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The Journal of Neuroscience, January 15, 2002, 22(2):389-395
Dopamine Uptake through the Norepinephrine Transporter in Brain
Regions with Low Levels of the Dopamine Transporter: Evidence from
Knock-Out Mouse Lines
José A.
Morón,
Alicia
Brockington,
Roy A.
Wise,
Beatriz A.
Rocha, and
Bruce T.
Hope
Behavioral Neuroscience Branch, National Institute on Drug Abuse,
National Institutes of Health, Baltimore, Maryland 21224
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ABSTRACT |
Selective blockers of the norepinephrine transporter (NET) inhibit
dopamine uptake in the prefrontal cortex. This suggests that dopamine
in this region is normally cleared by the somewhat promiscuous NET. We
have tested this hypothesis by comparing the effects of inhibitors
selective for the three monoamine transporters with those of a
nonspecific inhibitor, cocaine, on uptake of 3H-dopamine
into synaptosomes from frontal cortex, caudate nucleus, and nucleus
accumbens from wild-type, NET, and dopamine transporter (DAT) knock-out
mice. Dopamine uptake was inhibited by cocaine and nisoxetine, but
not by GBR12909, in frontal cortex synaptosomes from wild-type or DAT
knock-out mice. At transporter-specific concentrations, nisoxetine and
GBR12909 failed to block dopamine uptake into frontal cortex
synaptosomes from NET knock-out mice. The efficacy of cocaine at the
highest dose (1 mM) was normal in DAT knock-out mice but
reduced by 70% in NET knock-out mice. Nisoxetine inhibited dopamine
uptake by 20% in caudate and nucleus accumbens synaptosomes from
wild-type and DAT knock-out mice but had no effect in those from NET
knock-out mice. Cocaine failed to block dopamine uptake into caudate or
nucleus accumbens synaptosomes from DAT knock-out mice. Cocaine and
GBR12909 each inhibited dopamine uptake into caudate synaptosomes from
NET knock-out mice, but cocaine effectiveness was reduced in the case
of nucleus accumbens synaptosomes. Thus, whereas dopamine uptake in
caudate and nucleus accumbens depends primarily on the DAT, dopamine
uptake in frontal cortex depends primarily on the NET. These data
underscore the fact that which transporter clears dopamine from a given
region depends on both the affinities and the local densities of the transporters.
Key words:
nucleus accumbens; caudate; frontal cortex; synaptosomes; nisoxetine; GBR 12909; cocaine
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INTRODUCTION |
Monoamines have long been thought to
play roles in depression. Even though dopamine (DA) is the monoamine
most closely associated with reward and affect, the DA hypothesis of
depression has received little recent attention because of the success
of antidepressant medications that selectively target the
norepinephrine transporter (NET) or the serotonin transporter (SERT)
with little or no affinity for the dopamine transporter (DAT)
(Eriksson, 2000 ; Gumnick and Nemeroff, 2000; Svensson, 2000). Although
antidepressants can be very selective for the NET or the SERT, these
transporters are not equally selective for their nominal substrates.
The SERT has too weak an affinity to be likely to take up DA at
physiological levels (Hoffman et al., 1991), but the NET can transport
DA as well as norepinephrine (NE) (Horn, 1973; Raiteri, 1977) and,
indeed, has greater affinity for DA than does the DAT itself (Giros et al., 1994; Gu et al., 1994; Eshleman et al., 1999). Indeed, the NET-selective antidepressant desipramine elevates levels of DA as well
as NE in the frontal cortex (FCx) (Carboni et al., 1990; Di Chiara et
al., 1992; Tanda et al., 1994; Yamamoto and Novotney, 1998), where the
NET is more concentrated than the DAT (Moll et al., 2000).
The present study was designed to compare the effects of blockade of
the NET and DAT on DA uptake into synaptosomes prepared from FCx and
other DA terminal fields. This assay allows us to dissociate changes in
extracellular DA that result from altered DA clearance from changes
that result from altered DA release, which can be secondary to
elevations in NE or 5-HT (Pozzi et al., 1994, 1999; Matsumoto et al.,
1999; Sakaue et al., 2000). We compared the effects of inhibitors for
each of the three monoamine transporters: nisoxetine (which selectively
blocks the NET), GBR 12909 (which selectively blocks the DAT), and
fluoxetine (which selectively blocks the SERT), with the effects of the
nonspecific inhibitor cocaine. We contrasted basal DA uptake and
drug-induced inhibition of DA uptake into synaptosomes from FCx, where
DAT expression is minimal (Freed et al., 1995; Sesack et al., 1998),
with uptake into synaptosomes from caudate nucleus, where DAT
expression is maximal, and from nucleus accumbens where intermediate
levels of the DAT are expressed. In each case, we compared uptake of [3H]DA into synaptosomes from DAT
knock-out, NET knock-out, and wild-type mice.
