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Vol. 49, Issue 3, 231-252, September 1997
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
I. Introduction
II. Molecular Biology
A. Receptor Taxonomy
B. Gene Organization and Receptor Synthesis
C. Receptor Isoforms
D. Protein Structure
III. Cellular Signaling Mechanisms
A. Signal Transduction in Expression Systems
B. Coupling in Brain
IV. Pharmacology
A. Radioligand Binding Studies
B. Functional Assays
V. Localization of D3 Receptors in Brain
A. Distribution of D3 Receptor Messenger Ribonucleic Acid
1. Distribution in rat brain.
2. Distribution in human brain.
B. Distribution of Putative D3 Receptors
1. Distribution in rat brain.
2. Distribution in human brain.
C. Implications of Regional Distribution
VI. D3 Receptors in Cellular and Organismal Function
A. Role in Behavior
B. Role in Neuronal Activity
C. Role in Neurochemistry
D. Role in Development
VII. Regulation of D3 Receptor Density and Messenger Ribonucleic Acid Expression
A. Modulation by Tonic Dopaminergic Activity
B. Modulation by Antidopaminergic Drugs
VIII. D3 Receptors and Disease
A. Genetic Linkage to Disease
B. Receptor Alterations in Neuropsychiatric Disorders
IX. Conclusion
References
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I. Introduction |
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Dopamine is a major neurotransmitter in the central nervous
system. Receptors for this catecholamine are of considerable interest, as they are the principal target of drugs employed in the treatment of
neuropsychiatric disorders such as schizophrenia and Parkinson's disease. Before 1990, the dopamine receptor population in brain and
periphery was believed to consist of two subtypes,
D1 and D2 (Seeman and
Grigoriadis, 1987
; Vallar and Meldolesi, 1989; Levant, 1996). These
receptors have been extensively studied by using a variety of
methodologies including behavioral, physiological, neurochemical,
pharmacological, and, more recently, molecular approaches in vivo and in vitro. The D1 receptor
is located postsynaptically, has low-nanomolar affinity for dopamine,
and stimulates adenylyl cyclase activity. The D2
receptor has nanomolar affinity for dopamine and is located both pre-
and postsynaptically. The D2 site is negatively
coupled to adenylyl cyclase and is also associated with other signal
transduction systems such as a potassium channel and the
phosphoinositide cascade. Both D1 and
D2 receptors exist in high- and low-affinity
states for dopamine agonists. Conversion between the high- and
low-affinity conformations appears to be mediated by sodium ions and
guanyl nucleotides. Likewise, both dopamine receptor subtypes are
distributed heterogeneously throughout the central nervous system with
highest densities in the striatum, nucleus accumbens, olfactory
tubercles, and substantia nigra pars compacta.
We now know that the D1 and
D2 subtypes represent families of dopamine
receptors. After the cloning of the D1 and
D2 receptors (Bunzow et al., 1988; Monsma et al.,
1990; Zhou et al., 1990), several additional low-abundance dopamine
receptors were identified. These novel subtypes include the
D3 and D4 receptors, which
are similar to D2, and the
D5 receptor, which is similar to
D1 (Sokoloff et al., 1990; Van Tol et al., 1991;
Sunahara et al., 1991). The D3 receptor was
initially cloned from a rat complementary DNA library by Sokoloff and
colleagues (1990) by using probes derived from the
D2 dopamine receptor sequence. The cloning of the
human D3 receptor was reported shortly thereafter
(Giros et al., 1990), followed by the murine D3
receptor (Fishburn et al., 1993). This receptor has been of particular
interest because of its hypothesized role as a therapeutic target in
the treatment of schizophrenia and drug abuse.
Although still in the early stages, considerable progress has been made in the study of the D3 receptor. As with the other recently identified receptors, the tools initially available to investigate the D3 receptor were molecular rather than pharmacological. These powerful tools enabled the selective study of the receptors in vitro by transfection in cells that do not normally express dopamine receptors. Molecular methods also allowed the study of receptor messenger ribonucleic acid (mRNAb) in brain. However, only in the last few years have putatively selective pharmacological agents and other tools been identified. These tools have enabled the study of the D3 receptor protein in brain. This article reviews the progress made to date in assessing the neurobiological role of this novel receptor. Its relevance in disease and as a potential therapeutic target is also discussed.
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II. Molecular Biology |
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A. Receptor Taxonomy
Based on amino acid sequence and gene
organization, the D3 receptor has been classified
as a member of the family of D2-like dopamine
receptors (Sibley et al., 1993) (fig. 1).
Unlike genes for the D1-like receptors that do
not contain introns, the D2, D3, and D4 receptor genes
contain intervening sequences. The D2-like receptors are also characterized by relatively long
3rd intracellular domains and short carboxy
termini relative to the D1-like receptors. The
D2-like receptors possess moderate sequence homology with the D1-like receptors. For example,
the rat D1 and D2 receptors
possess only 41% homology in the transmembrane domains (Monsma et al.,
1990). In contrast, the rat D3 receptor possesses 52% homology with the rat D2 receptor, with 75%
homology in the transmembrane domains (Sokoloff et al., 1990). The
D2 and D3 receptors exhibit
39% and 41% overall homology with the D4
receptor, respectively (Van Tol et al., 1991).
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B. Gene Organization and Receptor Synthesis
The rat D3 gene encodes a primary transcript
initially reported to contain six exons and five introns (Sokoloff et
al., 1990). Similarly, the human D3 receptor
gene, localized on chromosome 3, band 3q13.3 (Le Coniat et al., 1991),
encodes a primary mRNA of more than 53,000 base pairs with six exons
and five introns (Griffon et al., 1996) (fig.
2). The translated human protein exhibits
78% homology with the rat D3 receptor but
differs in that there is a deletion of 46 residues in the
3rd intracellular loop (Giros et al., 1990). The
primary transcripts for the rat and human D3
receptor mRNA appear to differ from that of the
D2 receptor in which both rat and human receptor
primary transcripts contain seven exons and six introns. The additional exon in the D2 receptor gene, located in the
region encoding the 3rd intracellular domain,
allows the formation of two functional alternate splice variants,
D2L and D2S, which vary in
the length of 3rd intracellular loop (Dal Toso et
al., 1989; Giros et al., 1989). The apparent lack of an analogous exon
in the rat and human D3 receptor primary
transcript suggests that a similar alternate splicing event does not
occur (Sokoloff et al., 1990; Giros et al., 1990).
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In contrast, primary mRNA for the murine D3
receptor is reported to contain a 6th intron
located in the 3rd intracellular domain (Fu et
al., 1995; Park et al., 1995). Two murine mRNA splice variants of the
D3 receptor that vary in the length of the
3rd intracellular domain, similar to
D2L and D2S, have been
identified. The long form encodes a receptor with 94% homology with
the rat D3 receptor. The short form contains a 63 base pair deletion in the 3rd intracellular loop
but retains binding activity and D3-like
pharmacological profile (Fishburn et al., 1993; Fu et al., 1995). Fu et
al. (1995) also report the presence of a 6th
intron in the rat D3 receptor primary transcript.
The presence of this additional intron could enable the generation of
long and short forms of the rat D3 receptor;
however, mRNA encoding the short variant of the receptor was not
detected in either rat or human brain.
