Electroacupuncture alleviates intestinal inflammation and barrier dysfunction by activating dopamine in a rat model of intestinal ischaemia.

BACKGROUND: To investigate whether the mechanism underlying the anti-inflammatory effects of electroacupuncture (EA) at ST36 involves dopamine (DA) and its receptor and whether it is mediated by the vagus nerve in a rat model of intestinal ischaemia-reperfusion (I/R) injury. METHODS: Rats were subjected to gut ischaemia for 30 min and then received EA for 30 min with or without abdominal vagotomy or intraperitoneal administration of butaclamol (D1 receptor antagonist) or spiperone (D2 receptor antagonist). Plasma levels of DA and tumour necrosis factor (TNF)-α were assessed 1 or 4 h after reperfusion. Myeloperoxidase (MPO) activity and malondialdehyde (MDA) content in intestinal tissues were assessed using enzyme-linked immunosorbent assay (ELISA) kits. Intestinal tissue injury was assessed by observation of the pathological lesions and permeability to 4 kDa fluorescein isothiocyanate (FITC)-dextran. RESULTS: EA significantly increased levels of DA and lowered levels of TNF-α. EA also inhibited intestinal levels of MPO and MDA and intestinal tissue injury and decreased intestinal permeability to FITC-dextran. Abdominal vagotomy and intraperitoneal administration of butaclamol (but not spiperone) inhibited the effects of EA. CONCLUSION: These findings suggest that EA at ST36 could attenuate intestinal I/R-induced inflammatory injury and that the underlying mechanism may involve EA-induced increases in levels of DA, mediated by the vagus nerve and D1 receptors.

Dopaminergic and Adrenergic Pathways as Targets for Drug Repurposing in the Neuroimmune Network.

Dopamine, noradrenaline and adrenaline are catecholamines, and are all produced along the same metabolic pathway. Their discovery dates back to the early 1900s, and they were appreciated until the second half of the century mainly for their role in the brain and in the regulation of autonomic functions. Nonetheless, in the 1970s characterization of the key role of sympathoadrenergic nerve fibers in the cross-talk between the brain and the immune system paved the way to the raise of modern neuroimmunology, and understanding the immune effects of dopamine occurred in the subsequent decades. Both adrenergic and dopaminergic transmission offer a possibly unparalleled wealth of therapeutic targets, and most of them have been already successfully exploited for cardiovascular, respiratory, neurologic and even psychiatric diseases, however so far the therapeutic potential of adrenergic and dopaminergic agents in the neuroimmune network remains relatively unexploited. This special issue provides a unique collection of expert contributions from some of the most prominent researchers currently studying dopaminergic and adrenergic agents in major diseases like cancer, autoimmunity, neurodegeneration, and even in emerging areas like hematology and metabolism. It is strongly hoped that these reviews will be not only helpful for researchers already working on topics related to the neuroimmune pharmacology of catecholamines, but will also attract novel researchers as much work is still needed to fully exploit the therapeutic potential of dopaminergic and adrenergic drugs for the benefit of patients.

Dopaminergic Pathways in Obesity-Associated Inflammation.

The overwhelming prevalence of obesity is a priority for public health compromising human lifespan and representing important economic burden worldwide. Obesity is characterized by a state of chronic low-grade inflammation associated to metabolic dysfunction. Although the efforts for unravelling the complex immunometabolic signaling pathways to explain the association of obesity with type 2 diabetes, cardiovascular diseases, cancer, neurodegenerative diseases and psychiatric disorders, we still do not have all the picture to design effective therapeutic to fight these immunometabolic disease clusters. Dopaminergic pathways apart from having a major role in the regulation of appetite and feeding behaviors are important immunoregulators in inflammation; thus, dopaminergic regulation is suggested to impact obesity- associated inflammation. Dopamine (DA) has been reported to modulate immune function and immune cells themselves produce endogenous DA. DA-induced immunomodulation is currently the focus of intense experimental research and dopaminergic pathways are increasingly considered a target for drug development in immune diseases. While the role of dopaminergic pathways in immune-mediated diseases has been intensively investigated in neurodegenerative diseases, dopaminergic immunomodulation in obesity-associated inflammation is largely unknown. This review will integrate the actual knowledge about dopaminergic pathways involved in obesity-associated inflammation with special focus on immune innate key cell players. We present an explanatory hypothesis with a model that integrate central and peripheral dopaminergic circuits in the relationship between neuroimmune and metabolic systems in obesity-associated inflammation. A perspective on the potential role of dopaminergic drugs in the context of obesity will be given. Graphical Abstract Graphical representation of central and peripheral dopaminergic pathways in obesity-associated inflammation.

