Minireview: New Roles for Peripheral Dopamine on Metabolic Control and Tumor Growth: Let’s Seek the Balance

In peripheral tissues, dopamine is released from neuronal cells and is synthesized within specific parenchyma. Dopamine released from sympathetic nerves predominantly contributes to plasma dopamine levels. Despite growing evidence for peripheral source and action of dopamine and the widespread expression of dopamine receptors in peripheral tissues, most studies have focused on functions of dopamine in the central nervous system. Symptoms of several brain disorders, including schizophrenia, Parkinson’s disease, attention-deficit hyperactivity disorder, and depression, are alleviated by pharmacological modulation of dopamine transmission. Regarding systemic disorders, the role of dopamine is still poorly understood. Here we describe the pioneering and recent evidence for functional roles of peripheral dopamine. Peripheral and central dopamine systems are sensitive to environmental stress, such as a high-fat diet, suggesting a basis of covariance of peripheral and central actions of dopaminergic agents. Given the extended use of such medications, it is crucial to better understand the integrated effects of dopamine in the whole organism. Delineation of peripheral and central dopaminergic mechanisms would facilitate targeted and safer use of drugs modulating dopamine action. We discuss the increasing evidence for a link between peripheral dopamine and obesity. This review also describes the recently uncovered protective actions of dopamine on energy metabolism and proliferation in tumoral cells.

Dopamine was discovered in brain 50 yr ago (1). Its name refers to its monoamine structure and derivation from the decarboxylation of 3,4-dihydroxy-l-phenylalanine (L-DOPA), which is itself derived from the hydroxylation of tyrosine (Fig. 1). Carlsson et al. (1) showed that brain dopamine is not just an intermediate in the synthesis of other catecholamines (noradrenaline/norepinephrine and adrenaline/epinephrine) but is also a genuine neurotransmitter. For this discovery, Carlsson received the 2000 Nobel Prize in Physiology or Medicine. The dopaminergic neurons of mammalian brain are clustered in the midbrain substantia nigra and ventral tegmental area. Dopaminergic neurons from substantia nigra give rise to ascending fibers densely innervating the basal ganglia, with highest dopamine levels occurring in the caudate and putamen. Ventral tegmental area dopaminergic neurons project axons mainly into the nucleus accumbens and prefrontal cortex. Dopamine acts on specific receptors, belonging to the G protein-coupled receptor family, which are categorized in two main families: D1-like (D1 and D5 receptors) and D2-like (D2, D3, and D4 receptors). Dopamine in the central nervous system regulates cognition, motor control, mood, and reward systems. It also plays an important role in pain perception (2) and sexual behavior (3). Thus, dopamine is involved at different time scales, mediating the reactivity of the organism to the environment to ensure survival (4). A small cohort of dopamine neurons in the hypothalamus modulates the secretion of prolactin by the anterior pituitary. In turn, prolactin exerts trophic, as well as dynamic, positive feedback on those neurons (5). Dopamine can be detected in urine along with its main metabolite homovanillic acid (6), which seems to have its origin mainly in the central nervous system. Because dopamine does not cross the blood-brain barrier, dopaminergic signaling in brain is functionally distinct from peripheral pathways. Accordingly, where does dopamine in peripheral blood and tissues arise?

Fig. 1.

Pathways for synthesis of dopamine, noradrenaline, adrenaline, and serotonin. 5-HTP, 5-Hydroxytryptophan; PNMT, phenylethanolamine-N-methyl transferase; MAO, monoamine oxidase; COMT, catechol-O-methyl transferase.

Peripheral dopamine can originate from at least three sources, i.e. neuronal fibers, adrenal medulla, and neuroendocrine cells, also named amine precursor uptake and decarboxylation (APUD) cells (7). Thus, peripheral dopamine synthesis is both dependent and independent of neuronal elements. First, changes in plasma dopamine levels are predominantly determined by the activity of sympathetic nerves, which may release the precursor dopamine along with noradrenaline (8) into the parenchyma of target organs. Additionally, in adult rat, some primary sensory neurons were found to express tyrosine hydroxylase, although not dopamine-β-hydroxylase, suggesting that peripheral dopaminergic sensory innervation exists (9), at least transiently (10). Second, some dopamine may be released directly into the circulation from catecholamine-synthesizing cells of the adrenal medulla, chromaffin cells, similarly to noradrenaline and adrenaline. This might specifically fulfill dopaminergic autocrine/paracrine functions at local target organs, simply by incidental release of noradrenaline precursor. In addition to the sympathetic nerves and the adrenal medulla, APUD cells constitute an additional source of dopamine in peripheral tissues. These APUD cells can be found in kidney (11, 12) both exocrine (13) and endocrine (14) pancreas, retinal cells (15), and peripheral leukocytes (16). Of note, carotid body, the main peripheral chemoreceptor, senses primarily oxygen tension in blood and releases dopamine upon hypoxia (17).