C. Receptor Isoforms
As discussed above, two splice variants of the murine
D3 receptor mRNA that vary in the length of the
3rd intracellular domain have been identified
(Fishburn et al., 1993; Fu et al., 1995). Although alternate splice
variants of the 3rd intracellular loop have yet
to be detected in the rat and human, several truncated isoforms of the
D3 receptor have been reported. These proteins
arise from alternate splicing events or exchange of cassette exons that
result in a large deletion or a change in reading frame. In some
instances, this establishes a premature stop codon. In the rat, two
truncated D3 receptor variants have been
identified. One variant arises from the deletion of the
3rd transmembrane domain resulting in translation
of only the first two transmembrane domains (Giros et al., 1991; Snyder
et al., 1991); the 2nd from the deletion of 119 base pairs coding for part of the 2nd
intracellular loop and 5th transmembrane domain
(Giros et al., 1991). A truncated D3 receptor variant resulting from deletion of the 3rd
transmembrane domain has also been identified in humans (Snyder et al.,
1991; Griffon et al., 1996). Additional variants arise from deletion of
143 base pairs primarily encoding transmembrane domain IV resulting in
translation of only the first three transmembrane domains (Nagai et
al., 1993; Griffon et al., 1996) or from an 84 base pair insertion
encoding a stop codon in the 1st intracellular
domain (Pagliusi et al., 1993). A human variant, D3nf, with a 98 base pair deletion in the
C-terminal region of the 3rd intracellular loop
that results in a frame shift has also been identified. Whereas mRNA
subsequent to the deletion appears to be translated, the resulting
amino acid sequence differs significantly from the wild-type receptor
(Schmauss et al., 1993). A final splice variant, identified in humans,
results from the deletion of the 3rd
transmembrane domain resulting in the translation of only the 1st, 2nd, and
4th transmembrane domains (Griffon et al., 1996).
To date, the functional properties of only some of the truncated
D3 receptor variants have been assessed. Both
truncated rat D3 receptor variants identified by
Giros et al. (1991) have been shown to lack binding activity in
transfected cell lines. The D3nf variant
identified by Schmauss et al. (1993) has also been shown to lack
high-affinity agonist binding. It is likely that the other truncated
forms are also nonfunctional.
Another question concerning the truncated variants is whether these
proteins are transcribed and inserted in the membrane. Immunoreactivity
for the D3nf protein has been observed in brain (Liu et al., 1994b). Whether the other truncated variants of the D3 receptor are translated remains to be
determined. Likewise, the physiological role of these receptor variants
is also unclear. It is speculated that the truncated receptors could be
expressed under certain circumstances as a mechanism for controlling
the density of functional D3 sites or might occur
in certain disease states (Giros et al., 1991) (See Section VIII.B.).
D. Protein Structure
The D3 receptor contains 446 amino acids and
is synthesized as a 35 to 37 kDa protein that undergoes
posttranslational glycosylation (Sokoloff et al., 1990; David et al.,
1993). Although biochemical evidence for the secondary structure of
this receptor has yet to be generated, hydrophobicity analysis
indicates that the most probable structure of the
D3 receptor is consistent with those of the seven
transmembrane-spanning, G-protein-coupled receptors (fig.
3). In computer models, the spatial
orientation of conserved amino acids is nearly identical with those of
the D2 receptors (Livingstone et al.,
1992). The seven transmembrane domains of the D3
site conform to idealized 
-helices, with the exception of
transmembrane domain IV in which the Cys (166)-Pro (167) bond may
introduce a bend in the -helix (Livingstone et al., 1992). This sort
of proline-induced deviation has been hypothesized to play a role in
the conformational changes that occur upon agonist binding (Lefkowitz
and Caron, 1988; Hulme et al., 1990).
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Computer modeling studies suggest several amino acid residues with
potential functional importance. For example, Cys (103) and Cys (181)
may form an extracellular disulfide bond (Sokoloff et al., 1990). Other
important residues are located in the binding-site crevice. These
include Ser (193) and Ser (196), which are located in transmembrane
domain V and are likely to be involved in the formation of H-bonds with
the two hydroxyl groups of catechols (Sokoloff et al., 1990; Malmberg
et al., 1994). Asp (110) may participate in salt-linking with the amine
groups of monoamines (Sokoloff et al., 1990). In addition, the location
and orientation of Ser (193) and Asp (110) appear to allow for optimal
bonds with oxygenated 2-aminotetralins, such as
7-hydroxy-dipropylaminotetralin (7-OH-DPAT), which may confer the
higher affinity of these compounds at the D3
receptor than the D2 (Malmberg et al., 1994).
Because of the high degree of homology between the
D2 and D3 receptors, it is
not surprising that these receptors exhibit similar pharmacological and
other properties. Chimeric
D2/D3 receptors have been
used as one approach to determine whether certain attributes of the
receptor are determined by specific domains of the receptor protein.
For example, the D3 receptor appears to possess
higher affinity for some agonists and lower affinity for certain
antagonists than the D2 receptor. In one study,
chimeric receptors were constructed in which the
D2 receptor contained the
3rd intracellular loop of the
D3 receptor. The chimeric receptors exhibited
higher affinity for agonists than the wild-type
D2 receptor (Robinson et al., 1994). Conversely,
a D3 receptor containing the
3rd intracellular loop of the
D2 receptor exhibited lower affinity for
agonists, implicating this region in conferring agonist binding properties (Robinson et al., 1994). Similar experiments suggest a role
for transmembrane domains VI and VII in the determination of antagonist
affinity (Norman and Naylor, 1994). Other studies using chimeric
receptors, however, indicate that D3 receptors containing the 3rd intracellular loop of the
D2 receptor exhibit binding and coupling attributes identical with D3 or intermediate
between D2 and D3 (McAllister et al., 1993; Van Leeuwen et al., 1995).
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III. Cellular Signaling Mechanisms |
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A. Signal Transduction in Expression Systems
Because of the similar pharmacological profiles of the
D3 and other D2-like
dopamine receptors, the primary means for initial studies of the
functional properties of this novel receptor required the expression of
the receptor in transfected cell lines. Because the host cells may not
express the same cellular components, e.g., G-proteins, as the native
tissue, receptors may display different functional properties in
various expression systems (Kenakin, 1996). Accordingly, it is not
surprising that reports on the coupling of the D3
receptor to signal transduction systems have varied considerably. The
initial cloning report indicated that the D3 receptor expressed in Chinese hamster ovary (CHO) cells did not exhibit
a decrease in affinity for agonists in the presence of guanyl
nucleotides, or G-shift, as would be expected for a G-protein-coupled receptor (Sokoloff et al., 1990). This suggested that the
D3 receptor might not be functionally coupled to
G-proteins. Other groups studying the receptor expressed in other cell
lines including neuronal mesencephalic MN9D cells, neuroblastoma
NG108-15 cells, and insect Sf21 cells observed a similar lack of
G-shift in D3 binding (Freedman et al., 1994b;
Tang et al., 1994a; Woodcock et al., 1995). G-shifts in
D3 receptor binding, however, were observed in
several studies by using a variety of other cell lines. Interestingly,
the magnitude of the decrease in agonist affinity observed in the
presence of guanyl nucleotides ranged from 5 to 10-fold (Seabrook et
al., 1992; Sokoloff et al., 1992; Chio et al., 1994; MacKenzie et al.,
1994) to 50 to 100-fold, similar to the roughly 100-fold shifts
observed for the D2 receptor (Castro and Strange,
1993; Pilon et al., 1994; Grigoriadis and Seeman, 1985).
