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Vol. 298, Issue 1, 129-140, July 2001
Yerkes Regional Primate Research Center, Emory University, Atlanta, Georgia (H.L.K., A.R.J., M.J.K.); and Research Triangle Institute, Research Triangle Park, North Carolina (F.I.C.)
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
References
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Neurotransmitter transporters play an important role in maintaining
synaptic homeostasis and in the actions of many drugs. Utilizing a
technique for measuring the kinetics (synthesis, degradation, and
half-life) of the dopamine transporter (DAT) protein in the rat
striatum and nucleus accumbens, we have investigated the effects of
systemic administration of dopamine receptor agonists and antagonists upon DAT kinetics in these brain regions. In the striatum, the dopamine
D1 receptor agonist SKF38393 and the dopamine D1 receptor antagonist
SCH23390 were without effect. However, the dopamine D2 receptor
agonists R-(
)-propylnorapomorphine hydrochloride (NPA)
and quinpirole decreased the half-life of DAT. This effect was blocked
by the dopamine D2 antagonist eticlopride, which, by itself, increased
the half-life of DAT. In the nucleus accumbens, the agonist SKF38393
increased the DAT half-life, whereas the antagonist SCH23390 decreased
the half-life. In contrast to the striatum, NPA and quinpirole
increased the DAT half-life, which was blocked by eticlopride and by
itself had no effect on DAT kinetics. Cocaine increased the half-life
of DAT in both the striatum and the nucleus accumbens. The results of
the present study suggest that, through dopamine receptors, dopamine
indirectly influences DAT protein turnover in the striatum and in the
nucleus accumbens, but in different ways.
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Introduction |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Neurotransmitter
uptake into the presynaptic terminal or glial cells is an important
mechanism for terminating the action of synaptic neurotransmitters,
thus maintaining neuronal homeostasis (Amara and Kuhar, 1993
). Mice
with a genetic deletion of the dopamine transporter (DAT) exhibit
elevated levels of dopamine and decreased rates of dopamine clearance
(Gainetdinov et al., 1998). These proteins responsible for uptake are
sites of action for many drugs with both therapeutic and abuse
potential (Amara and Pacholczyk, 1991; Giros and Caron, 1993; Kuhar,
1993; Reith et al., 1997). Changes in DAT density and function are
implicated in neurological and psychiatric disorders, including
Parkinson's disease, schizophrenia, and addiction (Giros and Caron,
1993; Reith et al., 1997; Miller et al., 1999). Since DAT has several
important functions, it is necessary to examine the localization and
regulation of these transporter proteins.
In the rat, the highest density of DAT protein is found in the
striatum, where the brain dopamine levels are highest. Although DAT
proteins are abundant in the plasma membrane of axons and axon
terminals, they are not observed within the active zones of the synapse
(Nirenberg et al., 1996; Hersch et al., 1997; Kuhar et al., 1998). This
suggests that dopamine uptake occurs primarily outside of synapses and
that there is a diffusion gradient of dopamine in the synapse. DAT is
colocalized with dopamine D2 receptors, although the presence of one
does not determine the presence of the other (Hersch et al., 1997).
The balance of protein production and degradation in the cell
determines the level of DAT protein. DAT proteins are synthesized in
the rough endoplasmic reticulum, then transported to Golgi bodies for
post-translational modifications. From the Golgi bodies, DAT proteins
are distributed to dendritic and axonal smooth endoplasmic reticula,
then to the plasma membrane (Hersch et al., 1997; Nirenberg et al.,
1997b). Catabolism of DAT proteins takes place by double endocytosis
into endosomes and into multivesicular body vesicles (Hersch et al.,
1997). Systemic administration of the DAT blocker buproprion increases
DAT mRNA in the ventral tegmental area and substantia nigra of rats,
suggesting that DAT mRNA expression in the brain is regulated by
dopaminergic mechanisms (Petrie et al., 1998).
Changes in DAT result in alterations in dopamine neurotransmission by
affecting dopamine inactivation (Reith et al., 1997). Internal cellular
mechanisms have been shown to play a role in regulation of dopamine
transport. For example, cAMP enhances dopamine uptake in rat
hypothalamic tuberoinfundibular neurons (Kadowaki et al., 1990).
