Howard Hughes Medical Institute, Departments of Cell Biology and Medicine, Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina 27710
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ABSTRACT |
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The mechanisms by which dopamine (DA)
influences gastrointestinal (GI) tract motility are incompletely
understood and complicated by tissue- and species-specific differences
in dopaminergic function. To improve the understanding of DA action on
GI motility, we used an organ tissue bath system to characterize motor
function of distal colonic smooth muscle segments from wild-type and DA
transporter knockout (DAT /
) mice. In wild-type mice, combined
blockade of D1 and D2 receptors resulted in
significant increases in tone (62 ± 9%), amplitude of spontaneous
phasic contractions (167 ± 24%), and electric field stimulation
(EFS)-induced (40 ± 8%) contractions, suggesting that endogenous
DA is inhibitory to mouse distal colonic motility. The amplitudes of
spontaneous phasic and EFS-induced contractions were lower in DAT
/
mice relative to wild-type mice. These differences were eliminated by
combined D1 and D2 receptor blockade,
indicating that the inhibitory effects of DA on distal colonic motility
are potentiated in DAT
/
mice. Motility index was decreased but
spontaneous phasic contraction frequency was enhanced in DAT
/
mice
relative to wild-type mice. The fact that spontaneous phasic and
EFS-induced contractile activity were altered by the lack of the DA
transporter suggests an important role for endogenous DA in modulating
motility of mouse distal colon.
transgenic mice; motility index; dopamine receptor antagonists; electric field stimulation; peripheral hyperdopaminergia
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INTRODUCTION |
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GASTROINTESTINAL (GI) motility is modulated by a complex system of intrinsic and extrinsic nerves, circulating hormones, and locally produced mediators. One such modulator is dopamine (DA). A description of the effect of DA on GI motility is complicated for three main reasons. First, DA can produce both inhibitory and excitatory effects on GI motility (reviewed in Ref. 27). Generally, the excitatory response, which is mediated by D2 or presynaptic receptors, occurs at a lower agonist concentration than the inhibitory response, which is mediated by D1 or postsynaptic receptors. Second, the mechanism of DA action and location of DA receptors are controversial. For example, studies using guinea pig stomach and rabbit ileum suggest that DA-mediated inhibition of GI motility occurs through modulation of the enteric nervous system (9, 25), whereas reports using gastric tissue from opossum indicate direct DA effects mediated by DA receptors on smooth muscle cells (3, 22). Third, conclusions regarding the role of DA in modulating GI tract motility have primarily been reached using pharmacological techniques, interpretation of which is confounded by the ability of DA agonists to activate adrenergic receptors (reviewed in Ref. 27). Thus more research is required to improve our understanding of DA-mediated regulation of GI motility.
To better understand the role that DA plays in regulating GI motility,
we characterized DA-mediated regulation of distal colonic motility in
wild-type mice and in mice lacking the DA transporter (DAT /
mice).
The DA transporter (DAT) regulates the concentration of DA in the
synaptic cleft by rapidly removing the released neurotransmitter from
the extracellular space (reviewed in Ref. 6). Recently, there has also
been evidence demonstrating the presence of the DA transporter in
DA-producing endocrine cells of the gut (11). Despite
diminished intraneuronal levels of DA, extracellular DA levels are
elevated and DAT
/
mice display a central hyperdopaminergic phenotype characterized by increased locomotion, neuroendocrine dysfunction, and dwarfism (8). We explored whether DAT
/
mice may also exhibit a hyperdopaminergic phenotype in peripheral tissue such as the distal colon. In the present report, the effects of
DA and DA receptor antagonists on colonic contractility were evaluated
in wild-type and DAT
/
mice.
Our results demonstrate that motility of the mouse distal colon is
under basal inhibitory control by DA and that this effect is
potentiated in mice lacking the DAT. This hyperdopaminergic phenotype
associated with DAT /
mice is characterized by an impaired ability
to generate contractile force coupled with an increased frequency of
spontaneous phasic contractions. The DAT
/
mouse could be an
important model for further characterization of the role of DA in
regulating murine GI physiology, since DA modulates not only GI
motility but also GI secretion (19). Moreover, DAT
/
mice may be useful for the study of other peripheral systems under DA
regulation, such as the vasculature, kidneys, and immune system.
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METHODS |
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General Methods
DAT knockout mice were created through genetic deletion of the DAT by homologous recombination (8). Wild-type and homozygous DATDistal colon preparations were allowed to equilibrate in Krebs solution for at least 60 min before being adjusted to optimal length. The mechanical activity of the longitudinal muscle was measured isometrically with a calibrated force displacement transducer (Radnoti) and acquired using a computer data acquisition program (CODAS, DATAQ). Acquired data was analyzed using peak detection software, and data were imported into a spreadsheet for calculation of all tension parameters.