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MATERIALS AND METHODS |
Animals. The original breeding pairs from DAT and NET
knock-out mice were obtained from the laboratory of Dr. Marc Caron
(Duke University Medical Center, Durham, NC). They contained the DNA constructs previously shown to produce genetic deletions of the DAT and
NET, respectively (Giros et al., 1996; Rocha et al., 1998; Wang et al.,
1999; Xu et al., 2000). These mice were produced from 20 or more
generations of backcrossing on to a 129/SvJ background inbred strain.
We used female homozygous mice and their wild-type littermates derived
from the crossing of heterozygous breeding pairs. The animals were
housed (four or five per cage) on a 12 hr light/dark cycle with
ad libitum access to water and food. All animal procedures
were in compliance with the National Institutes of Health Guide for the
Care and Use of Laboratory Animals.
Measurement of [3H]DA uptake into
synaptosomes. DA uptake was measured using synaptosomal fractions
of tissue pooled from five or six mice for each brain region. Each
experiment was repeated three or four times on different days using
freshly pooled tissue from five or six mice each time. The mice were
killed by decapitation, and their brains were dissected on an
ice-cold dish. The FCx samples were cut from the frontal tip of the
brain with a razor blade. The caudate and accumbens (Acb)
samples were dissected from a 1 mm coronal slice. The Acb sample
included both the core and shell regions.
The pooled tissues from FCx, caudate, and Acb were placed in ice-cold
Krebs'-Ringer's solution buffer (in mM: NaCl 125, KCl 1.2, MgSO4 1.2, CaCl2 1.2, NaHCO3 22, NaH2PO4 1, and glucose 10, adjusted to pH 7.4) containing 0.32 M sucrose and
homogenized using a glass homogenizing tube and a Teflon pestle. The
samples were centrifuged for 10 min at 1000 × g, the
pellet was discarded, and the remaining supernatant was centrifuged for
an additional 15 min at 16,000 × g. The resulting P2
pellet containing the synaptosomes remained on ice until it was
resuspended for the uptake assay.
The synaptosomal uptake assay used in our experiments has previously
been described by Morón et al. (1998). The assay was performed in
Krebs'-Ringer's buffer containing 0.64 mM ascorbic acid,
0.8 mM pargyline, and 0.1 µM
[3H]DA (50 Ci/mmol). This concentration
of DA (0.1 µM) is the approximate Km value for DA uptake in brain
synaptosomes (Izenwasser et al., 1990, 1994; Elsworth et al., 1993;
Copeland et al., 1996). The uptake assay was initiated by the addition
of aliquots (FCx: 100-130 µg; Acb: 70-100 µg; caudate: 50-100
µg) of the synaptosomal fraction followed by incubation for 4 min at
37°C. Nonspecific uptake and adsorption of
[3H]DA was determined by incubation of a
parallel set of samples at 4°C (the specific monoamine transporters
are inactive at this temperature). The assay was terminated by placing
the samples on ice and adding 5 ml of ice-cold Krebs'-Ringer's
buffer. The synaptosomes were then separated from the assay solution by
filtration through Whatman glass microfiber filters (GF/C), that had
been presoaked in 0.1% polyethylenimine to reduce nonspecific binding, using a Brandel cell-harvester filtration apparatus. The synaptosomes, trapped on the filters, were washed twice with 5 ml of ice-cold Krebs'-Ringer's buffer. The filters were placed in scintillation vials, and 3 ml of Bio-Safe II scintillation fluid (Research Products, Mount Prospect, IL) were added to each vial, and the radioactivity was
determined by liquid scintillation spectrometry. Under these experimental conditions, total [3H]DA
uptake increased linearly with both protein concentration and time over
the 4 min incubation period in samples from each of the three brain
regions (data not shown).
Protein was measured using the Bio-Rad assay (Hercules, CA). The uptake
inhibition curves were obtained by the addition of varying
concentrations of the monoamine uptake blockers to the reaction mix.
IC50 values were determined using nonlinear curve fitting (Prism 2.0; GraphPad Software, San Diego, CA).