Observations on the coupling of the D3 receptor
in expression systems to specific signal transduction cascades have
also varied. In some systems, a G-shift in D3
binding was observed but alterations in second-messengers such as
cyclic adenosine monophosphate, phosphoinositides, or arachidonic acid
were not detected (Seabrook et al., 1992; MacKenzie et al., 1994).
Other groups observed a variety of D3-initiated signaling events including stimulation or inhibition of adenylyl cyclase, increased extracellular acidification, alterations in Ca2+ and K+ currents, and
induction of c-Fos expression (Chio et al., 1994; Cox et al., 1995;
Pilon et al., 1994; Potenza et al., 1994; Seabrook et al., 1994; Liu et
al., 1996; Werner et al., 1996). D3 receptors have also been shown to induce aggregation in melanocytes and to
stimulate mitogenesis in CHO cells (Chio et al., 1994; Pilon et al.,
1994; Potenza et al., 1994). Several of the
D3-mediated signaling events, including
stimulation of adenylyl cyclase, mitogenesis, alterations in
Ca2+ and K+ currents, and
increases rate of extracellular acidification were blocked by pertussis
toxin suggesting coupling to a Gi or
Go isoform (Pilon et al., 1994; Potenza et al.,
1994; Seabrook et al., 1994; Chio et al., 1994; Liu et al., 1996;
Werner et al., 1996). In another study, however,
D3-induced increases in the rate of extracellular acidification were not blocked by pertussis toxin (Cox et al., 1995).
Thus, these studies demonstrate functional coupling of the
D3 receptor to a variety of signaling cascades in
some expression systems. The cellular signaling pathways affected,
however, vary depending on the host cell and may not necessarily
reflect the signaling pathways associated with the receptor in brain.
B. Coupling in Brain
Whereas coupling of the D3 receptor has been
shown in some expression systems, the demonstration of functional
coupling in brain has been a more formidable task. Although all of the
D3-selective radioligands identified to date,
such as [3H]7-OH-DPAT,
[3H]PD 128907, and
[125I](R)-trans-7-hydroxy-2-[N-propyl-N-(3'-iodo-2'-propenyl)amino]tetralin (7-OH-PIPAT), have been agonists, which presumably label the
high-affinity state of a G-protein coupled receptor, most studies
indicate that the binding of these ligands at putative
D3 sites is insensitive to guanyl nucleotides
(Lévesque et al., 1992; Burris et al., 1994; Kung et al., 1994;
Bancroft et al., 1997). In fact, the binding of several
D2-like receptor agonists remaining in the presence of guanyl nucleotides has been suggested to represent labeling
of D3 sites in autoradiographic studies (Gehlert,
1992; Levant et al., 1993; Kung et al., 1994). One study, however, has reported the inhibition of [3H]7-OH-DPAT by
guanyl nucleotides and the sulfhydryl alkylating agent N-ethylmaleimide
indicating G-protein coupling (Liu et al., 1994c). This observation,
however, is most likely the result of the nonselective labeling of both
D2 and D3 sites due to the
presence of Mg2+ in the assay buffer.
Although these findings may suggest that D3 receptor in brain may lack functional G-protein coupling, there are other possible explanations. Whereas the high-affinity state of the D2 receptor exhibits approximately 100-fold higher affinity for agonists than the low-affinity state, the high-affinity conformation of the cloned D3 receptor in expression systems has been most often reported to exhibit only approximately 5 to10-fold higher affinity for agonists than the low-affinity state. Thus, whereas agonist radioligands are presumed to preferentially label the high-affinity state conformation of G-protein coupled receptors, the putative D3 binding observed in brain, albeit of nanomolar affinity, may be to receptors in the low-affinity state. As such, the binding of either agonist or antagonist ligands to these sites would be unaltered in the presence of guanyl nucleotides.
There are several possible reasons why the observed
D3 binding in brain tissue may represent
receptors in the low-affinity state. The first and simplest explanation
is that the affinity state of these sites is a function of the in vitro
assay conditions used to obtain putatively selective labeling of
D3 sites. Specifically, obtaining selective
labeling of the D3 site with the radioligands currently available appears to be dependent on the use of assay conditions that disfavor agonist binding at the
D2 site. The greatest D3/D2 selectivity for these
ligands has been obtained in the absence of Mg2+
and the presence of ethylenediamine-tetraacetic acid (Lévesque et
al., 1992; Akunne et al., 1995) in concordance with previous studies
indicating that the high-affinity state of
D2-like receptors is not favored in the absence
of Mg2+ (Sibley and Creese, 1983). Although these
conditions may also affect the affinity state of the
D3 receptor, the low-affinity conformation of the
D3 site exhibits much higher affinity for agonists than the low-affinity state of the D2
receptor. As such, selective labeling of D3 sites
occurs.
Alternatively, D3 sites in rat brain may exist
predominantly in the low-affinity state under basal conditions as has
been suggested for the D1 receptor (Richfield et
al., 1989). Although "D3-selective"
radioligands, such as [3H]7-OH-DPAT, label a
single site in rat brain (Lévesque et al., 1992; Akunne et al.,
1995; Levant, 1995), depletion of endogenous catecholamines resulted in
the detection of an additional [3H]7-OH-DPAT
binding site ex vivo (fig. 4). This
additional binding site exhibited roughly ten-fold higher affinity than
the single binding site detected in control animals without a
significant increase in the total number of sites (Levant, 1995).
Although the higher affinity sites may have been occupied, and thus
masked, by endogenous dopamine in control animals (Schotte et al.,
1992), preincubation and extensive washing of membranes from control animals to remove any residual dopamine failed to alter binding of
[3H]7-OH-DPAT (Levant, 1995). These
observations suggest that in the absence of dopamine, some
D3 sites, which under normal conditions are
predominantly in the low-affinity state, assume a high-affinity conformation. This hypothesis is supported by the observation that the
high-affinity state component of [3H]7-OH-DPAT
binding in catecholamine-depleted rats is inactivated by the alkylating
agent 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, whereas the
low-affinity component is not-a difference that might well be
conferred by a conformational change. In fact, when
catecholamine-depleted rats are treated with
1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, only low-affinity sites
remain and the density of these sites is reduced by roughly the same
amount as the density of high-affinity state sites present in the
catecholamine-depleted animals (Levant, 1995).
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Although the current lack of evidence of cellular signaling mechanisms
for the D3 receptor in brain is puzzling, it need
not imply a lack of function. In fact, several presumably
D3-mediated behavioral, neurochemical, and
electrophysiological effects have been reported (See Section VI.).
Likewise, the D3-preferring antagonist U99194A
has been reported to induce expression of c-fos mRNA in brain (Merchant
et al., 1996). Clearly, further study must address the issues of the
cellular signaling mechanism(s) associated with the
D3 receptor in brain as well as those related to
the affinity state of these sites under basal conditions.
