Physiological concentrations of dopamine inhibit the proliferation and cytotoxicity of human CD4+ and CD8+ T cells in vitro: a receptor-mediated mechanism.

OBJECTIVE: Dopamine, a catecholamine neurotransmitter, influences growth and proliferation of lymphocytes. Pharmacological doses of dopamine have been shown to modulate T cell functions significantly, but no information is available on the effect of physiological concentrations of circulating dopamine on CD4+ and CD8+ T cell functions. This information may be of importance since significantly elevated plasma dopamine levels were observed in humans during uncoping stress, and suppression of T cell functions during stress is a well-known phenomenon. However, the mechanism inducing the suppression of T cell functions during stress is not yet clear. In the present investigation, we evaluated the effect of the dopamine level attained in the plasma of individuals with uncoping stress on the proliferation and cytotoxicity of CD4+ and CD8+ T cells in vitro. METHODS: T cell subpopulations were separated by panning. The effect of dopamine on IL-2-induced cell proliferation in vitro was evaluated by [3H]thymidine incorporation and cytotoxicity by 51Cr release, receptors by radioligand binding, cAMP by an assay kit and apoptosis by DNA fragmentation. RESULTS: At these elevated physiological concentrations, dopamine was found to inhibit significantly the proliferation and cytotoxicity of CD4+ and CD8+ T cells in vitro. This dopamine-mediated inhibition of proliferation was more marked on CD8+ T cells than on CD4+ T cells. The underlying mechanism was found to be D1 class of dopamine-receptor-mediated stimulation of intracellular cAMP. CONCLUSION: Results may be of significance to understand the role of peripheral dopamine in human neuroimmune communication in terms of physiological homeostasis in health and disease.

Circulating dopamine level, in lung carcinoma patients, inhibits proliferation and cytotoxicity of CD4+ and CD8+ T cells by D1 dopamine receptors: an in vitro analysis.

Besides cardiovascular and renal functions, the role of dopamine in periphery as an endogenous regulator of immune functions is in the limelight. In human malignancy, depression of T cell functions is known. Interestingly, recent evidences indicate significant elevation of plasma dopamine in malignancy due to stress of the disease process. Therefore, this study evaluates whether this increased plasma dopamine exerts any influence on the proliferation and cytotoxicity of CD4+ and CD8+ T cells. Patients with lung carcinoma were selected for this study due to the high prevalence rate of this kind of cancer in developing countries and also due to strong positive biochemical and psychological criteria of stress in most of the patients. Results showed significant elevation of plasma dopamine (48.6 +/- 5.1 pg/ml) in lung cancer patients than normal controls (10.2 +/- 0.9 pg/ml). In vitro dopamine concentration, simulating the plasma concentration of the patients, significantly inhibited the proliferation and cytotoxicity of T cells of these patients and also of the normal volunteers, in presence of their respective serum. The mechanism has been attributed to be D1 class of dopamine receptor mediated elevation of intracellular cAMP in these cell populations. The results may be of significance in understanding the role of peripheral dopamine as an immunomodulator in human health and diseases.

The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor.

Angiogenesis has an essential role in many important pathological and physiological settings. It has been shown that vascular permeability factor/vascular endothelial growth factor (VPF/VEGF), a potent cytokine expressed by most malignant tumors, has critical roles in vasculogenesis and both physiological and pathological angiogenesis. We report here that at non-toxic levels, the neurotransmitter dopamine strongly and selectively inhibited the vascular permeabilizing and angiogenic activities of VPF/VEGF. Dopamine acted through D2 dopamine receptors to induce endocytosis of VEGF receptor 2, which is critical for promoting angiogenesis, thereby preventing VPF/VEGF binding, receptor phosphorylation and subsequent signaling steps. The action of dopamine was specific for VPF/VEGF and did not affect other mediators of microvascular permeability or endothelial-cell proliferation or migration. These results reveal a new link between the nervous system and angiogenesis and indicate that dopamine and other D2 receptors, already in clinical use for other purposes, might have value in anti-angiogenesis therapy.

Role of dopamine in malignant tumor growth.