It is remarkable that, despite the absence of specific dopamine sources in peripheral tissues, the concentration of free dopamine in plasma is similar to that of adrenaline. In humans, several conditions (stress, exercise, standing position, and hypovolemia) increase plasma dopamine levels, suggesting an origin in sympathetic nerves. Indeed, just as brain neurons (18), sympathetic nerves and cells of the adrenal medulla express the enzyme l-amino acid decarboxylase, also referred to as L-DOPA decarboxylase, and can synthesize dopamine from L-DOPA (11) (see Fig. 1). In view of the multiple sources of peripheral dopamine, the following question arises: are these different peripheral dopamine sources somehow functionally connected? In other words, is the release of dopamine from sympathetic nerves, adrenal glands, and that arising from APUD cells regulated in a concerted manner? Experiments conducted in the 1960s showed that both nerve-derived and peripheral tissue dopamine may have a common regulation. In particular, on chemical sympathectomy destroying the myocardial innervation, the activity tyrosine hydroxylase in the adrenal medulla increases, possibly as a compensatory mechanism (19). Nevertheless, neuronal tyrosine hydroxylase and L-DOPA decarboxylase genes are under the control of different promoter regions compared with their nonneuronal counterparts (20, 21). Several actions of peripheral dopamine have been described in the scientific literature. Peripheral dopamine regulates respiration (17), gastrointestinal motility, and blood pressure (22). Notably, dopamine signaling in the retina is essential for light-dependent control of circadian rhythms (23). This review focuses on the important role of dopamine in the modulation of other newly described physiological functions, presented in the context of side effects and consequences of dopaminergic medications.

A role for dopamine in the regulation of glucose homeostasis and body weight

Long before L-DOPA was recognized as the precursor of brain dopamine, Hirai and Gondo found that it could evoke hyperglycemia in rabbits (24). Some years after its discovery in brain and its linkage to the pathophysiology of Parkinson’s disease, dopamine was found to modulate endocrine pancreatic hormone levels in both animals and humans (25, 26). It was shown that dopamine inhibits insulin secretion in a preparation of isolated pancreas from golden hamster (27). Subsequently this finding was replicated in mouse and rabbit (25). Moreover, in the early phase of the treatment, L-DOPA transiently decreases insulin levels in Parkinson disease patients. This effect proved to be due to peripheral dopamine synthesis because there was no such effect on insulin levels when L-DOPA was coadministered with carbidopa, a peripherally acting inhibitor of L-DOPA decarboxylase (28).

Links have been established between obesity and hyposensitivity of dopaminergic systems, both within the central nervous system and in peripheral tissues (29, 30). This phenomenon might be due to convergence of central and peripheral actions of dopamine on pathways mediating metabolic homeostasis. In the basal ganglia, dopamine participates in the signaling of the rewarding effects secondary to food intake. In peripheral tissues, dopamine regulates pancreatic endocrine function including insulin release and also modulates the effects of insulin action on adipocytes. Food stimuli engage dopamine in reward circuits within the brain, in a similar way to mechanisms of drug abuse (31). This suggests that the behavioral aspects of obesity may be viewed as an addiction-like syndrome. Accordingly, the knockdown of striatal D2 receptors accelerates the onset of compulsive food seeking in rats with unrestricted access to palatable high-fat food (32). Treatment with the D2-like receptor agonist bromocriptine reduces hyperphagia and adiposity in rats with diet-induced obesity (33). Moreover, the discontinuation of pharmaceutical dopaminergic overstimulation is followed by elevated food consumption and weight gain in rats (34).