The Functional Significance of Endocrine-immune Interactions in Health and Disease.

Hormones are known to influence various body systems that include skeletal, cardiac, digestive, excretory, and immune systems. Emerging investigations suggest the key role played by secretions of endocrine glands in immune cell differentiation, proliferation, activation, and memory attributes of the immune system. The link between steroid hormones such as glucocorticoids and inflammation is widely known. However, the role of peptide hormones and amino acid derivatives such as growth and thyroid hormones, prolactin, dopamine, and thymopoietin in regulating the functioning of the immune system remains unclear. Here, we reviewed the findings pertinent to the functional role of hormone-immune interactions in health and disease and proposed perspective directions for translational research in the field.

IL-17A exacerbates neuroinflammation and neurodegeneration by activating microglia in rodent models of Parkinson's disease.

Neuroinflammation has been involved in pathogenesis of Parkinson's disease (PD), a chronic neurodegenerative disease characterized neuropathologically by progressive dopaminergic neuronal loss in the substantia nigra (SN). We recently have shown that helper T (Th)17 cells facilitate dopaminergic neuronal loss in vitro. Herein, we demonstrated that interleukin (IL)-17A, a proinflammatory cytokine produced mainly by Th17 cells, contributed to PD pathogenesis depending on microglia. Mouse and rat models for PD were prepared by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or striatal injection of 1-methyl-4-phenylpyridinium (MPP+), respectively. Both in MPTP-treated mice and MPP+-treated rats, blood-brain barrier (BBB) was disrupted and IL-17A level increased in the SN but not in cortex. Effector T (Teff) cells that were adoptively transferred via tail veins infiltrated into the brain of PD mice but not into that of normal mice. The Teff cell transfer aggravated nigrostriatal dopaminergic neurodegeneration, microglial activation and motor impairment. Contrarily, IL-17A deficiency alleviated BBB disruption, dopaminergic neurodegeneration, microglial activation and motor impairment. Anti-IL-17A-neutralizing antibody that was injected into lateral cerebral ventricle in PD rats ameliorated the manifestations mentioned above. IL-17A activated microglia but did not directly affect dopaminergic neuronal survival in vitro. IL-17A exacerbated dopaminergic neuronal loss only in the presence of microglia, and silencing IL-17A receptor gene in microglia abolished the IL-17A effect. IL-17A-treated microglial medium that contained higher concentration of tumor necrosis factor (TNF)-α facilitated dopaminergic neuronal death. Further, TNF-α-neutralizing antibody attenuated MPP+-induced neurotoxicity. The findings suggest that IL-17A accelerates neurodegeneration in PD depending on microglial activation and at least partly TNF-α release.

Dopamine and its receptors play a role in the modulation of CCR5 expression in innate immune cells following exposure to Methamphetamine: Implications to HIV infection.

