5-KO)] | D5 | Dopamine (20 μM) | ↑ Severity of DSS-induced colitis in drd5-KO mice and in WT recipients following bone marrow transplant from drd5-KO mice ↑ TNF-α, IL-6, NF-κB, and CCL2 in drd5-KO mice (blocked by dopamine) ↓ CD86, ↓ iNOS and ↑ M2-polarization markers with dopamine |
ELISA FACS Immunoblotting qPCR |
Liu, Wu et al., 2021 |
| Human | Serum (from healthy controls and patients with ulcerative colitis or Crohn’s disease) | D2 | N/A | DRD2 Taq1A polymorphism was associated with lower risk of development of refractory Crohn’s disease in individuals homozygous for the A2A2 allele | PCR-RFLP | Magro et al., 2006 |
| Mouse | T-cell (CD4+ T-cells from layers of small intestine of DSS-induced colitis mice) | D3 | PD128907 (50 nM) Dopamine (100 nM–1 μM) |
↓ Th17-mediated immunity in Drd3-KO mice ↑ IL-10 in Drd3 deficient Tregs ↑ CCR9 expression in Drd3 deficient Tregs isolated from mesenteric lymph node PD128907 limited Treg ability to suppress CD4+ T-cell proliferation in vitro |
Immunofluorescence in situ proximity ligation assay | Ugalde et al., 2021 |
| Mouse | T-cell (mesenteric lymph node CD3+ T-cells from DSS-induced colitis model) | D1-like D2-like |
Berberine (400 μL/mL) | ↓ IFNγ and IL-17 production with berberine | ELISA | Kawano et al., 2015 |
| Rheumatic diseases | ||||||
| Human | Synovial tissue samples and cells from patients with RA and OA | TH VMAT2 |
Reserpine (10 nM–1 μM) | TH+ cells only present in inflamed tissues and not healthy controls ↓ TNF, cAMP and CREB with reserpine |
Beadlyte cytokine assay | Capellino et al., 2010 |
| Human | B lymphocyte (peripheral blood B lymphocytes from RA and OA patients) | D1 D2 |
N/A | ↓ D2 receptor expression in both OA and RA patients compared with healthy controls ↓ D1 receptor expression in OA compared with healthy control D1-like receptor expression was negatively correlated with rheumatoid factor |
Flow cytometry | Wei et al., 2015 |
| Human | B lymphocyte (peripheral blood B lymphocytes and synovial tissues from RA and OA patients) | D2 | N/A | D2 receptor negatively correlated with serum TNFα levels in RA patients ↑ D2 expression in RA patients compared with OA patients and healthy controls |
Immulite immunoassay | Wei et al., 2016 |
| Human | T lymphocyte (human peripheral blood CD4+ T lymphocytes) | D1-like | Dopamine (1 μM) SCH23390 (10 μM) |
↑ Dopamine in RA synovial fluid ↑ IL-6-dependent IL-17 production by CD3/CD28 stimulated CD4+ T-cells with dopamine and SCH23390 |
ELISA | Nakano et al., 2011 |
| Mouse | Macrophage (bone marrow–derived macrophages) | D1-like | SCH23390 (0.005–0.05 mg/kg) A68930 (0.05 mg/kg) |
↓ Severity of collagen-induced arthritis in mice treated with SCH23390 | ELISA | Nakashioya et al., 2011 |
| Mouse | Macrophage (bone marrow–derived macrophages) | D1-like D2-like |
Low dopamine (2 μg/kg) High dopamine (10 μg/kg) Haloperidol (10 nM) |
↓ Osteoclast number in dopamine treated mice ↓ RANK-L, TNF-α, IL-1β and IL-6 in dopamine treated groups (reversed by haloperidol) |
ELISA Immunohistochemistry | Yang et al., 2016 |
| Human | Mast cell (from synovial fluid of patients with RA) | D3 | N/A | D3 receptor expression negatively correlated with disease severity and lipid oxidation D3 receptor expression positively correlated with antioxidant levels in synovial fluid |
Flow cytometry Thiobarbituric acid reaction |
Xue, Li et al., 2018 |
| Psoriasis and vitiligo | ||||||
| Human | T lymphocyte (Peripheral blood CD3+ T lymphocytes from psoriasis patients) | D1-like | Fenoldopam (1 μM) SKF38393 (100 nM) |
↑ D1, D4, and D5 receptor expression with CD3/28 stimulation ↓ T-cell chemotaxis toward SDF-1/CXCL12 with fenoldopam and SKF38393 ↓ TNF-α, IFN-γ, IL-1β, IL-2, IL-6, CD69 with fenoldopam |
Flow cytometry ELISA |
Keren et al., 2019 |
BDNF, brain-derived neurotrophic factor; DDS, dextran sulfate sodium; FACS, fluorescence-activated cell sorting; HPLC, high-performance liquid chromatography; IHC, immunohistochemical; IKK, IkappaB kinase; iNOS, NO synthase; iPSC, induced pluripotent stem cell; IRF7, interferon regulatory factor 7; MAGI, multinuclear activation of a galactosidase indicator; OA, osteoarthritis; PCR-RFLP, polymerase chain reaction–restriction fragment length polymorphism; PHA, phytohemagglutinin; qPCR, quantitative polymerase chain reaction; RT-PCR, reverse-transcription polymerase chain reaction; TLE, temporal lobe epilepsy.