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IV. Pharmacology |
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A. Radioligand Binding Studies
Considering the extensive homology between the
D2 and D3 sites, it is not
unexpected that the pharmacological profile of the D3 receptor is generally similar to that of the
D2 receptor. As such, the
D3 receptor exhibits high affinity for
nonselective and D2-selective agonists, such as
dopamine, quinpirole, and apomorphine, and significantly lower affinity
for the D1-selective agonist SKF 38393 (Sokoloff
et al., 1990). The D3 site also possess
significantly higher affinity for D2-selective
antagonists, such as spiperone and haloperidol, than the
D1-selective antagonist SCH 23390 (Freedman et
al., 1994b). Likewise, the D3 receptor exhibits
stereospecificity with higher affinity for (+)-butaclamol than
(
)-butaclamol and ()-sulpiride than (+)-sulpiride (Freedman et al.,
1994b; Kula et al., 1994; MacKenzie et al., 1994).
What is perhaps of greater interest than the pharmacological profile of
the D3 receptor is the relative affinities of
compounds for the D2-related subtypes. Several
studies have examined the relative affinities of dopaminergic compounds
for D2 and D3 receptors in
various expression systems and in brain. These studies suggest that
some dopaminergic agonists, such as dopamine and quinpirole possess
higher affinity for the D3 site whereas
antagonists, such as haloperidol, spiperone, and domperidone, have
higher affinity for D2 (Sokoloff et al., 1990).
However, as summarized in table 1,
results of these studies vary
considerably, depending, at least in part, on the expression system or
tissue, the radioligand, and the in vitro assay conditions used (Tang
et al., 1994a; Burris et al., 1995; Levant et al., 1995). For example,
quinpirole was found to have more than 100-fold higher affinity for the
D3 receptor than the D2
receptor in some assay systems (Sokoloff et al., 1990; Lévesque
et al., 1992; Burris et al., 1995) but roughly equal affinity for these
sites in others (Levant and DeSouza, 1993; Tang et al., 1994a; Burris
et al., 1995). In fact, the high-affinity state of the
D2 receptor appears to have similar affinity for agonists as the D3 site (Burris et al., 1995). As
such, the observed D3-selectivity of many
agonists may have resulted from the use of in vitro conditions that
disfavor the high-affinity conformation of the D2
receptor such as the inclusion of Na+ in in vitro
assay systems used for benzamide radioligands (Burris et al., 1995;
Levant et al., 1995; Grigoriadis and Seeman, 1985). What is clear from
these studies is that under certain conditions, several compounds
exhibit significant selectivity between the D2
and D3 dopamine receptors. This information is
likely to be of considerable utility in the design and interpretation
of in vitro studies, particularly for the determination of the
localization and density of D3 sites. On the
other hand, the attribution of in vivo pharmacological effects of these
drugs to specific receptor subtypes based on these data is, in most
instances, premature.
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B. Functional Assays
Several functional assays have established the agonist or
antagonist activity of a variety of dopaminergic compounds at the D3 receptor. D2 agonists,
such as dopamine, quinpirole, and bromocriptine, have been shown to
possess agonist activity at the D3 receptor as
assessed by the induction of CHO cell mitogenesis, melanocyte aggregation, or extracellular acidification (Chio et al., 1994; Pilon
et al., 1994; Potenza et al., 1994; Sautel et al., 1995a; Boyfield et
al., 1996). The putatively D3-selective compounds 7-OH-DPAT and PD 128907 also exhibit agonist activity in the
mitogenesis test (Chio et al., 1994; Pilon et al., 1994; Potenza et
al., 1994; Sautel et al., 1995a; Pugsley et al., 1995). In contrast,
antagonists, such as spiperone, (±)-sulpiride, and nafadotride, block
agonist-induced activity in these tests (Potenza et al., 1994; Sautel
et al., 1995b). The D2/D3
ligand (+)-UH 232 has been shown to be a partial agonist at the
D3 receptor in the mitogenesis assay (Griffon et al., 1995).
In addition to elucidating the agonist or antagonist activity of
compounds at the D3 receptor, the assays
described above are also useful in determining the
D2/D3-selectivity of drugs in a functional test. In contrast to the significant
D3-selectivity reported in some binding studies,
the agonists tested, including dopamine, quinpirole, and 7-OH-DPAT,
exhibited only modest, if any, D3-selectivity in
the mitogenesis, melanocyte aggregation, or extracellular acidification
assays (table 2) (Chio et al., 1994;
Pilon et al., 1994; Potenza et al., 1994; Sautel et al., 1995a;
Boyfield et al., 1996). In contrast, the antagonists spiperone and
(±)-sulpiride were roughly 65-fold more potent in inhibiting agonist-induced melanocyte aggregation at D2
receptors than D3 (Potenza et al., 1994). These
observations further underscore the need for caution in the use of in
vitro binding data in the interpretation of in vivo or in vitro
functional studies.
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V. Localization of D3 Receptors in Brain |
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A variety of approaches may be employed to study the localization of the D3 receptor including molecular, pharmacological, and immunological methods. Much of what is known about the distribution of the D3 receptor, and other novel dopamine subtypes, for which selective pharmacological tools have only recently been identified and have not been extensively validated, is based on the localization of receptor mRNA. Whereas the detection of mRNA with appropriate probes can be presumed to be specific for the receptor of interest, the distribution and relative abundance of mRNA does not necessarily parallel the distribution and density of the receptor it encodes.
Several means of selectively visualizing D3 sites
have also been developed. These methods include the use of a putatively selective D3 ligand such as
[3H]7-OH-DPAT (Lévesque et al., 1992),
[3H]PD 128907 (Akunne et al., 1995), or
[125I]trans-7-OH-PIPAT (Kung et al., 1994), in
radioligand binding and autoradiographic studies. Alternatively, a
ligand that labels both D2 and
D3 receptors such as
[3H]quinpirole, [3H]CV
205 502, [125I]iodosulpiride, or
[125I]epidepride may be used in the presence of
an unlabeled ligand selective for D2 receptors
(Murray et al., 1992; Schotte et al., 1992; Landwehrmeyer et al.,
1993a; Levant and DeSouza, 1993). Antibodies for the
D3 receptor have also been developed and used in
immunocytochemical studies. It must be noted, however, whereas these
radioligands and antibodies generally identify a similar, apparently
homogeneous population of dopaminergic sites that differ from the
classical D2 site in several respects, in vitro
assay conditions appear to significantly influence the activities of these ligands (Lévesque et al., 1992). For this reason, and
perhaps others, controversy has arisen over the
D3/D2-selectivity of
radioligands such as [3H]7-OH-DPAT (Gonzales
and Sibley, 1995). Interaction of [3H]7-OH-DPAT
with the sigma site has also been reported (Schoemaker, 1993; Wallace and Booze, 1995). Hence, sites identified by using these
tools are referred to as "putative" D3 sites.
).