The Human Immunodeficiency Virus (HIV) infects cells in the Central Nervous System (CNS), where the access of antiretrovirals and antibodies that can kill the virus may be challenging. As a result of the early HIV entry in the brain, infected individuals develop inflammation and neurological deficits at various levels, which are aggravated by drugs of abuse. In the non-human primate model of HIV, we have previously shown that drugs of abuse such as Methamphetamine (Meth) increase brain viral load in correlation with a higher number of CCR5-expressing myeloid cells. CCR5 is a chemokine receptor that may be involved in increasing inflammation, but also, it is a co-receptor for viral entry into target cells. CCR5-expressing myeloid cells are the main targets of HIV in the CNS. Thus, the identification of factors and mechanisms that impact the expression of CCR5 in the brain is critical, as changes in CCR5 levels may affect the infection in the brain. Using a well-characterized in vitro system, with the THP1 human macrophage cell line, we have investigated the hypothesis that the expression of CCR5 is acutely affected by Meth, and examined pathways by which this effect could happen. We found that Meth plays a direct role by regulating the abundance and nuclear translocation of transcription factors with binding sites in the CCR5 promoter. However, we found that the main factor that modifies the CCR5 gene promoter at the epigenetic level towards transcription is Dopamine (DA), a neurotransmitter that is produced primarily in brain regions that are rich in dopaminergic neurons. In THP1 cells, the effect of DA on innate immune CCR5 transcription was mediated by DA receptors (DRDs), mainly DRD4. We also identified a role for DRD1 in suppressing CCR5 expression in this myeloid cell system, with potential implications for therapy. The effect of DA on innate immune CCR5 expression was also detectable on the cell surface during acute time-points, using low doses. In addition, HIV Tat acted by enhancing the surface expression of CCR5, in spite of its poor effect on transcription. Overall, our data suggests that the exposure of myeloid cells to Meth in the context of presence of HIV peptides such as Tat, may affect the number of HIV targets by modulating CCR5 expression, through a combination of DA-dependent and-independent mechanisms. Other drugs that increase DA may affect similar mechanisms. The implications of these epigenetic and translational mechanisms in enhancing HIV infection in the brain and elsewhere are demonstrated.

Dopaminergic Regulation of Innate Immunity: a Review.

Dopamine (DA) is a neurotransmitter in the central nervous system as well as in peripheral tissues. Emerging evidence however points to DA also as a key transmitter between the nervous system and the immune system as well as a mediator produced and released by immune cells themselves. Dopaminergic pathways have received so far extensive attention in the adaptive branch of the immune system, where they play a role in health and disease such as multiple sclerosis, rheumatoid arthritis, cancer, and Parkinson's disease. Comparatively little is known about DA and the innate immune response, although DA may affect innate immune system cells such as dendritic cells, macrophages, microglia, and neutrophils. The present review aims at providing a complete and exhaustive summary of currently available evidence about DA and innate immunity, and to become a reference for anyone potentially interested in the fields of immunology, neurosciences and pharmacology. A wide array of dopaminergic drugs is used in therapeutics for non-immune indications, such as Parkinson's disease, hyperprolactinemia, shock, hypertension, with a usually favorable therapeutic index, and they might be relatively easily repurposed for immune-mediated disease, thus leading to innovative treatments at low price, with benefit for patients as well as for the healthcare systems.

Infiltration of circulating myeloid cells through CD95L contributes to neurodegeneration in mice.

Neuroinflammation is increasingly recognized as a hallmark of neurodegeneration. Activated central nervous system-resident microglia and infiltrating immune cells contribute to the degeneration of dopaminergic neurons (DNs). However, how the inflammatory process leads to neuron loss and whether blocking this response would be beneficial to disease progression remains largely unknown. CD95 is a mediator of inflammation that has also been proposed as an apoptosis inducer in DNs, but previous studies using ubiquitous deletion of CD95 or CD95L in mouse models of neurodegeneration have generated conflicting results. Here we examine the role of CD95 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP)-induced neurodegeneration using tissue-specific deletion of CD95 or CD95L. We show that DN death is not mediated by CD95-induced apoptosis because deletion of CD95 in DNs does not influence MPTP-induced neurodegeneration. In contrast, deletion of CD95L in peripheral myeloid cells significantly protects against MPTP neurotoxicity and preserves striatal dopamine levels. Systemic pharmacological inhibition of CD95L dampens the peripheral innate response, reduces the accumulation of infiltrating myeloid cells, and efficiently prevents MPTP-induced DN death. Altogether, this study emphasizes the role of the peripheral innate immune response in neurodegeneration and identifies CD95 as potential pharmacological target for neurodegenerative disease.