Dopamine transmission in peripheral organs can also modulate food intake. Dopamine release, from cells within the hypothalamus, tonically inhibits the secretion of prolactin from the pituitary. Blockade of dopamine D2 receptors with sulpiride, an antagonist with poor penetration of the blood brain barrier, increases food intake and body weight in female rats due to hyperprolactinemia (35). Prolactin stimulates receptors which are expressed on α- and β-cells of rat pancreatic islets (36), promoting β-cell proliferation and insulin secretion (37). In the hypothalamus, prolactin has a neurotrophic effect and maintains the population of dopaminergic neurons (5, 38). Noteworthy, prolactin is a proliferative signal for the β-cell (37), which also exhibits a dopaminergic phenotype (14). Thus, dopamine receptor antagonists may contribute to hyperinsulinemia and obesity via control of the pituitary hormone prolactin. Recent studies have shown that dopamine also directly inhibits the secretory response of pancreatic β-cells. We originally reported that dopamine D2 receptors are expressed in INS-1E insulinoma cells, as well as in rodent and human islets, and that these receptors mediate inhibition of the secretory response (14). Recently it has been confirmed that both dopamine (14, 39) and selective D2 receptor agonists (14, 40) inhibit insulin exocytosis. Such effects have been further substantiated by a study showing that islets isolated from Drd2^−/− mice lacking dopamine D2 receptor exhibit impaired glucose-stimulated insulin secretion (41).

Where does dopamine, acting on pancreatic islets, come from? Pancreatic islets are exposed to plasma dopamine, which may arise from the adrenal medulla and the composite of its potential sources. Dopamine may also be a cotransmitter along with noradrenaline released by sympathetic nerves, which directly innervate both exocrine and endocrine pancreas (42). Additionally, dopamine can be formed within the pancreas. Pancreatic islet cells were shown to express l-tyrosine hydroxylase and DOPA decarboxylase (43). Exocrine pancreas constitutes another important source of dopamine, although less likely to affect the endocrine pancreas because it is released with pancreatic juice into the small intestine (13). Thus, pancreatic islets may respond to circulating dopamine, dopamine released from sympathetic nerves innervating the pancreas, and dopamine directly formed within pancreatic cells, as an autocrine/paracrine signaling.

Separate lines of evidence indicate a role for dopamine in the regulation of pancreatic endocrine function. As noted above, dopamine may access pancreatic islets through blood circulation. Insulin release from β-cells is strongly inhibited by stress, a condition known to dramatically increase plasma dopamine (44) as well as epinephrine levels. Exercise, which promotes increases in plasma dopamine, is characterized by low insulin levels. Drugs with dopamine D2-like receptor antagonist action such as the antipsychotic drugs clozapine and olanzapine have been shown to increase insulin secretion in isolated rat pancreatic islets, consistent with relief of a tonic inhibitory mechanism (45, 46). Conversely, in ob/ob mice, dopamine agonists restore aberrant β-cell hyperplasia and reduce insulin levels in vivo (47). Taken as a whole, there is evidence that dopamine acts as an intraislet signal, regulating pancreatic hormone and peptide release in an autocrine and/or paracrine manner.

Besides the effects on food intake and endocrine function, dopamine seems to regulate the action of insulin in different tissues. This should be seen in light of the weight gain frequently experienced by patients under treatment with antipsychotic medications, which block D2-like dopamine receptors. Historically, antipsychotics are divided into two broad classes: 1) the first generation or typical antipsychotics, including chlorpromazine, trifluoperazine and haloperidol; 2) the second-generation or atypical antipsychotics, comprising clozapine, olanzapine, and risperidone. Antipsychotic-induced weight gain can be substantial and can contribute to poor compliance with medication (48), although the cellular localization of receptors mediating such effects is uncertain. Of note, trifluoperazine inhibits the action of insulin in adipocytes in vitro (49). In mice, second-generation antipsychotics induce insulin resistance and alter lipogenesis and lipolysis, thereby favoring progressive lipid accumulation in adipocytes (50). Nevertheless, second-generation antipsychotics act not only on D2-like receptors but also on other receptors, such as the type-2 serotonin receptors (5-HT2). Consequently, it is premature to draw conclusions about a specific dopamine-dependent regulation of insulin action on the basis of side effects of antipsychotic drugs.