Moderate to dense expression of D3 mRNA has also
been detected in the dentate gyrus, olfactory bulb, and the anterior
and intermediate lobes of the pituitary in in situ hybridization
studies (Bouthenet et al., 1991). However, the observation of
hybridization signal in these brain regions is controversial as
D3 mRNA was not detected in these brain regions
in other studies by Northern analysis, in situ hybridization, or PCR
(Sokoloff et al., 1990; Mengod et al., 1992), suggesting the
possibility of nonspecific hybridization. Low densities of
D3 mRNA are reported in the cerebral cortex,
caudate/putamen, ventral pallidum, substantia nigra pars reticulata,
ventral tegmental area, and cerebellar cortex (Bouthenet et al., 1991;
Mengod et al., 1992).
2. Distribution in human brain.
Although not as extensively
characterized, the distribution of D3 mRNA in
human brain appears to be generally similar to that observed in the
rat. Enrichment of D3 mRNA was observed in the nucleus accumbens and islands of Calleja with relatively low levels of
expression in the anterior caudate and putamen (Landwehrmeyer et al.,
1993b). D3 mRNA has also been observed in the
granular cell layer of the dentate gyrus (Meador-Woodruff et al., 1994)
B. Distribution of Putative D3 Receptors
1. Distribution in rat brain.
Although the distribution of
D3 receptors in rat brain has not been mapped in
detail, the localization of D3 receptors appears to parallel that of D3
mRNA. D3 receptors
appear to be expressed in highest density in brain regions such as the
islands of Calleja, olfactory bulb, and the pituitary intermediate
lobe. Moderately dense D3 binding is observed in
the nucleus accumbens, the molecular layer of the vestibulocerebellum,
and substantia nigra pars compacta. Relatively little
D3 binding is observed in the caudate/putamen (Levant et al., 1992 2. Distribution in human brain.
The distribution of
D3 receptors in human brain is generally similar
to that observed in the rat; however, the overall pattern of
distribution appears to be somewhat less restricted (Herroelen et al.,
1994 C. Implications of Regional Distribution
One of the issues of interest regarding the
D3 receptor is whether, like the
D2 site, this receptor is localized pre- or
postsynaptically. The detection of D3 mRNA in the
substantia nigra and ventral tegmental areas and putative binding sites
in dopaminergic terminal fields suggests that a subset of
D3 receptors may be presynaptic. In keeping with
this hypothesis, unilateral dopaminergic lesions produced a marked
decrease in D3 receptor density in the nucleus accumbens, suggesting the loss of presynaptic sites (Lévesque et
al., 1995 The D3 receptor is also of interest because of
its relatively restricted distribution in brain. Unlike the
D2 receptor, which is abundant in the
caudate/putamen and pituitary as well as in limbic brain regions
(Levant, 1996 Finally, the detection of D3 receptor mRNA and
binding in vestibulocerebellum is of potential significance.
D3 receptor mRNA, but not
D2 receptor mRNA, is reported in the Purkinje
cell layer of lobule X, whereas putative binding is observed in the
molecular layer. Purkinje cell dendrites arborize in the molecular
layer suggesting that the binding sites identified represent
D3 receptors localized on the Purkinje cell
dendrites. Purkinje cells in cerebellar lobule X project to the
vestibular system, which controls proximal muscle tone and thus,
posture and gait. Clinically, disorders involving cerebellar lobule X
produce symptoms such as ataxia, whereas lesions of this brain region
cause rigidity (Ghez and Fahn, 1981; Gehlert et al., 1992; Lévesque et al., 1992; Landwehrmeyer et al., 1993a; Parsons et al., 1993; Booze and
Wallace, 1995; Ricci et al., 1995). D3-like
immunoreactivity was associated with neuronal-type cells and was
concentrated at the cell body perimeter (Ariano and Sibley, 1994;
Larson and Ariano, 1995)
). Highest densities of putative D3 sites are
reported in the nucleus accumbens and islands of Calleja (Landwehrmeyer et al., 1993b; Murray et al., 1994). Moderate amounts of
D3 binding were observed in the basal ganglia,
parietal, temporal and occipital cortex, and cerebellar cortex,
followed by substantia nigra, hippocampus, and the basolateral, lateral
and basomedial amygdaloid nuclei (Herroelen et al., 1994; Murray et
al., 1994; Lahti et al., 1995). D3 receptors were
also detected in moderate density in the pituitary, with somewhat
greater labeling in the posterior lobe than the anterior (Herroelen et
al., 1994)
). Neurochemical studies also suggest a role for the D3 site as a synthesis- and/or release-modulating
autoreceptor (See Section VI.C.).), very low levels of expression of the
D3 receptor are detected in either the
caudate/putamen or pituitary, brain areas associated with the untoward
neurological and endocrine effects produce by most conventional
antipsychotics. These observations suggest that the
D3 receptor, alone or in conjunction with other
receptors, may be a target for novel antipsychotic drugs that might be
free of extrapyramidal and neuroendocrine effects (Sokoloff et al.,
1990). ). These symptoms are similar to the
neurological side effects associated with antipsychotic drugs
(Parkinsonian-like tremor, rigidity, and bradykinesia). Although the
contribution of the blockade of striatal dopamine receptors in
producing these symptoms is not disputed, cerebellar
D3 receptors could also contribute to these side
effects. Although this issue has not been directly addressed, recent
evidence suggests that microinjection of
D3-selective antagonists into the
vestibulocerebellum produces alterations in locomotor activity in rats
(Barik and Debeaurepaire, 1996). The source of dopaminergic innervation
and the function of the cerebellar D3 receptors,
however, is unclear. In addition, whereas cerebellar
D3 receptors are present in rats, mice and guinea
pigs do not appear to express dopamine receptors in the
vestibulocerebellum (Camps et al., 1990). Whether humans possess these
sites has yet to be definitively determined.
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VI. D3 Receptors in Cellular and Organismal Function |
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One of the primary aims in the study of the novel dopamine receptors is the elucidation of their role in cellular and organismal function. To date, pharmacological and molecular methods have been used in attempt to selectively study these novel sites. In the case of the D3 receptor, numerous pharmacological studies as well as several studies using targeted mutation and antisense technologies have been performed. To date, a large body of data has been generated. Because of the limitations of these experimental approaches, however, care must be taken in the interpretation of these findings.
Pharmacological studies have made considerable use of the agonists and
antagonists identified as exhibiting selectivity for the
D3 receptor in vitro. Some of these compounds,
particularly 7-OH-DPAT, have been widely employed in vivo to probe the
functional role of the D3 receptor in behavioral,
electrophysiological, and neurochemical studies. Recent pharmacological
characterization of the D3 receptor suggests that
the D2/D3-selectivity of
many compounds varies depending on the in vitro assay conditions used (Burris et al., 1995; Levant et al., 1995) (See Section IV.A.). Accordingly, there has been concern over the selectivity of these drugs
in vivo and the attribution of pharmacological effects to the
D3 receptor (Freedman et al., 1994a; Large and
Stubbs, 1994). In addition, the vast majority of the studies of
D3-mediated effects have used a single drug,
7-OH-DPAT. As such, some observed effects may be idiosyncratic to this
drug.
Another approach for the study of this novel receptor is the use of mice deficient in D3 sites resulting from a targeted mutation of the D3 receptor gene, or "knock-out" animals. Although this approach is of considerable merit, it also has significant limitations. Most notably, such "knock-out" animals are deficient in D3 receptors, and perhaps other proteins, throughout development. Because of the considerable plasticity of the developing nervous system, compensatory adaptations may occur, such as the expression of other receptors in place of the D3 receptor. As such, until proven, it cannot be assumed that "knock-out" animals represent otherwise normal animals that simply lack D3 sites. Likewise, it cannot be assumed that such animals made in different laboratories or by different methods are the same.