Dopamine inhibits the function of Gr-1+CD115+ myeloid-derived suppressor cells through D1-like receptors and enhances anti-tumor immunity.

MDSCs accumulate in tumor-bearing animals and cancer patients and are a major factor responsible for cancer-induced immunosuppression that limits effective cancer immunotherapy. Strategies aimed at effectively inhibiting the function of MDSCs are expected to enhance host anti-tumor immunity and improve cancer immunotherapy significantly. The neurotransmitter DA has been found to have anti-cancer activity, but the underlying mechanism is poorly understood. In this study, we sought to investigate the therapeutic mechanism and efficacy of DA on the inhibition of cancer development via the regulation of MDSC functions. The regulation of the suppressive function of Gr-1(+)CD115(+) MDSCs by DA was determined by use of murine syngeneic LLC and B16 graft models treated with DA in vivo, as well as Gr-1(+)CD115(+) MDSCs isolated from these model treated with DA ex vivo. Here, we show that Gr-1(+)CD115(+) monocytic MDSCs express D1-like DA receptors. DA dramatically attenuated the inhibitory function of tumor-induced monocytic MDSCs on T cell proliferation and IFN-γ production via D1-like DA receptors and retarded tumor growth. DA and other D1 receptor agonists inhibited IFN-γ-induced NO production by MDSCs from tumor-bearing mice and cancer patients. Decreased NO production was, in part, mediated via the suppression of p-ERK and p-JNK. In conclusion, the neurotransmitter DA potently inhibits the suppressive function of MDSC and enhances anti-tumor immunity. Our finding provides a mechanistic basis for the use of DA or D1-like receptor agonists to overcome tumor-induced immunosuppression in cancer immunotherapy.

Dopamine inhibits the effector functions of activated NK cells via the upregulation of the D5 receptor.

Several lines of evidence indicate that dopamine (DA) plays a key role in the cross-talk between the nervous and immune systems. In this study, we disclose a novel immune-regulatory role for DA: inhibition of effector functions of activated NK lymphocytes via the selective upregulation of the D5 dopaminergic receptor in response to prolonged cell stimulation with rIL-2. Indeed, engagement of this D1-like inhibitory receptor following binding with DA suppresses NK cell proliferation and synthesis of IFN-γ. The inhibition of IFN-γ production occurs through blocking the repressor activity of the p50/c-REL dimer of the NF-κB complex. Indeed, the stimulation of the D5 receptor on rIL-2-activated NK cells inhibits the binding of p50 to the microRNA 29a promoter, thus inducing a de novo synthesis of this miRNA. In turn, the increased levels of microRNA 29a were inversely correlated with the ability of NK cells to produce IFN-γ. Taken together, our findings demonstrated that DA switches off activated NK cells, thus representing a checkpoint exerted by the nervous system to control the reactivity of these innate immune effectors in response to activation stimuli and to avoid the establishment of chronic and pathologic inflammatory processes.

Inhibitory effect of N-Acyl dopamines on IgE-mediated allergic response in RBL-2H3 cells.