Mouse genetic models and genetic association studies have provided much information about the metabolic effects of dopamine. For instance, dopamine D3 receptor knockout mice display increased adiposity (51). Genetic association studies in humans provide further evidence for the regulatory role of dopamine in metabolism. Degradation of dopamine is catalyzed by monoamine oxidase A, which is expressed in half of human pancreatic islet cells (52). In male humans, the allele of the monoamine oxidase A promoter variable number tandem repeat correlates with body mass index (53). Other associations have been reported for dopamine receptor alleles. The third exon of the dopamine D4 receptor gene is highly polymorphic. Its long version, known as the seven-repeat allele, is characterized by impaired cellular response to dopamine and has been associated with higher maximal body mass index compared with probands without this allele (54), although others have dissented (55). Molecular imaging studies in mice showed that high levels of dopamine transporters and dopamine D2 receptors in brain correlate with resistance to high-fat-diet-induced obesity (56, 57). Similarly, relatively low D2 receptor availability in striatum has been reported in obese individuals. In humans, presence of the TaqIA1 allele in DRD2, the gene encoding dopamine receptor 2, is associated with lower D2 receptor availability in the striatum, reduced dopamine signaling, and obesity (58). Thus, several lines of evidence implicate dopamine in the control of glucose metabolism and body weight in humans.

Dopamine decreases blood pressure and the release of the procoagulant von Willebrand factor

Dopamine lowers blood pressure by both renal and nonrenal mechanisms. Dopamine is natriuretic through inhibition of renal tubule sodium reabsortion. In the kidney, all dopamine receptors subtypes participate in the modulation of sodium balance to maintain blood pressure. Accordingly, animals lacking any of the dopamine receptors (D1^−/−, D2^−/−, D3^−/−, D4^−/−, and D5^−/− knockout mice) exhibit high blood pressure (59). In humans, it has been proposed that genetic variation in D1R may influence systolic blood pressure, which is an important risk factor for renal, cerebral, and cardiovascular diseases (60). A direct role for dopamine in the regulation of vascular contractibility is believed to contribute to changes in blood pressure. In rhesus monkeys, it was shown that dopaminergic and noradrenergic terminals innervate cortical and extraparenchymal cerebral vasculature, respectively (61). Also, vascular endothelial cells form dopamine, thanks to the action of L-DOPA decarboxylase (62). Plasma dopamine levels and blood pressure are usually negatively correlated. Physiologically, during a low sympathetic discharge, the hypotensive action of dopamine predominates. However, under certain circumstances such as shock states, treatment with dopamine can also increase blood pressure (63).

In addition to blood pressure modulation, dopamine inhibits the secretion of the procoagulant von Willebrand factor from human endothelial cells through its action on D2, D3, and D4 receptors (62). High levels of von Willebrand factor is a recognized risk factor for coronary heart disease (64). Dopamine decreases vascular permeability induced by the cytokine vascular endothelial growth factor (65, 66) by impairing vascular endothelial growth factor receptor phosphorylation (67).

Metabolic and cardiovascular consequences of the use of dopamine receptor ligands in humans

A clear link can be established between dopamine signaling, glucose metabolism, body weight, and cardiovascular tone. Consistent with these actions, several studies showed that dopaminergic agents modulate metabolism in humans. A clinical trial performed in obese women showed that short-term treatment with the D2-like receptor agonist bromocriptine ameliorates the metabolic features (68). Similarly, a phase II clinical trial showed that treatment with tesofensine, an inhibitor of dopamine uptake, decreases body weight in obese individuals (69). Conversely, dopamine receptor antagonists can evoke opposite metabolic alterations in humans.

The antipsychotic medications used for the treatment of schizophrenia exhibit D2-like receptor antagonist action. Schizophrenic patients are at risk for the metabolic syndrome, i.e. obesity, insulin resistance, dyslipidemia, impaired glucose tolerance, and hypertension (70–72). This might reflect lifestyle and heredity, although this might result from antipsychotic side effects. Treatment with antipsychotics is linked to changes in glucose homeostasis, potentially leading to obesity and type 2 diabetes (73). As mentioned above, antipsychotics are divided into first-generation or typical antipsychotics and second-generation or atypical antipsychotics. Clinically the atypical antipsychotics evoke less severe extrapyramidal side effects because of lower blockade of dopamine receptors in the basal ganglia. Drug-associated obesity and type 2 diabetes are observed with both typical and atypical antipsychotics (74–77). However, recent studies indicate that atypical forms are more likely to cause metabolic alterations, maybe due to different pharmacological specificities. Whereas typical antipsychotics are potent D2 and D3 antagonists, atypical antipsychotics target D4 receptors (78) and cause blockade of 5HT2A/5HT2C/5HT1A serotonin receptors. Thus, D4 receptor antagonism or serotonin receptor antagonism might be a contributing factor in metabolic syndrome. Noteworthy, D4 receptors are expressed in human pancreatic islets (14) and mice lacking 5HT2C receptors exhibit impaired glucose homeostasis (79).