An alternative technique for generating an animal's deficiency in a protein of interest is the use of antisense oligonucleotides. Although this approach avoids problems associated with developmental plasticity, caution must again be exercised as the product of the targeted mRNA is likely to only be reduced, not eliminated, and other compensatory changes may occur.
Clearly, all of the methodologies currently available for the study of the role of the D3 receptor in cellular and organismal function possess certain limitations. Taken together, however, certain themes are gradually becoming apparent in the large body of data amassed to date that suggest a potential role for the D3 receptor in several cellular and organismal functions.
A. Role in Behavior
Although the D3 receptor has been implicated
in numerous behaviors, the receptor is most widely cited in the
modulation of locomotor activity (fig.
5). In contrast to the
D2 receptor, in which stimulation is believed to
increase locomotion, stimulation of the D3 site
appears to inhibit locomotor activity. This effect was initially
reported in several studies using the
D3-preferring drug 7-OH-DPAT. This drug produced
a biphasic effect on locomotor activity in rats in which locomotion was
inhibited at lower doses and stimulated at higher doses (Daly and
Waddington, 1993; McElroy et al., 1993; Ahlenius and Salmi, 1994;
Svensson et al., 1994a,b; Khroyan et al., 1995; Depoortere et al.,
1996; Kagaya et al., 1996). The inhibitory effects of the drug were
attributed to activity of the drug at the D3
receptor; the stimulatory effects were attributed to the actions of
higher doses of the drug at the D2 receptor (Daly
and Waddington, 1993; Ahlenius and Salmi, 1994; Svensson et al.,
1994a). This interpretation was supported by demonstration that the
inhibitory effects of 7-OH-DPAT were produced by doses of the drug that
do not produce significant occupancy of D2
receptors in vivo (Levant et al., 1996). The
D3-preferring agonist PD 128907 produced similar
biphasic effects on locomotor activity (Pugsley et al., 1995), and
inhibition of locomotor activity was observed after microinjection of
7-OH-DPAT into the nucleus accumbens (Gilbert and Cooper, 1995;
Kling-Petersen et al., 1995). Inhibition of locomotor activity by
7-OH-DPAT has also been reported in mice (Starr and Starr, 1995).
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Consistent with the effects of D3 agonists on
locomotor activity, the D3-preferring antagonist
nafadotride produced biphasic effects on locomotor activity in rats,
stimulating locomotion at lower doses and inhibiting locomotion at
higher doses (Sautel et al., 1995b). As with 7-OH-DPAT, doses of
nafadotride that increased locomotor activity were shown to produce
negligible occupancy of D2 receptors, whereas
those that inhibited locomotion produced significant
D2 occupancy (Levant and Vansell, 1997). Another
D3-preferring antagonist, U99194A, has also been
reported to increase locomotor activity (Waters et al., 1993, 1994).
Finally, increased locomotor activity and rearing behavior and
hyperactivity in an exploratory test were observed in one strain of
D3 "knock-out" mice (Accili et al., 1996).
Likewise, a preliminary report on another strain of
D3-deficient mice indicated a transient increase
in activity in a novel environment compared with wild-type mice,
although no alterations in agonist-stimulated locomotor behavior were
observed (Xu et al., 1995; Koeltzow et al., 1995). Taken together,
these findings indicate the probable involvement of the
D3 receptor in the modulation of locomotor
activity in a manner opposite of that of the D2
receptor.
Based on the somewhat limited in vivo and in vitro pharmacological data
currently available, it is possible that the D3
site may play a role in several additional behaviors. These include agonist-induced yawning and hypothermia (Damsma et al., 1993; Ahlenius
and Salmi, 1994; Millan et al., 1994, 1995a,b; Ferrari and Guiliani,
1995; Khroyan et al., 1995; Kurashima et al., 1995), decreased sniffing
(Daly and Waddington, 1993), decreased alcohol consumption (Meert and
Clincke, 1994), and increased penile erection and ejaculatory behavior
(Ahlenius and Larsson, 1995; Ferrari and Guiliani, 1995). Clearly,
further study must confirm the role of the D3
receptor in these behaviors, particularly in light of the significant
variability in the in vitro pharmacological profile of the
D2 and D3 sites on which
much of the interpretation of these data is based. Likewise, in vivo
occupancy studies may underestimate the interaction of an agonist with
the D2 site. Finally, in vivo interaction of the
putative D3 agonists with the
D3 receptor has yet to be demonstrated.
Stimulation of the D3 receptor has also been
implicated in intriguing behavioral effects involving reinforcement and
reward. Of note, 7-OH-DPAT has been reported to decrease
self-administration of cocaine (Caine and Koob, 1993) and
self-stimulation of the ventral tegmental area (Depoortere et al.,
1996). Likewise, stimulation of D3 sites is
implicated in blocking the reinforcing effects of cocaine and
d-amphetamine (Kling-Petersen et al., 1994), decreasing the rate of
food-reinforced responding in a fixed-ratio operant paradigm (Sanger et
al., 1996), and producing an aversive effect in a conditioned
place-preference paradigm (Chaperon and Thiebot, 1996). The subjective
effects of 7-OH-DPAT and other D3-preferring agonists generalize to cocaine in drug-discrimination paradigms in both
rats and monkeys (Acri et al., 1995; Lamas et al., 1996). These
observations have important implications for the understanding and
treatment of drug addiction. However, as discussed above, further study
must determine the role of specific dopamine receptor subtypes in these
observations.
A variety of other behavioral and physiological effects of putatively
D3-preferring compounds have been reported. These
effects include conditioned taste aversion (Bevins et al., 1996),
disruption of huddling behavior in rats (Kagaya et al., 1996),
decreased grooming (Khroyan et al., 1995), alterations in performance
in an elevated maze test (Rodgers et al., 1996), decreased prepulse inhibition (Caine et al., 1995), catalepsy (Millan et al., 1995b; Sautel et al., 1995b), enhancement of morphine-induced conditioned place preference (Rodriguez De Fonseca et al., 1995), inhibition of
pilocarpine-induced limbic seizures (Alam and Starr, 1994), induction
of depressant electroencephalogram patterns (Popoli et al., 1996),
increased oxytocin secretion (Uvnas Moberg et al., 1995), and decreased
gastric acid secretion (Glavin, 1994). The D3
receptor has also been suggested to play a role in emesis in the dog
(Yoshida et al., 1995) and decreased climbing in mice (Sautel et al.,
1995b). The involvement of dopamine receptors in these effects is
likely; however, evidence for the selective involvement of the
D3 site is currently lacking.
Although the body of literature of the pharmacological effects of
D3-preferring compounds has implicated the
D3 site in certain behaviors, such as the
modulation of locomotor activity, these studies also indicate the
probable lack of involvement of the D3 receptor in other
behaviors. For example, increases in sniffing and stereotyped behaviors
produced by 7-OH-DPAT are observed only after treatment with doses that
produce significant in vivo occupancy of D2
receptors (Daly and Waddington, 1993; Damsma et al., 1993; Ferrari and
Guiliani, 1995; Khroyan et al., 1995; Kurashima et al., 1995; Pugsley
et al., 1995; Levant et al., 1996). Thus, these behaviors probably
result from the stimulation of D2 receptors.