Chemicals. Chemicals and reagents were obtained from the
following sources: 7,8-[3H]DA (50 Ci/mmol) from Amersham (Arlington Heights, IL); pargyline hydrochloride
and ascorbic acid from Sigma (St. Louis, MO); cocaine hydrochloride
from the National Institute on Drug Abuse (Bethesda, MD); and GBR12909
and nisoxetine hydrochloride from Research Biochemicals (Natick, MA).
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RESULTS |
DA uptake into synaptosomes from DAT and NET knock-out mice
differed as a function of brain structure (Fig.
1). The rate of DA uptake was 0.45 pmol · min 1 · mg1
into FCx synaptosomes, 3.44 pmol · min1 · mg1
into caudate synaptosomes, and 2.70 pmol · min1 · mg1
into Acb synaptosomes. Uptake in FCx synaptosomes was normal in DAT
knock-out mice but severely attenuated in NET knock-out mice (Fig. 1).
DA uptake was 40% less in Acb and caudate synaptosomes from NET
knock-out mice and was >70% less in Acb and caudate synaptosomes from
DAT knock-out mice. An overview of the effects of cocaine, nisoxetine,
and GBR 12909 is shown in Table 1.
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Figure 1.
Total [3H]DA uptake in
synaptosomes obtained from FCx, Acb, and caudate from DAT knock-out
(DAT-KO), NET knock-out (NET-KO), and
wild-type (WT) mice. Absolute values for total
[3H]DA uptake rates in each genotype of mice are
expressed as a percentage of that observed in wild-type mice. Values
represent mean ± SEM obtained from three or four independent
experiments using fresh tissue pooled from five or six mice each
time.
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Table 1.
Summary of inhibition of DA uptake by cocaine, nisoxetine,
and GBR 12909 in wild-type, DAT, and NET knock-out mice
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Cocaine inhibited DA uptake into synaptosomes differentially as a
function of brain structure and mouse genotype (Fig.
2). The highest concentration of cocaine
used (1 mM) inhibited 50% of DA uptake into FCx
synaptosomes, 90% of DA uptake into caudate synaptosomes, and 70% of
DA uptake into Acb synaptosomes from wild-type mice. The apparent
IC50 values for cocaine-dependent inhibition of
DA uptake were ~1 mM in FCx, 1 µM in
caudate, and 10 µM in Acb synaptosomes. Cocaine blocked
DA uptake equally into FCx synaptosomes from both wild-type and DAT
knock-out mice but failed to block DA uptake into caudate or Acb
synaptosomes from DAT knock-out mice. Cocaine blocked DA uptake equally
into caudate synaptosomes from wild-type and NET knock-out mice.
Cocaine also blocked DA uptake into Acb synaptosomes from NET
knock-outs, although there was a decrease in cocaine potency across
the range of doses testedfor inhibition of DA uptake into Acb
synaptosomes from NET knock-out mice. Cocaine blocked DA uptake into
FCx synaptosomes from wild-type but not from NET knock-out mice.
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Figure 2.
Effects of cocaine on [3H]DA
uptake in synaptosomes obtained from FCx, Acb, and caudate from DAT
knock-out (DAT-KO) (A), NET
knock-out (NET-KO) (B), and
wild-type (WT) mice. The rate of
[3H]DA uptake at each concentration of cocaine is
expressed as a percentage of that observed for each genotype with only
the vehicle present in the assay. Values represent mean ± SEM
obtained from three or four independent experiments using fresh tissue
pooled from five or six mice each time.
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Nisoxetine attenuated DA uptake into wild-type but not NET-knock-out
synaptosomes from all three regions (Fig.
3). At low concentrations
(109 to
107 M), nisoxetine
attenuated by 20% the DA uptake into synaptosomes from each of the
three brain regions of wild-type mice. At nonselective concentrations
of 106 to
103 M, nisoxetine attenuated
DA uptake into synaptosomes from both caudate and Acb of both wild-type
and NET knock-out mice. At these higher concentrations, nisoxetine
blocked 60% of the DA uptake into FCx synaptosomes from wild-type
mice. Nisoxetine, even at high concentrations, failed to block DA
uptake into FCx synaptosomes from NET-knock-out mice.
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Figure 3.
Effects of nisoxetine on
[3H]DA uptake in synaptosomes obtained from FCx,
Acb, and caudate from NET knock-out (NET-KO) and
wild-type (WT) mice. The rate of
[3H]DA uptake at each concentration of nisoxetine
is expressed as a percentage of that observed for each genotype with
only the vehicle present in the assay. Values represent mean ± SEM obtained from three or four independent experiments using fresh
tissue pooled from five or six mice each time. The shaded
area indicates the effects of higher nonselective
concentrations (>100 nM) of nisoxetine.