Antipsychotic treatment is associated with increased cardiovascular risk (70). In particular, the atypical antipsychotic clozapine increases the risk of thrombotic events, which can arise during the first months of treatment before the onset of weight gain (80). Antipsychotic treatment may provoke cardiovascular diseases through increased secretion of the procoagulant von Willebrand factor (62) and blockade of dopamine receptors in vascular epithelium (64). The metabolic effects of drugs or conditions influencing dopaminergic transmission are summarized in Fig. 2 and Table 1.

Fig. 2.

Proposed model for dopamine metabolic regulatory actions. The putative effects of dopamine (DA) signaling deficiency are described as dotted lines. Centrally, impairment of DA effects would reduce satiety, favoring food intake. Peripherally, a decrease in DA action would increase prolactin release, mediating prolactin-induced food intake and an increase in insulin secretion. DA inhibits insulin secretion through D2 receptors present in the pancreatic β-cells. Blockade of DA receptors would augment insulin release, promoting adipogenesis, weight gain, insulin resistance, and ultimately type 2 diabetes. Lack of DA effects would also cause blood flow alterations and increased circulating levels of procoagulant von Willebrand factor (vWF), favoring the onset of cardiovascular events. D2R, Dopamine receptor 2; D3R, dopamine receptor 3; D4R, dopamine receptor 4.

Table 1.

Metabolic effects of drugs modifying dopamine signaling when administered in vivo

	Drug	Effect on dopamine signaling	Species/model	Lipidemia/dyslipemia	Glycemia	Basal insulinemia	Stimulated insulinemia	Food intake	Weight/adiposity/BMI	During treatment	Reference
DA ag. or increased DA levels
Nonobese model	L-DOPA	Increased DA levels	Rat	n.d.	n.d.	n.d.	n.d.	Increased	Weight increased	No, after withdrawal	Reinholz et al. (34)
		L-DOPA	Increased DA levels	Humans	n.d.	n.d.	n.d.	Decreased	n.d.	n.d.	n.d.	Rosati et al. (28)
Obese model	Bromocriptine	D2R ag.	Humans	Increased free fatty acids	Decreased	Decreased	Decreased	n.d.	n.d.	Yes	Kok et al. (68)
		SKF38393	D1R ag.	ob/ob mice	Decreased	Decreased	Decreased	n.d.	n.d.	n.d.	Yes	Jetton et al. (47)
		Bromocriptine	D2R ag.
		Bromocriptine	D2R ag.	Rat with D.I.O. and leptin receptor-deficient Zucker rats	Decreased	Decreased	n.d.	n.d.	Decreased	Adiposity decreased	Yes	Davis et al. (33)
DA ant.
Conventional	Sulpiride	D2R ant.	Female rats	n.d.	n.d.	n.d.	n.d.	Increased	Increased weight	Yes	Parada et al. (35)
		Haloperidol	D2R ant.	Humans	Unchanged	Unchanged	n.d.	n.d.	n.d.	Increased weight	Yes	Lindenmayer et al. (77)
Atypical	Clozapine	D2R and 5-HT2 ant.	Humans	n.d./increased cholesterol	n.d.	n.d.	n.d.	n.d.	Increased weight	Yes	Cohen et al. (74); Lindenmayer et al. (77)
		Olanzapine	D2R and 5-HT2 ant.	Humans	Increased total cholesterol and LDL cholesterol	n.d.	n.d.	n.d.	n.d.	Increased weight	Yes	Gupta et al. (75); Lindenmayer et al. (77)
		Risperidone	D2R and 5-HT2 ant.	Humans	Increased total cholesterol and LDL cholesterol	Glucose intolerance	n.d.	n.d.	n.d.	Increased weight	Yes	Wirshing et al. (76)

Effects of dopamine (DA) receptor agonists (ag.), drugs with DA receptor antagonist (ant.) activity, such as antipsychotics, or drugs increasing DA levels, such as L-DOPA, on metabolic parameters in animal models and humans. D2R, D2-like receptors; D1R, D1-like receptors; 5-HT2, type 2 serotonin receptors; D.I.O., diet-induced obesity; LDL, low-density lipoprotein; n.d., not determined; BMI, body mass index.