The regulatory role of dopamine, a monoamine neurotransmitter and/or a neurohormone in controlling the secretion of several anterior pituitary hormones, cardiovascular, and renal functions, has already been extensively used by clinicians for therapeutic purposes. In addition to these important functions of dopamine, some recent reports also indicate its novel role in regulating malignant cell proliferation and controlling immune functions in tumor-bearing animals. Therefore, in this article, we discuss all the relevant information correlating dopamine and malignant tumor growth in order to understand the host-tumor relationship at the level of a neurotransmitter and/or a neurohormone.

Dopamine, a neurotransmitter, influences the immune system.

Dopamine (DA) is a monoamine neurotransmitter of both central and peripheral nervous system. Its role in the neural-immune communication has been discussed in the present review. Results reveal that in vivo damage or stimulation of specific central dopaminergic system suppresses or enhances functional activities of the immune effector cells. The possible influences of other immunomodulators of the brain by altering brain DA may be the underlying mechanism. Direct effects of DA on the immune effector cells are also contradictory, it is suppressive in vitro, while in pharmacological doses, it is mostly stimulatory in vivo. The possible mechanisms have been discussed. Lastly, future areas of relevance on DA and immunity have been highlighted to advance our knowledge regarding DA as an immune regulator.

Decreased dopamine receptor expression and its second-messenger cAMP in malignant human colon tissue.

As an important enteric neurotransmitter, the role of dopamine as a mitotic inhibitor as well as a protective factor of epithelial cells of stomach and colon indicates its significance in malignant growth of gastrointestinal tract. Our previous results have shown significant alteration of dopamine receptors in human malignant stomach tissues. The present experiments, therefore, evaluate DA content, its receptor expression, and its second-messenger cAMP in human malignant colon tissues to evaluate its role. Results demonstrate a significant decrease of dopamine content, its receptor expression, and its second-messenger cAMP in malignant tissues of human colon. These results may provide insight into the role of dopamine as an enteric neurotransmitter on malignant growth of human colon and may also suggest a therapeutic approach targeting dopamine receptors and its signal transduction.

Alteration of dopamine D2 receptors in human malignant stomach tissue.

Dopamine is an important enteric neurotransmitter with a wide spectrum of physiological actions on the gastrointestinal tract. In addition, it showed inhibition of malignant cell proliferation as well as a protective influence on experimental carcinogenesis in the gastrointestinal tract of murine hosts. It is well established that dopamine acts on target cells through specific receptors. Therefore the status of dopamine receptors in malignant tumors of the stomach has been evaluated. Normal, benign, and malignant stomach tissue showed the presence of high-affinity D2 dopamine receptors. The concentration (Bmax) and affinity (Kd) of dopamine binding sites in normal and benign tumor tissues were similar. In malignant stomach tissue Bmax showed a significant decrease compared to normal and benign controls; however, Kd was similar. This alteration of dopamine receptors may be of significance in understanding the etiopathogenesis of gastric cancer at the level of peripheral neurotransmitters. Rational use of dopamine receptor antagonists for various stomach diseases may be suggested.

Enhanced tumor growth in brain dopamine-depleted mice following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment.

Brain dopamine influences immune functions and the role of immune functions in tumor growth is well established. Therefore, a study has been carried out to evaluate the correlation, if any, between brain dopamine and tumor growth. MPTP selectively destroys dopaminergic neurons in the brain. In the present study, Ehrlich carcinoma growth was evaluated in MPTP-treated mice. Results showed a correlation between depletion of striatal dopamine and enhanced tumor growth. Since in the present study striatal dopamine depletion in mice was associated with significantly decreased immune responses, the suggested correlation between brain dopamine and tumor growth was possibly mediated by the immune system.

Uptake and biodistribution of dopamine in bone marrow, spleen and lymph nodes of normal and tumor bearing mice.

Significant labelled dopamine uptake was evident in bone marrow, spleen and lymph nodes of normal murine hosts in vivo. On the contrary animals bearing solid Ehrlich carcinoma, 3H-dopamine uptake was significantly reduced. The tumor tissue itself incorporated only insignificant amount of dopamine. Bone marrow cells, splenocytes and lymphocytes from lymph nodes showed specific uptake of this monoamine. At present the peripheral role of dopamine in the regulation of heart and kidney functions are well documented and utilized clinically for treatment of congestive heart and renal failure. The present result of specific dopamine uptake by bone marrow, spleen and lymph nodes and alterations following tumor growth where hematopoesis and immune functions are disrupted, strengthens our previous idea that dopamine might also influence the functions of these peripheral organs. Knowledge of this possible effect of DA on these peripheral organs may be of future clinical significance in the management of hematological and immune abnormalities.