Protein kinase C (PKC) activation decreases dopamine uptake by DAT in
the rat (Kitayama et al., 1994) and in the human (Huff et al., 1997).
Protein kinase C activation also causes a rapid sequestration of human
DAT, which is then recycled rather than degraded (Huff et al., 1997;
Pristupa et al., 1998; Melikian and Buckley, 1999). Conversely, protein
kinase C inhibition increases DA uptake by the insertion of
internalized or intracellular transporters to the plasma membrane
(Pristupa et al., 1998). It has been suggested that other
post-translational modifications may also contribute to the function of
transporter proteins by altering the distribution of these proteins
within the cell (Amara and Pacholczyk, 1991).
Previously, we developed a method for measuring the production rate,
the degradation rate constant, and the half-life of the rat DAT protein
using the irreversible DAT ligand, RTI-76
[3
-(3-p-chlorophenyl) tropan-2-carboxylic acid
p-isothiocyanatophenylethyl ester hydrochloride] (Kimmel et
al., 2000). In that study, we determined the half-life of the DAT
protein in both the rat striatum and nucleus accumbens to be about 2 days. In the present study, we sought to determine how stimulation and
blockade of the D1 and D2 dopamine receptor families affect the
degradation rate constant and the production rate of DAT, and thus its
half-life in the rat striatum and nucleus accumbens. We administered
the dopamine D1-like receptor agonist, SKF38393, the dopamine D1-like
receptor antagonist, SCH23390, the dopamine D2-like receptor agonists,
quinpirole, and R-()-propylnorapomorphine hydrochloride
(NPA), or the dopamine D2-like receptor antagonist, eticlopride,
systemically to rats, then determined DAT protein kinetics in the two
brain regions. We also administered the psychostimulant cocaine to rats
to determine the effect of an indirect dopamine agonist on the kinetics
of DAT in both brain regions.
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Materials and Methods |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Animals. Before surgery, male Sprague-Dawley rats (250-275 g, Charles River, Raleigh, NC) were grouped three per cage, with food and water available at all times. Animals were housed with a 12-h light/dark cycle. The animals were maintained in accordance with the National Institutes of Health Guide for Care and Use of Laboratory Animals (NIH/85-23), and all experimental protocols were approved by the Institutional Animal Care and Use Committee.
Drug Treatment and Surgery.
Animals were randomly divided
into seven treatment groups that were given SKF38393, SCH23390, NPA,
quinpirole, eticlopride, eticlopride + quinpirole, or cocaine
(n = 64 for each treatment group) (Table
1). Each group of animals was treated by
injections once a day for three consecutive days. On the fourth day,
each group of rats (n = 64) was given a unilateral
injection of saline (n = 32) or 100 nmol of RTI-76
(n = 32) in the right lateral ventricle (Fleckenstein
et al., 1996). Animals were anesthetized with 400 mg/kg i.p. of chloral
hydrate and placed in a stereotaxic frame. Stereotaxic coordinates used
relative to bregma were: antero-posterior = 0.8,
medio-lateral = 1.4, dorso-ventral = 4.0. A 25-µl
Hamilton syringe was used to inject 10 µl of saline or RTI-76
solution over a 1-min period. Upon completion of the injection, the
needle was kept in place for 3 min to minimize the back flow of the
solution. Since RTI-76 is light- and temperature-sensitive, all
manipulations of this compound were done under low-light conditions,
and the containers were wrapped in foil and kept on ice.
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Preparation of Membranes.
Brains were removed immediately
and placed in cold saline. The olfactory tubercles were removed with
the aid of fine forceps, exposing the diagonal bands of Broca. A razor
blade was used to cut away the frontal cortex and to dissect the
nucleus accumbens from both hemispheres. The pair of nucleus accumbens
was pooled for each animal, for a total weight of 10 to 20 mg. Fine
forceps were used to remove the right striatum, weighing 20 to 30 mg. No differences between left and right striatum were found in this assay
(data not shown). All tissues were removed rapidly and frozen on dry
ice and then stored at 80°C until assayed within 4 weeks.