Involvement of dopamine in cell survival and proliferation, development, and cancer

There is increasing evidence showing that dopamine exerts control on cell survival and proliferation, possibly in a cell-type specific manner. In nontransformed cells, dopamine mainly promotes cell proliferation and survival, whereas in tumor cell lines dopamine seems to exhibit predominantly antiproliferative effects. Such a paradoxical two-way outcome has been described for other endogenous substances, such as endocannabinoids (81). Agonists of dopamine D2 receptors increase the proliferation of neuronal precursors (82) and neuronal stem cells (83). Catecholamine cells from the peripheral nervous system can still divide after differentiation, indicating that the presence of dopamine does not prevent their replication (84). Dopamine has important effects in the immune system, promoting the migration and repopulation of immature human CD34+ cells (85). Moreover, in the retina (86), dopamine regulates cell mitosis and apoptosis (87).

Dopamine may also modulate proliferation of pancreatic islet cells. Pancreatic precursors transiently express dopamine-synthesizing enzymes (43). Interestingly, neuronal signals are essential to stimulate pancreatic cell proliferation during the islet hyperplasia promoted by obesity (88), dopamine being a likely candidate mediating this effect. Mice lacking D2 receptors exhibit lower β-cell mass and replication rate, indicating that D2 receptors play an important role in β-cell proliferation (41). The gene encoding for l-amino acid decarboxylase (Fig. 1) is severely down-regulated in pancreatic islets isolated from the transcriptional activator hepatocyte nuclear factor-1α knockout mice, Hnf1a^−/−. The Hnf1a^−/− mouse is used as a model for Maturity Onset Diabetes of the Young 3, one of the most common types of human monogenic diabetes (89). Pancreatic islets from Hnf1a^−/− mice are smaller and their β-cells exhibit reduced proliferation rate (89). It can be hypothesized that reduced dopamine synthesis in pancreatic islets contributes to the Maturity Onset Diabetes of the Young 3 phenotype. In addition to its direct action on cell proliferation, dopamine might protect against apoptosis (90).

In contrast to its effects on differentiated cells, dopamine seems to exert mainly an inhibitory effect on cancer growth. Proliferation of human small lung cancer cells is inhibited by the D2-like receptor agonist bromocriptine (91). Both dopamine and SKF-38393, a selective D1/D5 receptor partial agonist, inhibit the growth of human meningioma cells in culture (92). Dopamine evokes cell-cycle arrest accompanied by apoptosis in B cells from a human lymphoid malignancy (93). A mouse model lacking the dopamine transporter displays elevated dopamine levels and reduced tumoral growth (94). In mice, chemical sympathectomy (by ip injection of the neurotoxin 6-hydroxydopamine) stimulates malignant tumor growth (95), whereas dopamine slows down the growth of xenotransplanted human gastric cancer (96), an effect attributed to inhibition of angiogenesis (65, 96). Furthermore, administration of dopamine to mice increases the efficacy of anticancer drugs on breast and colon tumors (97). This result seems to be the consequence of an inhibitory role of dopamine on tumor neovessel formation through the control of endothelial progenitor mobilization from bone marrow (98). Indirectly the important role of dopamine on the regulation anabolic signals [decrease of insulin release (14)] and immunity [increase migration and proliferation of immune cells (85, 99)] may underlie some of the tumor-protective effects of dopamine.

Additionally, lack of D2 receptors causes formation of adenomas in mice (100) and DRD2 receptor polymorphisms increase the risk of colorectal cancer (101). The formation of heterodimers and/or heteromers containing dopamine D2 and cannabinoid CB1 receptors (102, 103) could participate to cross talk between dopamine and endocannabinoid signaling. CB1 receptors act as suppressors of breast cancer (104), glioma (81), and melanoma (105). The effects of drugs or conditions influencing dopamine system in tumoral growth is summarized in Table 2.

Table 2.