Alteration of brain catecholamines during growth of benzo(a)pyrene induced murine fibrosarcoma.

Brain catecholamines (CA) were studied in discrete brain areas of benzo(a)pyrene (b(a)p) induced fibrosarcoma bearing mice. Dopamine (DA) and norepinephrine (NE) levels decreased significantly in different brain areas especially in corpus striatum and hypothalamus with the tumor progression, indicating an inverse relationship between brain DA and NE levels and tumor growth. Since impaired hormonal and immunological functions are manifestation of systemic alteration during tumor growth, it appears that during malignant growth an alteration of these brain CA may play an important role in the regulation of systemic alterations.

Decrease in dopamine and norepinephrine concentration in different brain regions of mice during progression of Sarcoma 180 tumour.

The distribution and concentration of dopamine (DA) and norepinephrine (NE), the catecholamine neurotransmitters, were studied in discrete brain areas of Sarcoma 180 tumour bearing mice. With the progression of tumour, marked depletion of DA and NE concentration was observed in some brain areas richly innervated with dopaminergic and noradrenergic neurons suggesting an inverse relationship between brain CA and tumour growth. Since brain CA influence different important physiological activities like hormonal and immunological functions, it's alteration in brain areas during malignant growth suggests the possibility that the hormonal and immunological alterations during tumour growth is at the level of brain CA.

Tumor inhibition and hematological improvements by dopamine analog 3,4-dihydroxybenzylamine in mice bearing transplantable carcinoma.

The cancer chemotherapeutic efficacy of 3,4-dihydroxybenzylamine (DHBA), a dopamine analog with reduced neurotoxic effects, was evaluated in strain A mice bearing transplantable Ehrlich's ascites carcinoma. The analog was administered intraperitoneally on day 1 post-transplantation at dose schedules of 50, 100 and 200 mg/kg/day for 7 consecutive days. The results demonstrated a significant inhibition of tumor growth and prolongation of the survival time of EAC tumor bearing mice following DHBA treatment. Diminished activity of the growth-related respiratory enzyme succinate dehydrogenase along with the stimulated activity of the lysosomal enzyme beta-glucuronidase in the DHBA-treated tumor cells indicated inhibition of tumor growth as well as active lysis of the tumor cells. Tumor inhibition was accompanied by marked improvements in hemoglobin concentration. RBC count and bone marrow cellularity. The results demonstrated that DHBA did not adversely affect hematological profile of the host while it inhibited the growth of Ehrlich's ascites carcinoma.

Antitumor effect of i.p. dopamine in mice bearing Ehrlich ascites carcinoma.

The cancer chemotherapeutic efficacy of dopamine (DA) was evaluated in female strain A mice bearing transplantable Ehrlich ascites carcinoma. The results demonstrated significant inhibition of tumor growth with appreciable increase in the host survival time following DA treatment. Diminished activity of the growth-related respiratory enzyme succinate dehydrogenase along with stimulated activity of the lysosomal enzyme, beta-glucuronidase in DA-treated tumor cells indicated inhibition of tumor growth as well as active lysis of the tumor cells. The direct effect of this compound on tumor proliferation was demonstrated by marked inhibition of DNA synthesis. RNA synthesis was only marginally inhibited.

On the concept of optimum population.

PIP: The economic welfare of a community is affected by policies that determine both the rate of capital accumulation and the rate of growth of population. The optimum size of population at any point is time will depend on the size of the existing capital stock and the optimum rate of savings will depend on the existing number of people. Consequently, in this sense, a population policy cannot be developed without a concurrent savings policy. The criterion of optimality that will be used is the ma ximization of the total discounted welfare of all generations from now to infinity. The problem will be to select that rate of savings and that size of population at every moment which will achieve this maximum welfare if, in fact, a maximum exists. An inquiry is made into the existence of an optimum policy under various circumstances. An attempt is made to evaluate the consequences of various ethical beliefs.^ieng