[3H]GBR12935 Binding. After the final centrifugation, the tissue pellet was resuspended in buffer for a final concentration of 5.0 mg wet tissue weight/ml. Polystyrene test tubes were filled with 1.5 ml buffer (50 mM Tris-HCl, pH 7.7 at 24°C, containing 120 mM NaCl and 0.01% bovine serum albumin), 100 µl of buffer, 400 µl of radioligand (0.5, 2.0, 5.0, or 20 nM final concentration), and 40 µl of tissue for a total volume of 2.04 ml. Nonspecific binding values were generated by adding 100 µl of 100 µM mazindol (5.0 µM final) instead of buffer. Tubes were incubated at room temperature for 60 min, and the incubations were terminated by rapid filtration over Whatman GF/B filters that were pretreated with 0.05% polytheylenimine. The filters were rinsed 3 times with 4.0 ml of ice-cold buffer, and the radioactivity remaining on the filters was measured by conventional liquid spectrometry.
Drugs. RTI-76 was obtained from the Research Triangle Institute (Research Triangle Park, NC). [3H]GBR12935 (specific activity = 53.5 Ci/mmol with label position at propylene-2,3-[3H]) was obtained from PerkinElmer Life Science Products (Boston, MA). Bovine serum albumin, chloral hydrate, eticlopride, mazindol hydrochloride, NPA, quinpirole, SCH23390, SKF38393, polyethylenimine, and potassium chloride were obtained from Sigma (St. Louis, MO). Cocaine hydrochloride was a generous gift from the National Institutes of Drug Abuse (Bethesda, MD). Sodium chloride was obtained from Fisher Scientific (Pittsburgh, PA). Tris hydrochloride and Tris base were obtained from EM Science (Cincinnati, OH).
Chloral hydrate, cocaine, eticlopride, NPA quinpirole, RTI-76, and SKF38393 were dissolved in 0.9% saline. SCH23390 was dissolved in distilled water, then diluted with 0.9% saline. Compounds used in the binding assay were dissolved in the appropriate buffer.Binding Data Curve Fitting. Bmax and Kd values were determined in each binding assay by fitting a nonlinear least-squares analysis and by a linear Scatchard plot. Data were analyzed using GB-STAT version 6.5 (Dynamic Microsystems, Silver Spring, MD).
Calculation of DAT Kinetic Parameters.
The half-life of
recovery of [3H]GBR12935 binding of DAT in the
striatum and the nucleus accumbens following inactivation by RTI-76 was
determined, assuming a zero-order transporter production rate and a
first-order transporter degradation rate constant. The repopulation
kinetics of an irreversibly inactivated transporter can be defined by
the monoexponential repopulation equation (Mauger et al., 1982;
Sladeczek and Bockaert, 1983):
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(1) |
1). As time nears infinity, transporter
recovery reaches the steady-state levels
(Bss), and the term
ekt approaches 0, so eq. 1 may be
restated as:
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(2) |
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![<UP>ln</UP>[B<SUB><UP>ss</UP></SUB>/(B<SUB><UP>ss</UP></SUB>−B<SUB><UP>t</UP></SUB>)]=kt](/content/vol298/issue1/fulltext/129/img004.gif)
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(3) |
Bt)] versus time.
[3H]GBR12935 binding at DAT is used to
determine Bt and
Bss. In some of these graphs,
Bt was so close to
Bss that
(Bss Bt) was close to zero at the 7-day
time point and could not be plotted; therefore, some graphs have three
points, whereas others have four points.
The time for Bt to reach any
particular percentage of control Bss
values is dependent on k but not on r. Therefore,
changes in k would change the time needed to reach a certain
percentage of control, Bss. To
determine the half-life of recovery, i.e., t = t1/2, let
Bt = Bss/2 and eq. 3 becomes ln 2 = kt1/2
(t1/2 = ln 2/k = 0.693/k). Since we have the experimentally determined Bss and the calculated k,
we can obtain r from restating eq. 2 as r = kBss. In these studies,
Bss was taken to be the concentration of recoverable transporters (Bmax
average of saline controls minus residual
Bmax at 1 day after RTI-76 treatment).