B. Role in Neuronal Activity
As with behavioral studies, 7-OH-DPAT has been used to probe the
effects of D3 receptor stimulation on neuronal
activity. The D3-preferring agonist has been
shown to inhibit firing of neurons in both the substantia nigra and
ventral tegmental areas, as well as in brain slice preparations by
activation of an 85 picosiemen K+ channel (Bowery
et al., 1994; Liu et al., 1994a; Devoto et al., 1995; Kreiss et al.,
1995; Lejeune and Millan, 1995). 7-OH-DPAT has also been reported to
decrease firing of spontaneously active or glutamate-driven neurons in
the nucleus accumbens (Amano et al., 1994; Liu et al., 1994a). Although
selective action of 7-OH-DPAT at D3 receptors
cannot be assumed in these studies, Kreiss et al. (1995) have shown
that the potencies of ten dopamine agonists in inhibiting firing of
neurons in the substantia nigra pars compacta correlated with their
affinities at D3, but not
D2 receptors. Caution, of course, must be
exercised in the interpretation of such findings in view of the
significant variability in the in vitro pharmacological profile of the
D2 and D3 sites in various assay systems. In contrast, preliminary studies in
D3-receptor-deficient mice indicate increased
sensitivity of nucleus accumbens neurons to the
D2/D3 agonist quinpirole
(Koeltzow et al., 1995). This observation may suggest a possible
excitatory role for the D3 receptor although
up-regulation of D2 receptor mechanisms must be
ruled out by further study.
C. Role in Neurochemistry
In vivo and in vitro studies suggest a role for the
D3 site as an autoreceptor that modulates
dopaminergic activity. Stimulation of D3
receptors expressed in neuronal mesencephalic MN9D cells resulted in a
dose-dependent inhibition of dopamine release (Tang et al., 1994b).
Likewise, the D3-preferring agonist 7-OH-DPAT produced decreases in dopamine release in vivo as assessed by microdialysis or voltametry, as well as in accumbal slice preparations (Damsma et al., 1993; Rivet et al., 1994; Yamada et al., 1994; Devoto
et al., 1995; Gilbert et al., 1995; Patel et al., 1995; Gainetdinov et
al., 1996). Similar effects were also reported for PD 128907 (Pugsley
et al., 1995). Both 7-OH-DPAT and PD 128907 have also been shown to
decrease extracellular dihydrophenylacetic acid concentrations as
assessed by in vivo microdialysis consistent with a decrease in
dopamine release (Pugsley et al., 1995; Gainetdinov et al., 1996). In
addition, D3 "knock-out" mice exhibited
higher basal levels of extracellular dopamine (Cooper et al., 1996). It
is difficult, however, to ascertain that the inhibition of dopamine
release observed in heterogeneous tissues results from selective
actions at the D3 receptor as stimulation of
D2 receptors expressed in MN9D cells also
inhibits dopamine release (Tang et al., 1994b). Likewise, similar
inhibitory responses to PD 128907 were observed for both
D3 "knock-out" and wild-type mice (Cooper et
al., 1996).
The D3 receptor has also been implicated in the
modulation of dopamine synthesis. In
D3-expressing MN9D cells, the application of
agonist produced a decrease in K+-stimulated
tyrosine hydroxylase activity (O'Hara et al., 1996). In vivo,
D3-selective drugs 7-OH-DPAT and PD 128907 have
been reported to decrease dopamine synthesis (Aretha et al., 1995; Gobert et al., 1995; Gainetdinov et al., 1996; Pugsley et al., 1995).
This effect appears to be presynaptic, as it is observed in both normal
rats and in rats treated with 
-butyrolactone, which blocks impulse
flow in nigrostriatal and mesolimbic dopamine neurons (Aretha et al.,
1995; Pugsley et al., 1995). The involvement of the
D3 receptor in this effect is supported by the
observation that 7-OH-DPAT produced a greater decrease in dopamine
synthesis in the nucleus accumbens, in which D3
sites are relatively abundant, than in the caudate nucleus, in which
D3 sites are sparse (Aretha et al., 1995). A
preliminary report by Nissbrandt et al. (1995) also suggests that
reduction in the density of D3 sites by
intracerebroventricular infusion of antisense oligonucleotides for the
D3 receptor may result in increased
dihydroxyphenylalanine accumulation, indicating a possible increase in
dopamine synthesis. However, a preliminary report on
D3-receptor-deficient mice indicated no
alteration in dopamine synthesis compared with wild-type animals
(Cooper et al., 1996). It must be borne in mind that these data are
subject to same limitations as those discussed above for the behavioral studies. Even so, when taken together, these observations suggest a
potential role for the D3 receptor as an
autoreceptor modulating dopamine release and/or synthesis. Further
study, however, must confirm the role of specific dopamine receptor
subtypes in these observations.
One additional observation suggests a possible role for the
D3 receptor in the modulation of the
neuromodulatory peptide neurotensin. Although blockade of
D2 receptors increases expression of
proneurotensin mRNA in the caudate and nucleus accumbens shell cone,
blockade of D2-like dopamine receptors with
haloperidol decreased expression of proneurotensin mRNA in the
ventromedial nucleus accumbens shell, an area enriched in
D3 receptor mRNA (Diaz et al., 1994). Although this observation suggests that blockade of D3
sites may ultimately decrease neurotensinergic neurotransmission in
some brain areas, it should be noted that the effects of
D3 receptor manipulations on neurotensin
concentration or release have yet to be determined.
D. Role in Development
Expression of the D3 receptor in brain
occurs quite early in development. In rat brain,
D3 receptor mRNA is detectable by polymerase
chain reaction as early as embryonic day 11 and is clearly detectable
by embryonic day 14 (Cadoret et al., 1993). Similarly, in mouse brain,
D3 receptor mRNA is detectable on embryonic day
9.5, 4 days before the detection of D2 receptor
mRNA (Fishburn et al., 1996). D3 receptor
binding, as assessed with [3H]7-OH-DPAT, is
detectable in the islands of Calleja and olfactory tubercle at birth in
mouse brain. D3 binding in the nucleus accumbens is detectable on postnatal day 4, substantia nigra on postnatal day 8, and in the vestibulocerebellum on postnatal day 11. Binding in these
brain areas was observed to increase in density through development
until adult levels were reached. In addition, transient expression of
D3 binding was observed in the dorsolateral
parietal cortex between postnatal days 6 and 15 (Demotes-Mainard et
al., 1996).
Interestingly, during the 2nd trimester of
gestation, D2-like receptors are transiently
expressed in the cortical-plate of developing human brain (Todd, 1992;
Unis and Dorsa, 1993). Preliminary reports also indicate transient,
dense expression of D3 receptor mRNA in the
cortical plate of human brain at midgestation (Unis and Dorsa, 1993;
Unis et al., 1995), suggesting that these receptors are of the
D3 subtype. This transient expression of
D3 receptors suggests a role for dopamine in
orchestrating neuronal migration and differentiation during this period
of accelerated cortical development that is mediated by the
D3 receptor. This hypothesis is supported by the
observation that stimulation of D3 sites induces increased branching and extension of neurites in both mesencephalic MN9D cells and primary mesencephalic neuronal cultures (Swarzenski et
al., 1994).