Recently, endogenous N-acyl dopamines have been found to show anti-inflammatory and immunomodulatory activities. However, the effect of the N-acyl dopamines on allergic responses was not reported. In this study, we investigated whether N-acyl dopamines might inhibit immunoglobulin E-mediated degranulation in RBL-2H3 cells. When RBL-2H3 cells were exposed to palmitoyl dopamine (NP-DA), oleoyl dopamine (NO-DA) or arachidonoyl dopamine (NA-DA) at micromolar levels, all these compounds significantly inhibited the release of ß-hexosaminidase, a marker of degranulation, as well as tumor necrosis factor (TNF)-α. In comparison, NP-DA, potently suppressing the release of ß-hexosaminidase (IC50, 3.5 µM) and TNF-α (IC50, 2.2 µM), was more potent than NO-DA or NA-DA. Additionally, NP-DA markedly suppressed the formation of prostaglandin E2, prostaglandin D2 and leukotriene C4, corresponding to pro-inflammatory lipid mediators in asthma. In the mechanistic analyses, where the effect of NP-DA on the FcεRI cascade was examined, NP-DA significantly inhibited the phosphorylation and expression of Syk, but not Lyn. And, NP-DA also suppressed phosphorylation of ERK1/2 and Akt. Further, NP-DA decreased the phosphorylation of cPLA2 and 5-lipoxygenase (5-LO), but not cyclooxygenase-2 (COX-2). Based on these results, it is suggested that NP-DA exert anti-allergic effect on allergic response through suppressing the activation of Syk, ERK1/2, Akt, cPLA2 and 5-LO. Besides, a strong inhibition of COX-2 activity by NP-DA may be additional mechanism for its anti-allergic action. Such an anti-allergic action of N-acyl dopamines may contribute to further information about biological functions of N-acyl dopamines.

Immunoprotection against toxic biomarkers is retained during Parkinson's disease progression.

The aim was to ascertain any possible linkage between humoral immune responses to principal biomarkers (α-synuclein monomers, its toxic oligomers or fibrils, dopamine and S100B) and cellular immunity in Parkinson's disease development. There were elevated autoantibody titers to α-synuclein monomers, oligomers plus fibrils in 72%, 56%, and 17% of Parkinsonian patients respectively with a 5-year disease duration. Additionally, there were increased titers to dopamine and S100B (96% and 89%) in the 5-year patient group. All of these values subsided in 10-year sufferers. Furthermore, CD3+, CD4+, CD8+ T-lymphocyte and B-lymphocyte subsets declined in the patient cohort during Parkinsonism indicating disease associated reductions in these lymphocyte subsets.

[Case report : Severe anaphylactic shock followed by positive skin-prick-test to multiple vasoconstrictors].

A 71-year-old woman was scheduled for revision of total hip replacement under general anesthesia. Twenty minutes before entering the operating room, slight urticaria was caused by drop infusion of cefotiam. It was stopped immediately and the patient entered the operating room without any symptoms. Anesthesia was induced and maintained with sevoflurane and remifentanil. After 3 hours, systolic arterial pressure (SAS) dropped to 80 mmHg. Injecting of ephedrine 8 mg was not effective, and we injected a total of 3 mg of methoxamine. Then SAS dropped to 50 mmHg. We injected epinephrine 0.2 mg twice and also started continuous infusion of norepinephrine. Severe skin rash indicated that anaphylactic reaction had occurred. About 20 minutes after starting norepinephrine, the SAS was stabilized. We decided to stop the operation, and the patient was moved to the intensive care unit (ICU). A few hours after entering the ICU, she was extubated and moved to the general ward next day. Skin-prick-tests performed 14 days later indicated that she was allergic to ephedrine, methoxamine, epinephrine, dopamine and a few more drugs.

Dopamine released by dendritic cells polarizes Th2 differentiation.

A major neurotransmitter dopamine transmits signals via five different seven transmembrane G protein-coupled receptors termed D1-D5. It is now evident that dopamine is released from leukocytes and acts as autocrine or paracrine immune modulator. However, the role of dopamine for dendritic cells (DCs) and T(h) differentiation remains unclear. We herein demonstrate that human monocyte-derived dendritic cells (Mo-DCs) stored dopamine in the secretary vesicles. The storage of dopamine in Mo-DCs was enhanced by forskolin and dopamine D2-like receptor antagonists via increasing cyclic adenosine 3',5'-monophosphate (cAMP) formation. Antigen-specific interaction with naive CD4(+) T cells induced releasing dopamine-including vesicles from Mo-DCs. In naive CD4(+) T cells, dopamine dose dependently increased cAMP levels via D1-like receptors and shifts T-cell differentiation to T(h)2, in response to anti-CD3 plus anti-CD28 mAb. Furthermore, we demonstrated that dopamine D2-like receptor antagonists, such as sulpiride and nemonapride, induced a significant DC-mediated T(h)2 differentiation, using mixed lymphocyte reaction between human Mo-DCs and allogeneic naive CD4(+) T cells. When dopamine release from Mo-DCs is inhibited by colchicines (a microtubule depolymerizer), T-cell differentiation shifts toward T(h)1. These findings identify DCs as a new source of dopamine, which functions as a T(h)2-polarizing factor in DC-naive T-cell interface.