Time Course Statistics. The time course data were analyzed using a one-way ANOVA, followed by a Tukey's post hoc test when appropriate. Points were determined to be significantly different from saline at p < 0.05.
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Results |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Striatum.
The time course of recovery of
[3H]GBR12935 binding to DAT in the striatum of
animals that received systemic saline injections for 3 days followed by
i.c.v. injection of saline or RTI-76 is shown in Fig.
1A. Each drug treatment study that
follows includes both of these control groups (see Table
2). However, since the control groups
were similar, we combined all of the data from animals that received
systemic saline and i.c.v. saline into this single figure. The
Bmax values of animals that received
i.c.v. saline did not differ across the time points studied, so these values were pooled and are given in the last column of Table 2.
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1, and the production rate was calculated
to be 202 ± 6.0 fmol/mg/day (Table 2; Fig. 1B).
Neither treatment with the dopamine D1 receptor agonist SKF38393 nor
with the dopamine D1 receptor antagonist SCH23390 altered DAT kinetics
in the striatum (Table 2; Fig. 2). In
addition, neither SKF38393 nor SCH23390 significantly altered
[3H]GBR12395 binding to DAT in i.c.v.
saline-treated animals on any day (Fig. 2, A to D).
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Nucleus Accumbens.
The time course of recovery of
[3H]GBR12935 binding to DAT in the nucleus
accumbens of animals that received systemic saline injections for 3 days followed by i.c.v. injection of saline or RTI-76 is shown in Fig.
5A. Each drug treatment study that
follows includes both of these control groups (see Table
3). However, since the control groups
were similar, we combined all of the data from animals that received
systemic saline and i.c.v. saline into this single figure. The
Bmax values of animals that received i.c.v. saline did not differ across the time points studied, so these
values were pooled and are given in the last column of Table 3.
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1, and the production rate was calculated
to be 106 ± 6.2 fmol/mg/day (Fig. 5B; Table 3).
Treatment with the dopamine D1 receptor agonist SKF38393 and with the
dopamine D1 receptor antagonist SCH23390 altered DAT kinetics in the
nucleus accumbens (Table 3; Fig. 6).
SKF38393 (Fig. 6B) increased the half-life of DAT while decreasing the degradation rate constant and the production rate in the nucleus accumbens (Table 3). Conversely, SCH23390 (Fig. 6D) decreased the
half-life of DAT while increasing the degradation rate constant and the
production rate (Table 3). In addition, neither SKF38393 nor SCH23390
significantly altered [3H]GBR12935 binding to
DAT in i.c.v. saline-treated animals on any day (Fig. 6, A to D).
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Discussion |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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In this study, we confirmed previous results in which we
determined that the half-life of DAT in the rat striatum and nucleus accumbens was approximately 2 days (Kimmel et al., 2000). The degradation rate constant was similar for the two regions, but the
synthesis rate was higher in the striatum, reflecting a higher density
of DAT in this brain region (see Tables 1 and 2). The synthesis rate
and the degradation rate constant measured here reflect the summations
of complex processes. The calculated overall synthesis rate includes
DAT protein synthesis, axonal flow, and insertion at the nerve
terminal, whereas the experimentally determined degradation rate
constant reflects retrieval from the cell membrane, degradation, and
retrograde transport. Although we show dopamine receptors clearly
influence DAT kinetics, the precise mechanism by which synthesis and
degradation are affected is not yet clear.