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In the case of DAT-knock-out synaptosomes, nisoxetine blocked DA uptake
at both low and high concentrations into synaptosomes from both
wild-type and knock-out mice (Fig. 4). At
low (109 M) concentration,
nisoxetine blocked ~20% of DA uptake into synaptosomes from each of
the three brain regions of both wild-type and DAT knock-out mice. At
high concentrations (106 to
103 M), nisoxetine blocked
DA uptake by ~60% in FCx and Acb synaptosomes from both wild-type
and DAT-knock-out mice. At the highest concentrations used
(104 and
103 M), nisoxetine blocked
uptake into caudate synaptosomes from wild-type, but not from
DAT-knock-out mice, by >80%.
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Figure 4.
Effects of nisoxetine on
[3H]DA uptake in synaptosomes obtained from FCx,
Acb, and caudate from DAT knock-out (DAT-KO) and
wild-type (WT) mice. The rate of
[3H]DA uptake at each concentration of nisoxetine
is expressed as a percentage of that observed for each genotype with
only the vehicle present in the assay. Values represent mean ± SEM obtained from three or four independent experiments using fresh
tissue pooled from five or six mice each time. The shaded
area indicates the effects of higher nonselective
concentrations (>100 nM) of nisoxetine.
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GBR 12909 blocked DA uptake equally in wild-type and NET-knock-out
synaptosomes regardless of brain region (Fig.
5). GBR 12909 blocked DA uptake into FCx
synaptosomes only at the highest concentration (103 M). At DAT-selective
concentrations (107 and
106 M), GBR 12909 blocked
70-80% of DA uptake into Acb and caudate synaptosomes. Because of the
limited productivity of our breeding pairs, the effects of GBR 12909 were not tested on synaptosomes from DAT knock-out mice.
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Figure 5.
Effects of GBR 12909 on
[3H]DA uptake in synaptosomes obtained from FCx,
Acb, and caudate from NET knock-out (NET-KO) and
wild-type (WT) mice. The rate of
[3H]DA uptake at each concentration of GBR 12909 is expressed as a percentage of that observed for each genotype with
only the vehicle present in the assay. Values represent mean ± SEM obtained from three or four independent experiments using fresh
tissue pooled from five or six mice each time. The shaded
area indicates the effects of nonselective concentrations
(>100 nM) of GBR12909.
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Fluoxetine, a SERT-specific blocker, had no effect on DA uptake into
FCx or caudate synaptosomes from wild-type mice (data not shown).
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DISCUSSION |
DA uptake in FCx
The present study confirms that extracellular DA is cleared from
FCx primarily by the NET. This possibility was first suggested on the
basis of microdialysis studies (Carboni et al., 1990; Di Chiara et al.,
1992; Tanda et al., 1994; Yamamoto and Novotney, 1998) that did not
reveal whether the observed elevations in DA levels were because of
clearance of DA by the NET or rather were secondary to a presynaptic
action such as that of elevated NE on DA release (Pozzi et al.,
1994). In the present assay, exogenous NE was not present
and thus could not affect the DA nerve terminals. Moreover, DA of
intracellular origin, which was unlabeled, could not be confused with
the exogenous, labeled, DA of extracellular origin that was taken up by
synaptosomes. Furthermore, use of the DAT and NET knock-out mice
allowed an examination of DA uptake mechanisms under conditions where
all contributions of the DAT or NET could be ruled out.
DA uptake into FCx synaptosomes from NET knock-out mice was 55% lower
than those from wild-type mice. This was not a consequence of
developmental compensations in the knock-out mice, because nisoxetine,
an uptake inhibitor selective for the NET, caused similar inhibition of
DA uptake into FCx synaptosomes from wild-type mice. The residual DA
uptake into FCx synaptosomes from NET knock-out mice was not because of
uptake via the DAT because DA uptake into FCx synaptosomes from NET
knock-out mice was not inhibited by selective concentrations of GBR
12909, an uptake inhibitor selective for the DAT. This is consistent
with the observation of similar levels of DA uptake into FCx
synaptosomes from DAT knock-out mice and wild-type mice. The DAT
appears to be ineffective in clearing DA from FCx (Carboni et al.,
1990; Di Chiara et al., 1992; Tanda et al., 1994; Yamamoto and
Novotney, 1998) because of its sparse concentration (Sesack et al.,
1998) relative to the dense concentration of the NET (Schroeter et al.,
2000), which has a stronger affinity for DA than does the DAT (Giros et
al., 1994; Gu et al., 1994; Eshleman et al., 1999). The rate of DA
uptake is so low around the sites of DA release and in the surrounding
regions, that DA is able to diffuse to a much larger volume (Stamford
et al., 1988; Garris and Wightman, 1994; Cass and Gerhardt, 1995; Jones
et al., 1996) where the NET is the predominant transporter capable of transporting DA (Schroeter et al., 2000).