Effect of dopamine signaling on cell proliferation and tumor growth

	Model	Substance	Effect on dopamine signaling	Effect on cells	Reference
rowspan="6" align="left" valign="top">Noncancerous cells	Neural precursors	Bromocriptine	D2-like receptor agonist	Increased proliferation	Höglinger et al. (82)
	Adult neural stem cells	Dopamine	n.d.	Proliferation	O'Keeffe et al. (83)
	Retina	Dopamine	n.d.	Increased proliferation and reduced apoptosis	Kralj-Hans et al. (87)
	Human progenitor immune cells	(+)SKF-38393	D1-like receptor agonist	Increased proliferation	Spiegel et al. (85)
			7-OH-DPAT			D3 receptor agonist
			Clozapine	D2-like receptor antagonist		Decreased proliferation
Cancerous cells	Human small lung cancer cells	Bromocriptine	D2-like receptor agonist	Decreased proliferation	Ishibashi et al. (91)
		Human meningioma cells	(+)SKF-38393	D1-like receptor agonist	Inhibition of cell growth	Schrell et al. (92)
				Dopamine	n.d.		Inhibition of cell growth
		B cells from human lymphoid malignancy	Dopamine	n.d.	Cell cycle arrest	Meredith et al. (93)
		DAT knockout mice	n.d.	Elevated levels of dopamine	Reduced rates of tumor growth	Asada et al. (94)
		Xenotransplanted human gastric cancer in nude mice	Dopamine	n.d.	Slower tumoral growth	Chakroborty et al. (96)
	Breast and colon tumors in mice	Dopamine	n.d.	Increased efficiency of anticancer drugs	Sarkar et al. (97)
	D2 receptor knockout mice	n.d.	Lack of D2 receptor signalling	Appearance of highly vascularized prolactinomas	Hentges and Low (100)

Effects of dopamine, drugs influencing dopamine signaling, or animal models lacking dopamine related-genes on cell proliferation. DAT, Dopamine transporter; n.d., not determined.

Effects of dopaminergic drugs on immune system and tumor growth in humans

It is well established that immune, hormonal, and metabolic systems are closely interacting. Remarkably, neuroendocrine cells, such as pancreatic islet cells and neurons, and immune cells share common signaling pathways mediated by dopamine, such as D2 receptors (14). Other common markers include chromogranin, a protein present in the secretory granules, which is expressed both in neuroendocrine and immune cells (106). Given the existence of shared signaling pathways, pharmacological blockade of dopamine receptors may influence immune function. This is illustrated by agranulocytosis, a syndrome of leukocyte deficiency, induced by the atypical antipsychotic clozapine (107). Dopamine systems are under investigation for their potential as therapeutic target for immune disorders, such as non-Hodgkin lymphoma, a cancer of the immune system, which arises from neoplastic expansion of lymphocytes (99). However, there is still a paucity of studies regarding potential effects of dopaminergic drugs on cancer development in humans.

Dopamine agonists are used for treatment of individuals suffering from Parkinson’s disease (PD), the most common neurodegenerative movement disorder. Interestingly, these patients have an overall lower incidence of cancer (108–111), although this picture suffers from some well-documented exceptions. Specifically, PD patients present with higher rates of melanoma (109–111), some other forms of skin cancer (110, 111), breast cancer (110, 111), and thyroid cancer (109). Because dopamine agonists, alternative dopaminergic agents, or the dopamine precursor levodopa (L-DOPA) are used for treatment of PD patients (Fig. 1), L-DOPA was pointed as a putative causal factor (109). Therefore, the associations between PD, L-DOPA, and cancer remain a matter of controversy. Early observations of reduced cancer rates in PD patients (108) were reported in the 1950s, thus before the introduction L-DOPA, which was the first dopamine-related treatment for PD. Indeed, L-DOPA was introduced for treatment of PD in the early 1960s, whereas it became widely used only in the 1970s. Recent investigations have shown that incidences of melanoma and skin carcinoma are in fact higher, even before PD diagnosis and treatment with L-DOPA (112, 113). A retrospective study on patients under L-DOPA medication proposed that the occurrence of both PD and melanoma is coincidental rather than causal (114).

Common genetic polymorphisms or mutations may underlie a link between cancer and the nigrostriatal dopamine pathway, which is affected in PD (110, 115). Mutations associated with both PD and cancer concern at least two genes, i.e. Parkin and DJ-1. Parkin mutations cause up to half of the early-onset hereditary PD, and it has been identified as a tumor suppressor (116). DJ-1 is an oncogene that inhibits the tumor suppressor gene PTEN (117) and which mutations are associated to PD (118). Currently the U.S. Food and Drug Administration is evaluating clinical data suggesting that PD patients taking a dopaminergic combination of entacapone (peripheral catechol-O-methyl transferase inhibitor), carbidopa (peripheral l-amino acid decarboxylase inhibitor), and L-DOPA (Fig. 1) might be at higher risk for developing prostate cancer than PD patients taking a combination of carbidopa and levodopa alone (119). Altogether clinical data available to date do not allow definitive conclusions concerning a putative link between dopaminergic medications used in the treatment of PD and cancer development. In vitro, dopamine-mediated suppression of prolactin secretion may account for its antiproliferative capacity in cancerous cells. Prolactin acts as growth factor on cancer cells (120, 121) and prolactin receptor antagonists inhibit cancer cell growth in some models (122, 123). Prolactin levels are associated with increased risk of breast cancer (124). One can speculate that dopamine antagonists, by enhancing prolactin secretion, favor the development of tumors in vulnerable cell types. It has been reported that antipsychotic drugs with dopamine antagonist activity increase the risk of breast cancer in humans (125). The converging data obtained in vitro and in animal models support an anticancer effect of dopamine (Fig. 3) and call for complementary epidemiological and clinical studies.