Acute and repeated stimulation of dopamine receptors can influence
dopamine uptake by DAT in the striatum and the nucleus accumbens. In
vitro rotating disk electrode voltametry studies using rat striatal
synaptosomal suspensions showed that acute administration of the
dopamine D2 receptor agonist, quinpirole, increased dopamine uptake
(Meier-gerd et al., 1993). Repeated systemic administration of the
dopamine D2 receptor antagonist, pimozide, blocked the up-regulation of
dopamine uptake and release induced by repeated cocaine administration
in the rat (Parsons et al., 1993). The absence of dopamine receptors
can also influence DAT function, as shown by dopamine D2
receptor-deficient mice, which exhibit decreased striatal DAT uptake
(Dickinson et al., 1999). Although these studies suggest that dopamine
receptor stimulation can influence DAT function, the present study is
the first to show that DA receptors can influence the synthesis rate
and degradation rate constant of DAT proteins. In these experiments,
dopamine receptor agonists and/or antagonists were administered
systemically for 3 days before the i.c.v. injection of RTI-76 and
continued until sacrifice. Thus, the receptor stimulation or inhibition was repeated, but only once daily, during the study. Although RTI-76
binds to DAT (Carroll et al., 1992) and presumably increases dopamine
levels, recent studies in our laboratory show that the dose of RTI-76
used in this study (100 nmol) does not produce locomotor activity,
although doses that are 25-fold higher did (Kimmel et al., 2001). Thus,
the dose of RTI-76 used in this study is not a behaviorally active
dose, and although we did not measure dopamine levels, it is unlikely
that they were increased to a functionally significant degree.
The effects of the dopamine agonists and antagonists within each region were very consistent, but differed between the two regions. In the striatum, DAT half-life was decreased by both dopamine D2 receptor agonists, and increased by the dopamine D2 receptor antagonist. Furthermore, the agonist-induced change in DAT kinetics was inhibited by the coadministration of an antagonist. Dopamine D1 receptor agonists and antagonists had no effect on DAT kinetics in the striatum. In contrast, in the nucleus accumbens, the dopamine D1 receptor agonist increased the half-life of DAT, whereas the dopamine D1 receptor antagonist decreased it. Two dopamine D2 receptor agonists increased DAT half-life, an effect that was inhibited by coadministration with a dopamine D2 receptor antagonist. Alone, the dopamine D2 receptor antagonist had no effect on DAT half-life. Despite the different regional effects on DAT induced by the dopamine receptor-related compounds, the DAT inhibitor, cocaine, which is a nonspecific and indirect dopamine receptor agonist, increased DAT half-life in both brain regions. The finding that some antagonists alone can alter DAT half-life suggests that endogenous dopamine tone affects DAT kinetics.
The strikingly different effects of dopamine D1 and D2
receptor-selective compounds on DAT kinetics between the two brain regions are presumably due to differences in dopamine receptor localization and/or function in the nigrostriatal and mesolimbic pathways. The dopamine D1 receptor is the most widespread of all the
dopamine receptors and is generally expressed at a higher level in the
brain than the other dopamine receptors. The mRNA for this receptor is
found in many brain regions, including the striatum and nucleus
accumbens (Vallone et al., 2000). In particular, the striatum of the
rat, monkey, and human is characterized by dopamine D1 receptor-rich
patches that are also rich in dopamine and tyrosine hydroxylase
(Graybiel, 1984, 1990). In the striatum of the rat, DAT is localized in
the plasma membrane of axons and terminals, along with D2 dopamine
receptors, but not with D1 dopamine receptors (Hersch et al., 1997).
However, the nucleus accumbens shell contains patches of dopamine D1
receptors that do not contain high levels of dopamine D2 receptors or
DAT. Areas containing high levels of dopamine D2 receptors and DAT
surround these patches. In the core, however, dopamine D1 receptor-rich
compartments are also rich in dopamine D2 receptors, but low in
dopamine and tyrosine hydroxylase (Jansson et al., 1999). Within these
brain regions, the majority of D1 and D2 receptors are found
postsynaptically, although D2 receptors are also found presynaptically
in dopamine neurons, where they function as autoreceptors (Levey et
al., 1993; Sesack et al., 1994; Yung et al., 1995). The influence of D2
receptor ligands on DAT turnover may be partially explained by the
colocalization of D2 receptors with DAT on the presynaptic membrane, as
described previously.