The remaining of DA uptake into FCx synaptosomes from NET knock-out
mice is likely attributable to a cocaine-insensitive transporter similar to that observed in rat brain (Izenwasser et al., 1990; Elsworth et al., 1993). Thus, the NET is the only transporter in FCx
likely to have mediated the observed cocaine-dependent inhibition of DA
uptake into FCx synaptosomes from wild-type and DAT-knock-out mice;
cocaine had no effect on DA uptake in FCx synaptosomes from NET
knock-out mice. This is consistent with the finding that reverse
dialysis of the NET blocker desipramine blocks the increase in DA
levels in rat prefrontal cortex after intraperitoneal cocaine
administration (Tanda et al., 1997).
DA uptake in caudate
DA uptake into caudate synaptosomes from DAT knock-out mice was
depressed 76%. This was not a consequence of developmental compensations in the knock-out mice, because DAT-selective
concentrations of GBR 12909 produced a similar level of inhibition of
DA uptake into caudate synaptosomes from wild-type mice. The remaining
amount of DA uptake into caudate synaptosomes from DAT knock-out mice was reduced only 20% by nisoxetine, similar to that in wild-type mice.
These results suggest that DA uptake in caudate is mediated primarily
by the DAT with only a minor contribution from the NET. This is
consistent with the fact that the DAT is abundant and the NET is sparse
in caudate (Schroeter et al., 2000). Despite the fact that the NET
contributes 20% of total DA uptake into caudate synaptosomes from DAT
knock-out mice, DA uptake via the NET does not appear to play an
important role in regulation of DA levels in the intact caudate.
Systemic administration or reverse dialysis of desmethyimipramine (DMI)
into rat caudate does not significantly increase DA levels in this
brain region (Carboni et al., 1990; Di Chiara et al., 1992; Yamamoto
and Novotney, 1998). One possibility is that DA is normally intercepted
by the DAT, which is located perisynaptically (Nirenberg et al., 1997),
before it can reach the higher-affinity but more distant and sparse NET in this brain structure. Even in DAT knock-out mice, the NET does not
transport a significant amount of DA in the intact caudate; cyclic
voltammetry studies demonstrated that the clearance rate for DA in
caudate slices from DAT knock-out mice is similar to the calculated
rate for diffusion-mediated clearance and unaffected by the addition of
DMI (Jones et al., 1998).
Cocaine-dependent inhibition of DA uptake in caudate seems almost
entirely attributable to inhibition of the DAT because
cocaine-dependent inhibition of DA uptake into caudate synaptosomes was
similar in wild-type and NET knock-out mice but completely absent in
DAT knock-out mice. Surprisingly, the NET in caudate synaptosomes from
DAT knock-out mice was insensitive to cocaine, whereas it remained
somewhat sensitive to nisoxetine.
DA uptake in the nucleus accumbens
Transporter-specific inhibition of DA uptake into Acb synaptosomes
was similar to that into caudate synaptosomes. This result suggests
that total DA uptake in our preparations of both the shell and core
subregions of Acb combined is mediated mostly by the DAT with a smaller
contribution from the NET. However, Acb may not be homogenous in this
regard. Reverse dialysis of DMI into the shell subregion of the intact
rat Acb increased DA levels (Yamamoto and Novotney, 1998). As with FCx,
it remains to be determined whether this DMI-dependent increase in DA
was attributable to a decrease in transport through the NET or to
noradrenergic interactions with DA terminals. The rightward shift in
the dose-response curve for cocaine inhibition of DA uptake into our
Acb synaptosomal samples from NET-knock-out mice suggests that the NET
can transport a small but significant amount of DA in Acb from
wild-type mice. This is consistent with the hypothesis that DMI in the
microdialysis studies increased DA levels by directly inhibiting
NET-mediated DA uptake, similar to that in FCx. The heterogeneous
distribution of the DAT and NET in Acb suggests that the mechanisms for
DA transport may vary dramatically depending on the microregion of Acb.