A Grass S88 stimulator was used to produce electric field stimulation (EFS) of tissues by passing current pulses between ring electrodes. In all experiments, pulses of 0.1-ms duration, 40 V, and 5 Hz were applied for 10 s. These stimulus parameters were chosen on the basis of preliminary studies that demonstrated maximal contractile tension with little or no direct effect on smooth muscle, as assessed by the ability of 1 µm TTX to abolish the response.
Experimental Protocols
Dose response to DA. Increasing doses of DA were added, in half-log increments, to the organ tissue bath. With each new addition of DA, tissues were allowed to equilibrate for 2 min before EFS.
Effect of D1 and D2 receptor blockade. For antagonist dose- response protocols, tissues were incubated with 10 µM sulpiride and Sch-23390 for 8 min before EFS or addition of DA. If tissues were used for more than one protocol, a 30-min washout period was conducted between protocols.
Motility index. We used a modified equation to calculate motility index (2, 14). The motility index of phasic activity was calculated as the total area under the tension curve minus the area due to smooth muscle tone. Smooth muscle tone was calculated as the tension measured when no spontaneous phasic contraction was in progress. For each 2-min period (over the 30-min interval), each valley (minimum tension between spontaneous phasic contractions) was marked, sorted, and averaged. Each 2-min average tension was multiplied by 120 s, and these products were summed to give the area due to smooth muscle tone. Data used to calculate motility index were recorded before addition of test agents.
KCl depolarization. KCl was added to the Krebs solution with equimolar replacement of NaCl (18).
HPLC assessment of tissue content of DA. Dissected GI tissue was homogenized in 5 vol of 0.1 M HClO4 containing 50 ng/ml 3,4-dihydroxybenzylamine as an internal standard. Homogenates were centrifuged for 10 min at 10,000 g. Supernatants were filtered through a 0.22-µm filter and analyzed for levels of DA using HPLC with electrochemical detection as described previously (26). Monoamines and metabolites were separated on a microbore reverse-phase column (C-18, 5 µm, 1 × 150 mm; Unijet, Bioanalytical Systems) with a mobile phase consisting of 0.03 M citrate-phosphate buffer with 2.1 mM octyl sodium sulfate, 0.1 mM EDTA, 10 mM NaCl, and 17% methanol (pH 3.6) at a flow rate of 90 µl/min and detected by a 3-mm glass carbon electrode (Unijet) set at +0.65 V. The volume of injection was 5 µl.
Drugs and Chemicals
DA, sulpiride (D2 receptor antagonist), and Sch-23390 (D1 receptor antagonist) were purchased from Research Biochemicals. Carbachol and sodium nitroprusside (SNP) were purchased from Sigma Chemicals. Other chemicals used were of reagent grade.Calculations and Statistics
The maximal contractile response to 100 µM carbachol was measured in each experiment. The amplitude of EFS-induced or spontaneous phasic contractions was calculated as the difference between peak tension developed and the average control baseline tension. Statistical analyses were carried out using the computer software package GraphPad Prism. To determine differences between mouse genotypes, a Student's two-tailed t-test was used. To determine the effect of treatment within a mouse genotype, a Student's two-tailed t-test for repeated measures was used. Results were considered significantly different if P < 0.05. ![]() |
RESULTS |
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Maximal Contractile Response to Carbachol
The maximal contractile tonic tension generated in response to 100 µM carbachol was significantly less in DATEffect of DA on EFS-Induced Contractions in Wild-Type Mouse Distal Colon
To assess the effect of DA on distal colonic contractions, the amplitude of EFS-induced contraction was measured in the presence of increasing concentrations of DA. Figure 1 shows that DA inhibits the amplitude of EFS-induced contraction in a dose-dependent manner and that this effect is competitively antagonized by combined D1 and D2 receptor blockade. (EC50: intact, 4.5 × 10
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Effect of DA on the Motility of Wild-Type Mouse Distal Colon
To determine whether DA participates in the regulation of intrinsic distal colonic motility, we measured tonic and spontaneous phasic contractile activity before and after D1 and D2 receptor blockade. A representative recording (Fig. 3A) shows that smooth muscle tone and spontaneous phasic contraction amplitude are enhanced following D1 and D2 receptor blockade. Figure 3B illustrates the average effect of D1 and D2 receptor blockade on basal smooth muscle tone and spontaneous phasic contractions. Thus spontaneous phasic motility and tone of mouse distal colon are under basal inhibitory control by a DA-mediated system.