Fig. 3.

Model describing the role of dopamine in the control of cell proliferation. Dopamine (DA) promotes the proliferation of neuronal precursors and can attenuate apoptosis triggered by oxidative stress. Dopamine inhibits the secretion of prolactin from the adenohypophysis and insulin from pancreatic β-cells. In the bone marrow, DA induces migration and repopulation of immature human CD34+ cells. The possible effects of DA signaling deficiency are drawn in dotted lines. D2R, Dopamine receptor 2; DR, dopamine receptors.

Nonpharmacological alterations in dopamine balance

Catecholaminergic tonus can be modified by environmental and behavioral factors, such as stress levels, social interactions, and diet. Acute stress induces tyrosine hydroxylase enzyme in the noradrenergic locus caeruleus (126) and increases plasma dopamine levels after increased peripheral sympathetic system function (44). Chronic stress can lead to hyperplasia and hypertrophy of the adrenal gland (126, 127) and has detrimental effects on the dopaminergic system (128–130). Accordingly, stress-susceptible animal strains show diminished induction of central and peripheral catecholamine production in response to chronic stress (126). Extreme life events can provoke chronic anxiety disorder, also referred to as posttraumatic stress disorder. Individuals with such a disorder show increased urinary excretion of catecholamines, including dopamine, due to increased sympathetic arousal, persisting even years after disclosure of the causative trauma (131, 132). Interestingly, social interactions activate dopaminergic regions (133), whereas social deprivation alters brain dopamine signaling (134). With respect to diet habits, a high-fat diet contributes to dopaminergic dysregulation (135) and epigenetic modifications of dopamine-related genes (136) in the offspring of mice fed a high-fat diet during pregnancy. Thus, lifestyle activities and environmental factors are important elements contributing to dopamine imbalance.

Future directions: dopamine balance, new therapeutical perspectives, and safety issues

In the basal ganglia, dopamine signals rewarding effects of food intake, whereas hypothalamic dopamine neurons modulate the release of prolactin, which in turn influences pancreatic function. Dopamine has direct inhibitory effects on the secretion of the adipogenic hormone insulin and modifies the action of insulin in peripheral tissues. In a synergistic central and peripheral way, dopamine participates in glucose homeostasis and body weight. Additionally, dopamine inhibits angiogenesis and has been shown to influence growth and apoptosis of tumoral cells. Hence, dysregulation of dopamine signaling alters cancer cell proliferation. The newly described roles of dopamine in glucose metabolism, body weight, and tumor growth should be considered in the context of chronic treatment with antipsychotic drugs influencing dopamine signaling. Additionally, dopamine-related drugs might be envisaged as new targets in the metabolic syndrome, cardiovascular diseases, diabetes, obesity, and cancer. It might be hypothesized that environmental and lifestyle changes could influence the development of diseases through readjustment of dopamine balance. Future delineation of the role of dopamine in metabolic homeostasis and cell growth might open new avenues in the prevention and treatment of obesity and cancer.

Acknowledgments

The authors thank Professor Paul Cumming (Munich) for critical revisions of the manuscript.

This work was supported by the Spanish Ministry for Science and Innovation (MICINN) (Ramón y Cajal Fellowship to B.R.), the European Foundation for the Study of Diabetes/AstraZeneca (Young Investigator Award to B.R.), and the Swiss National Science Foundation (to P.M.).

Disclosure Summary: The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work.

Abbreviations

 
• APUD

  Amine precursor uptake and decarboxylation

 
• 5-HT2

  type 2 serotonin receptors

 
• L-DOPA

  3,4-dihydroxy-l-phenylalanine

 
• PD

  Parkinson’s disease