Immunity and cognition: what do age-related dementia, HIV-dementia and 'chemo-brain' have in common?

Until recently, dogma dictated that the immune system and the central nervous system (CNS) live mostly separate, parallel lives, and any interactions between the two were assumed to be limited to extreme cases of pathological insult. It was only a decade ago that T cells in the injured brain were shown to play a protective rather than a destructive role. In this article, we explore the role of the immune system in the healthy brain, focusing on the key function that T lymphocytes have in the regulation of cognition. We discuss candidate mechanisms underlying T cell-mediated control of cognitive function in human cognitive diseases associated with immune decline, such as age- and HIV-related dementias, 'chemo-brain' and others.

Harnessing serotonergic and dopaminergic pathways for lymphoma therapy: evidence and aspirations.

Growing evidence supports the notion that pharmaceutical targeting of the 5-hydroxytryptamine (5-HT) and dopamine (DA) systems offers the potential to treat human immune system disorders. This review describes this emerging area of research, which has the benefit of being supported by a relatively detailed understanding of these monoamine systems within other tissues of the body. Furthermore, the availability of a number of pharmaceutical agents originally developed to manipulate central monoamine function, offer many suitable drug candidates to test their therapeutic potential in the immune pathology arena.

Catalpol protects dopaminergic neurons from LPS-induced neurotoxicity in mesencephalic neuron-glia cultures.

Inflammation plays an important role in the pathogenesis of Parkinson's disease (PD). Microglia, the resident immune cells in the central nervous system, are pivotal in the inflammatory reaction. Activated microglia can induce expression of inducible nitric-oxide synthase (iNOS) and release significant amounts of nitric oxide (NO) and TNF-alpha, which can damage the dopaminergic neurons. Catalpol, an iridoid glycoside, contained richly in the roots of Rehmannia glutinosa, was found to be neuroprotective in gerbils subjected to transient global cerebral ischemia. But the effect of catalpol on inflammation-mediated neurodegeneration has not been examined. In this study, microglia in mesencephalic neuron-glia cultures were activated with lipopolysaccharide (LPS) and the aim of the study was to examine whether catalpol could protect dopaminergic neurons from LPS-induced neurotoxicity. The results showed that catalpol significantly reduced the release of reactive oxygen species (ROS), TNF-alpha and NO after LPS-induced microglial activation. Further, catalpol attenuated LPS-induced the expression of iNOS. As determined by immunocytochemical analysis, pretreatment by catalpol dose-dependently protected dopaminergic neurons against LPS-induced neurotoxicity. These results suggest that catalpol exerts its protective effect on dopaminergic neurons by inhibiting microglial activation and reducing the production of proinflammatory factors. Thus, catalpol may possess therapeutic potential against inflammation-related neurodegenerative diseases.

Review of evidence that posttransplantation psychiatric treatment commonly affects prolactin levels and thereby influences graft fate.