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Tissue DA Concentration in Mouse Distal Colon
Tissue DA concentration primarily reflects intracellular DA stores (reviewed in Ref. 7) and was found to be significantly reduced in the distal and proximal colon of DAT
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Characterization of Distal Colonic Motility in the
DAT /
Mouse
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Motility Index of Wild-Type and DAT /
Mouse
Distal Colon
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To determine whether the difference in phasic contraction frequency was
a function of a more depolarized membrane potential in DAT /
mice,
tissues were incubated in modified Krebs solution containing increasing
concentrations of K+. According to Mangel et al.
(17) a greater increase in extracellular K+ is
required to depolarize cells with an already depolarized resting membrane potential. In wild-type mice, 10-20 mM KCl significantly increased spontaneous phasic contraction frequency relative to control.
These concentrations of KCl had no significant effect on spontaneous
phasic contraction frequency in DAT
/
mice, suggesting that the
resting membrane potential in DAT
/
distal colon is depolarized
relative to wild-type mice (Fig. 7C). In both wild-type and
DAT
/
mice, incubation with KCl concentrations >20 mM resulted in
decreased spontaneous phasic contraction frequency (Fig.
7C).
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DISCUSSION |
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In this study we demonstrated that DA-mediated inhibitory input is
tonically supplied to the mouse colon. Furthermore, we showed that this
inhibition is enhanced in the DAT /
mouse, which is consistent with
a peripheral hyperdopaminergic phenotype. Finally, these studies
provide evidence that endogenously released DA inhibits both
spontaneous phasic and EFS-induced contraction amplitude.
Little is known about the role of DA in regulating GI motility in the mouse. Eaker et al. (4) provided evidence indicating the presence of DA-containing neurons in the myenteric plexus of the GI tract of mice; however, an earlier report by Fontaine et al. (5) reported that DA receptors were not present in the mouse colon. Our findings indicate a role for DA in regulating murine distal colon motility and highlight the importance of the DA transporter for this regulation.
This study demonstrates that DA inhibits distal colonic tone and the
amplitude of spontaneous phasic and EFS-induced contractions in
wild-type mice. This inhibitory effect of DA is more pronounced in DAT
/
mice, suggesting that DAT
/
mice display peripheral hyperdopaminergia. This "functional" excess of DA in the periphery is consistent with that previously described for the central nervous system of DAT
/
mice (6, 8). In central
neurons, one of the hallmarks of this hyperdopaminergic phenotype is
depletion of DA stores. We also found decreased DA stores in DAT
/
mouse distal colon.
In distal colonic smooth muscles, both spontaneous phasic and
tonic components of tension are present (reviewed in Ref. 16). Spontaneous rhythmic or "phasic" smooth muscle cell contractions are initiated by slow waves. These slow waves depolarize the smooth muscle cell membrane potential, leading to opening of voltage-sensitive Ca2+ channels with a subsequent influx of Ca2+
and, ultimately, contraction (reviewed in Ref. 10). The increased frequency of spontaneous phasic contractions observed in DAT /
mice, combined with their diminished response to KCl depolarization, would be consistent with the membrane potential of smooth muscle cells
being depolarized in DAT
/
mice relative to wild-type mice.
Although transient depolarization of the membrane is usually associated
with increased amplitude of contraction (due to opening of
voltage-gated Ca2+ channels), the DAT
/
mice exhibit
decreased amplitude of contraction, as could occur with sustained
depolarization at rest. However, to concretely determine whether or not
the cell membrane potential is depolarized in DAT
/
mice would
require electrophysiological recording.
DAT /
mice display decreased distal colonic smooth muscle tone. We
used SNP, a nitric oxide (NO) donor, to relax distal colonic smooth
muscle and observed that DAT
/
mice relax less than wild-type mice.
There are at least two possible explanations for these results. First,
according to Tare et al. (24), NO has a reduced capacity
to relax smooth muscle when membrane potential is depolarized. As
mentioned above, the results of the KCl depolarization protocol could
suggest that membrane potential is depolarized in DAT
/
mice
relative to wild-type mice. Second, the reduced tone observed in DAT
/
mice could be a result of interactions of DA with other steps in
the process of pharmacomechanical coupling. For example, stimulation of
G protein-coupled receptors, such as DA receptors, leads to activation
of second messenger-dependent protein kinases (21). These
kinases can affect smooth muscle tone by regulating voltage-sensitive
Ca2+ channels, decreasing the sensitivity of contractile
proteins to Ca2+, or altering the release/sequestration of
sarcoplasmic reticulum Ca2+ stores (reviewed in Ref. 1).