Moreover, the signal transduction pathways are different for dopamine
D1 versus dopamine D2 receptors; dopamine D1 receptor stimulation
activates intracellular adenylate cyclase whereas dopamine D2 receptor
stimulation inhibits adenylate cyclase (Sibley et al., 1993; Jaber et
al., 1996). In mammalian species, the DAT protein has several sites for
phosphorylation by cAMP-dependent protein kinase A and PKC (Shimada et
al., 1991; Giros and Caron, 1993). Activation of PKC inhibits DAT
activity in mammalian cells by phosphorylation of DAT (Copeland et al.,
1996; Huff et al., 1997; Vaughan et al., 1997; Zhang et al., 1997),
which then causes a rapid internalization of the protein from the cell
membrane (Pristupa et al., 1998; Daniels and Amara, 1999; Melikian and Buckley, 1999). In contrast, the inhibition of protein kinase A or PKC
produces an increase in dopamine uptake by the insertion of
internalized or intracellular transporters to the plasma membrane (Pristupa et al., 1998). Thus, stimulation or inhibition of second messenger systems can influence DAT protein localization and, perhaps,
levels. Further experiments are necessary to determine by which
pathways dopamine D1 and D2 receptor stimulation influences DAT
turnover in the brain regions studied.
Whereas the difference in second messenger coupling might explain the
different effects of the dopamine D1- and D2-receptor selective drugs
on DAT kinetics within one region, the mechanism underlying the
regional differences are not clear. However, if the signal transduction
pathways are dissimilar in these brain regions, this difference,
coupled with the differences in the cellular location of dopamine D2
receptors in these two regions, might begin to explain how DAT proteins
could be differentially regulated in these two brain regions. In slices
of rat striatum, dopamine D2 receptors mediate a selective inhibition
of dopamine D1 receptor-stimulated cAMP accumulation, but in the
nucleus accumbens, dopamine D2 receptors are not coupled to dopamine D1
receptor-linked adenylate cyclase (Kelly and Nahorski, 1987).
In addition to the disparity in the localization of the dopamine
receptors in the striatum and nucleus accumbens, DAT density is
significantly lower in the nerve terminals of the nucleus accumbens than in those of the striatum (Cass et al., 1992; Nirenberg et al.,
1996, 1997a). As a result, dopamine is cleared from the synapse more
quickly in the striatum than in the nucleus accumbens, presumably due
to the increased density of DAT (Cass and Gerhardt, 1995). However, it
is unclear how this discrepancy in DAT density would account for the
different effects of dopaminergic compounds on DAT kinetics. One issue
to consider is that the dopamine D1- and D2-receptor ligands were
administered systemically to the animals, which could recruit many
differing influences on the two different DA containing pathways. Thus,
trying to determine the mechanisms underlying these receptor-mediated
differences can be difficult. Future experiments using more localized
administration of the drugs into brain or using an appropriate cell
line may be useful.
Although the results clearly show that receptors can influence the synthesis rate, degradation rate constant, and half-life of DAT, the physiological significance of the receptor-mediated influence is not clear, since significant changes in the density of DAT were not observed following treatment with any of the dopaminergic ligands. Despite the lack of a clear physiological role of this regulation, the present results suggest an important relationship between dopamine receptor activation and the kinetics of the DAT protein.
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Acknowledgments |
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We acknowledge the expert technical assistance of April B. Chang and Steven C. Payne.
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Footnotes |
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Accepted for publication April 4, 2001.
Received for publication November 16, 2000.
This research was supported by the National Institutes of Health Grants RR00165, DA00418, DA10732, and DA005935.
Address correspondence to: Dr. Heather L. Kimmel, Yerkes Regional Primate Research Center, Emory University, 954 Gatewood Road, N.E., Atlanta, GA 30329. E-mail: hlkimme{at}emory.edu
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Abbreviations |
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DAT, dopamine transporter;
DA, dopamine;
RTI-76, 3-(3-p-chlorophenyl) tropan-2-carboxylic
acid p-isothiocyanato-phenylethyl ester hydrochloride;
NPA, R-()-propylnorapomorphine hydrochloride;
i.c.v., intracerebroventricular;
ANOVA, analysis of variance;
PKC, protein
kinase C.
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References |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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-(3p-chlorophenyl)tropan-2-carboxylic acid p-isothiocyanatophenylethyl ester hydrochloride}.
J Pharmacol Exp Ther
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