Delirium, depression and other psychiatric difficulties are commonly encountered by posttransplantation patients, and antipsychotic medicines are frequently used to treat these difficulties. This article reviews previous research data concerning the immunological effects of these medicines, with particular focus on the consequences of prolactin elevation. Unproven but of concern is that these effects may influence graft fate. Older antipsychotic medicines such as haloperidol and chlorpromazine have a high likelihood of elevating prolactin. Prolactin is an immunologically active molecule generally promoting bone marrow function. This may be of benefit post-stem-cell transplant, helping engraftment, but could further rejection of solid-organ transplants. Elevated prolactin is implicated in the facilitation of graft-versus-host disease. Aripiprazole is the antipsychotic medicine least likely to increase prolactin (and may actually decrease prolactin); risperidone, the most likely to increase prolactin. Olanzapine, quetiapine and ziprazadone are antipsychotic medicines with a lower likelihood of elevating prolactin. Older ("neuroleptic") antipsychotics, such as chlorpromazine, droperidol and haloperidol, perphenazine and many others, are likely to elevate serum prolactin. Among antidepressants, most serotonin reuptake inhibitors, with the exception of sertraline, can slightly elevate prolactin. The atypical (i.e., alone in their class) antidepressants bupropion and mirtazapine are prolactin neutral. The immunological consequences of psychiatric medicines should be considered when treating transplant patients for delirium, depression and thought disorders; in addition, if elevation of prolactin is thought to be of immunological importance during psychiatric treatment, then it should be monitored and treated. The dopamine agonists used to treat Parkinson's disease--bromocriptine, pergolide, pramipexole, ropinerole--usually reverse antipsychotic-induced prolactin increases without compromising psychiatric effectiveness.

Dopamine exerts no acute effects on Kv1.3 in activated encephalitogenic T cells.

Apart from a central function in the extrapyramidal motor system, dopamine has been suggested to play a role in neuroimmune interactions. Particularly in diseases of the central nervous system, such as multiple sclerosis, alterations in dopamine homeostasis might have immunological consequences. We investigated potential effects of dopamine stabilized by ascorbic acid on specifically activated encephalitogenic T cells at the peak of activation. Those cells exhibited an upregulation of voltage-sensitive K+ channels which play a role in many neurotransmitter responses of lymphocytes and fulfilled a prerequisite to respond to dopamine, i.e. stable expression of mRNA for dopamine receptors DRD1, DRD2 and DRD3. However, whole-cell and perforated whole-cell recordings revealed no change in voltage-sensitive K+ currents. Moreover, T cell proliferation was not changed in the presence of dopamine. Previously reported dopamine effects on T cells may be explained by a comparatively lower activation of the cells under investigation, suggesting an activation dependence of dopamine effects that may not be mediated by K+ channels. Alternatively, the occurrence of dopamine degradation products under unprotected conditions may account for the changes reported. Nevertheless, care should be taken when using the dopamine-protecting anti-oxidant ascorbic acid, since we found that it markedly inhibited both K+ currents and lymphocyte proliferation at higher concentrations.

Further evidence for the depressive effects of cytokines: anhedonia and neurochemical changes.

Although human studies have emphasized a role for IL-2 in depressive illness, limited attention has been devoted to the behavioral and neurochemical effects of this cytokine in animal studies. The present review assesses the behavioral effects of IL-2 in rodents, in counterpoint to the effects of interleukin-1beta (IL-1beta), necrosis factor-alpha (TNF-alpha) and endotoxin challenge. Unlike IL-1beta, systemic IL-2 provokes modest effects on hypothalamic-pituitary-adrenal (HPA) functioning, and does not provoke marked signs of illness or anxiety. In some respects, however, IL-2 elicits effects reminiscent of traditional stressors, including anhedonia (diminished pleasure gained from otherwise rewarding stimuli). Additionally, when chronically administered, IL-2 may impact on cognitive processes, including spatial working memory. While IL-2 may induce depressive-like symptoms, the available data are sparse, have hardly considered the impact of chronic cytokine treatment, only assessed behavior in a narrow range of tests, and it remains to be established whether the effects of IL-2 are modifiable by antidepressant treatments. Finally, as the effects of IL-2 on CNS processes vary in a biphasic fashion, and may also engender neurotoxic effects, further analyses are necessary to discern under what conditions this cytokine provokes depressive-like behavioral outcomes.