Carbachol induces distal colonic smooth muscle contraction. In
the present study, the amplitude of carbachol-induced contraction was
significantly reduced in DAT /
mice relative to wild-type mice.
Although this measure can be used to normalize differences in tissue
cross-sectional area, values reported herein were not normalized. The
data in Fig. 5 show that a reduction in cross-sectional area of the
smooth muscle wall is not responsible for the reduced contraction
amplitude observed in DAT
/
mice. Rather, the results suggest that
the tension developed by DAT
/
mouse colon is similar to that of
wild-type mice when D1 and D2 receptors are
blocked, suggesting that DA is responsible for the reduced capacity to develop tension in DAT
/
mice.
Although the mechanism of action of DA has not been fully characterized
in the GI tract, it is generally accepted that in gut tissue
D1 and D2 receptors are the primary functional
subtypes of DA receptors (reviewed in Ref. 27). D1
receptors are mainly located postsynaptically, whereas D2
receptors are located pre- and postsynaptically. The use of receptor
antagonists to discriminate DA effects from the effects of other
catecholamines is not trivial and has led to some confusion regarding
the physiological role of DA. There is some promiscuity among
dopaminergic and adrenergic agonists/antagonists (reviewed in Ref. 27).
Being aware of the controversy surrounding selectivity, or lack
thereof, of DA receptor antagonists, we carefully chose and used agents
that would simplify interpretation of the data. Sch-23390 is a potent
and selective D1 receptor antagonist that has very little
effect on other receptors (12). Although D2
receptors and 2-adrenergic receptors are functionally similar, sulpiride (a D2 receptor antagonist)
has a 200-fold greater affinity for D2 receptors than
2-adrenergic receptors (reviewed in Ref. 13). Thus
Sch-23390 and sulpiride were used because they exhibit minimal
nonspecific effects on other receptor systems.
Despite this selectivity, the relatively unimpressive effect of D1 and D2 blockade on the DA dose-response curve (Fig. 1) may lead one to conclude that Sch-23390 and sulpiride are poor receptor inhibitors or have nonspecific excitatory effects. The more likely explanation for the modest shift in the DA dose-response curve is nonspecific effects of DA at adrenergic receptors. Exogenously administered DA is known to activate adrenergic receptors, and if some fraction of the DA-mediated inhibition of EFS-induced contraction amplitude was mediated through adrenergic receptors, it would not be inhibited by the DA receptor antagonists used.
The data presented herein highlight the difficulty in trying to determine peripheral DA function by the addition of exogenous DA or its analogs. Through neuronal or autocrine release (4, 11, 20, 23), a high concentration of DA localizes at DA receptors in the GI tract, resulting in altered motility or secretion. This localized release of DA cannot be mimicked by exogenous addition of DA, which would have an ubiquitous distribution throughout the tissue. Thus exogenously administered DA may be of sufficient concentration to activate adrenergic receptors. Therefore, addition of exogenous DA is a less than optimal method of mimicking the physiological effects of DA in the GI tract.
The difficulties associated with adding exogenous DA to assess
physiological function emphasize the importance of an animal model,
such as the DAT /
mouse, which is characterized by excessive endogenous DA. This mouse model provides an opportunity to study peripheral DA function simply by comparing the physiology of DAT
/
mice to wild-type mice.
Characterization of mouse physiology, and its relevance to that of
humans, is of increasing importance given the current trend of linking
genes to function. The DAT /
mouse could be a valuable tool used to
delineate the mechanisms of DA action on GI tract motility. Such
studies may provide information useful in the delineation of
therapeutic targets. Furthermore, studies investigating the role of DA
in other peripheral systems may find the DAT
/
mouse to be an
attractive model, since peripheral DA-mediated physiological effects
can be revealed in these mice without exogenous administration of DA.
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ACKNOWLEDGEMENTS |
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We thank Susan Suter and Jason Holt for animal care and genotyping.
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FOOTNOTES |
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M. G. Caron is an Investigator of the Howard Hughes Medical Institute. J. K. L. Walker is the recipient of an Medical Research Council/Canadian Lung Association Postdoctoral Fellowship. R. R. Gainetdinov is a visiting scientist from the Institute of Pharmacology, Russian Academy of Medical Sciences.
This work was supported in part by National Institute of Health Grants 5T32-DK-07568 (to M. A. Shetzline) and NS-19576, Bristol-Myers Squibb, and Zeneca Pharmaceuticals (M. G. Caron).
Address for reprint requests and other correspondence: M. G. Caron, Duke Univ. Medical Center, Box 3287, Durham, NC 27710.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Received 3 December 1999; accepted in final form 15 March 2000.
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