The DAT is more densely concentrated in the core subregion than in the
shell subregion (Ciliax et al., 1995; Freed et al., 1995; Hersch et
al., 1997). The shell subregion itself is divided into patches of
densely distributed DAT surrounded by areas with sparse DAT. The NET is
present in the shell subregion and distributed along the rostrocaudal
axis from low to medium density (Schroeter et al., 2000). Thus, in
areas of the shell subregion with sparse DAT and higher levels of the
NET, it is possible that DA uptake is locally dependent on the NET.
Cocaine-dependent inhibition of DA uptake into Acb synaptosomes from
DAT-knock-out mice was not evident, whereas the dose dependence curve
for cocaine-dependent inhibition of DA uptake into Acb synaptosomes
from NET knock-out mice was shifted strongly to the right. This
suggests that whereas cocaine-dependent inhibition of DA uptake in Acb
is mostly attributable to inhibition of the DAT, inhibition of the NET
plays some role, at least in wild-type mice. Indeed, the 20-25%
difference between NET knock-out and wild-type mice for inhibition of
DA uptake by 103 M cocaine
was comparable with the 20% inhibition of DA uptake into Acb
synaptosomes from wild-type mice by nanomolar concentrations of nisoxetine.
Differential cocaine-sensitivity between brain regions
In brain regions where the DAT mediates the majority of DA uptake,
such as caudate, DA uptake is highly sensitive to cocaine. In brain
regions where the NET mediates the majority of DA uptake, such as FCx,
DA uptake has much lower sensitivity to cocaine. The NET has been shown
to have lower sensitivity to cocaine than the DAT in cell culture (Gu
et al., 1994) and in rat brain (Ritz et al., 1990). Thus, the apparent
cocaine sensitivity of total DA uptake may decrease in brain regions
where the NET mediates the greatest portion of total DA uptake.
Not all DA uptake in the frontal cortex and accumbens was blocked by
cocaine. Cocaine-insensitive DA uptake (not inhibited by
103 M cocaine)
may be mediated by the recently cloned and characterized polyspecific
cation-monoamine transporters Oct2 and Oct3/EMT, which are found in
rat brain (Russ et al., 1996; Busch et al., 1998; Grundemann et al.,
1998; Wu et al., 1998). The levels of cocaine-insensitive DA uptake are
low. In brain regions where the DAT is abundant and total DA uptake
rates are high, such as in caudate, cocaine-insensitive DA uptake does
not contribute significantly toward total DA uptake. In brain regions where the DAT and NET are less abundant and total DA uptake rates are
low, such as in FCx, cocaine-insensitive DA uptake contributes significantly toward total DA uptake. In our study, only millimolar levels of GBR 12909 could inhibit this cocaine-insensitive transporter.
Potential implications
The present data underscore the fact that transporter-selective
uptake inhibitors are not necessarily transmitter-selective uptake
inhibitors. This may explain the fact that cocaine self-administration, which is well known to be dopamine-dependent (de Wit and Wise, 1977;
Roberts et al., 1977) is not lost in DAT knock-out mice (Rocha et al.,
1998). For example, cocaine blockade of NET and consequent accumulation
of DA in a critical subregion of Acbpresumably some portion of Acb
shell (Carlezon et al., 1995)could account for the rewarding effects
of cocaine in these animals (Rocha et al., 1998; Sora et al., 2001).
Transporter promiscuity might also explain why NET-selective uptake
inhibitors are each effective in treatment of depression (Eriksson,
2000; Gumnick and Nemeroff, 2000; Svensson, 2000); it may be the
transmitter, not the transporter, that is critical. Thus, it appears
critical to determine transmitter selectivity for a given transporter
blocker before assuming that the blocker's effectiveness is mediated
by the transporter for which the blocker is most selective.
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FOOTNOTES |
Received June 28, 2001; revised Oct. 23, 2001; accepted Oct. 31, 2001.
We thank Dr. Marc Caron for providing the knock-out mice and for his
critical review of the manuscript.
Correspondence should be addressed to Dr. Bruce T. Hope, Behavioral
Neuroscience Branch, National Institute on Drug Abuse, National
Institutes of Health, 5500 Nathan Shock Drive, Baltimore, MD 21224. E-mail: bhope{at}intra.nida.nih.gov.
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TOP
ABSTRACT
INTRODUCTION