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VII. Regulation of D3 Receptor Density and Messenger Ribonucleic Acid Expression |
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A. Modulation by Tonic Dopaminergic Activity
Unilateral 6-hydroxydopamine lesion of the ascending dopaminergic
projections results in up-regulation of striatal
D2 receptors (Seeman, 1981). In contrast,
unilateral dopaminergic lesions have been reported to produce a marked
decrease in both D3 receptor mRNA and
D3 receptor in the nucleus accumbens
(Lévesque et al., 1995). The decrease in the density of
D3 binding is consistent with a loss of
presynaptic sites. On the other hand, the concurrent decrease in
D3 receptor mRNA expression tends to indicate a
loss of D3-receptor-expressing cell bodies and
thus a probable decrease in postsynaptic sites. Although further study
may be required to fully understand the regulation of the
D3 site after dopaminergic lesions, it is clear
from this study that the regulation of D3 sites
is distinctly different from that of D2 receptor
sites.
In contrast to dopaminergic lesions, pharmacologically induced
depletion of catecholamines produced different results. Treatment with
reserpine for 5 days failed to alter expression of
D3 receptor mRNA (Lévesque et al., 1995).
On the other hand, acute depletion of catecholamines, using reserpine
and -methyl-tyrosine, produced an apparent increase in affinity of a
subset of putative D3 sites, as assessed by using
[3H]7-OH-DPAT, without an increase in the total
number of sites detected (Levant, 1995) (See Section III.B.). This
observation suggests the rapid up-regulation of
D3 sites in the absence of tonic dopaminergic
activity.
B. Modulation by Antidopaminergic Drugs
The fact that antidopaminergic drugs produce up-regulation of
D2 receptors is well-established (Seeman, 1981).
Because the D3 receptor has been proposed as a
potential antipsychotic site, there has been a great deal of interest
in whether antipsychotic drugs produce a similar up-regulation in
D3-sites. To date, several studies have been
performed, examining the effects of antipsychotic drugs on the
expression of D3 receptor mRNA with differing
results. Chronic treatment with haloperidol, sulpiride, and clozapine
has been reported to produce increases in
D3-receptor mRNA in whole brain of three to
five-fold as assessed by ribonuclease protection (Buckland et al.,
1992, 1993). More modest increases in D3 receptor mRNA (40-60%) were observed in olfactory tubercle after treatment with haloperidol and sulpiride, but not clozapine, for 14 days as
assessed by polymerase chain reaction (Wang et al., 1996). Other
studies, using different treatment paradigms, reported no change in
D3 receptor mRNA expression (Fishburn et al.,
1994; Fox et al., 1994; Lévesque et al., 1995) or
D3 binding (Lévesque et al., 1995).
Clearly, the conflicting results observed in these studies may result
from the different treatment paradigms used and must be resolved by
further study. Moreover, these studies did not assess whether the
observed antipsychotic-induced alterations in D3
receptor mRNA expression resulted in changes in the density or affinity
of D3 receptors.
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VIII. D3 Receptors and Disease |
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A. Genetic Linkage to Disease
In addition to the truncated forms of the D3
receptor believed to result from alternative splicing events (See
Section II.C.), several polymorphisms have been identified in the human
D3 receptor gene. The BalI, or
MscI, restriction fragment length polymorphism was first
identified by Lannfelt and colleagues (1992). This polymorphism corresponds to a point mutation in the 1st exon
of the D3 receptor gene, which results in a
serine-to-glycine substitution in the N-terminal extracellular domain
of the receptor. This mutation appears to result in receptors with
higher affinity for dopamine than wild-type receptors (Lundstrom and
Turpin, 1996). An additional polymorphism, the MspI, has
been localized to the 4th intron of the gene
(Sabaté et al., 1994).
Linkage studies have been performed in an attempt to establish the
involvement of the D3 receptor gene in the
pathogenesis of schizophrenia and other neuropsychiatric disorders.
These studies, which identify genes that exert a relatively large
effect on a particular phenotype in families containing affected
individuals, have failed to establish linkage of the
D3 receptor gene in schizophrenia (Coon et al.,
1993; Wiese et al., 1993; Nanko et al., 1994b; Sabaté et al.,
1994), bipolar disorder (Mitchell et al., 1993; Nanko et al., 1994a),
or Tourette syndrome (Brett et al., 1993, 1995).
Association studies, however, have suggested a possible contribution of
the D3 receptor gene in schizophrenia. These
studies compare the frequency of a given allele in unrelated persons of a given phenotype with a group of ethnically matched controls, with the
aim of identifying candidate genes involved in polygenic inheritance.
Initial studies identified an association between homozygosity for
either allele of the BalI polymorphism and schizophrenia in
French and English populations (Crocq et al., 1992), suggesting that
this gene may contribute to the susceptibility of developing the
disease. This finding has been supported by several subsequent studies
of subjects in the United Kingdom, France, and the United States,
particularly in patients with good response to antipsychotic treatment
(Mant et al., 1994; Kennedy et al., 1995; Griffon et al., 1996; Shaikh
et al., 1996). One study, however, found a positive association between
homozygosity and the BalI polymorphism only in male subjects
(Asherson et al., 1996), another only in patients with a familial
history of the disease (Nimgaonkar et al., 1993). Even so, an
association between BalI polymorphism and schizophrenia has
not been supported by several other studies of Chinese, Japanese, Swedish, German, British, Italian, and American populations (Jonsson et
al., 1993; Nanko et al., 1993; Yang et al., 1993; Di Bella et al.,
1994; Saha et al., 1994; Macciardi et al., 1994; Higuchi et al., 1995;
Gaitonde et al., 1996; Nimgaonkar et al., 1996; Rietschel et al., 1996;
Tanaka et al., 1996). No association has been detected between the
MspI polymorphism and schizophrenia (Dollfus et al., 1996;
Griffon et al., 1996).
Association studies have also examined the potential contribution of
the D3 receptor gene to susceptibility to bipolar
disorder. One study has indicated an increase in allele 1, containing
genotypes of the BalI polymorphism among bipolar families
(Parsian et al., 1995). Several other studies of European and Japanese
populations, however, have failed to detect an association between the
D3 receptor gene and this disorder (Rietschel et
al., 1993; Shaikh et al., 1993; Manki et al., 1996; Souery et al.,
1996). A lack of association with the D3 receptor
gene alleles has also been shown for alcoholism (Gorwood et al., 1995;
Higuchi et al., 1996), cocaine dependence (Freimer et al., 1996),
obsessive-compulsive disorder (Catalano et al., 1994), and Parkinson's
disease (Nanko et al., 1994c; Higuchi et al., 1995).
Although there is no clear relationship between
D3 receptor alleles and the predisposition toward
certain neuropsychiatric disorders, a recent study suggests a
relationship between D3 receptor genotypes and
monoaminergic transmission in the central nervous system.
Concentrations of 5-hydroxyindoleacetic acid in cerebrospinal fluid
were shown to differ significantly between subjects with D3-receptor homo- and heterozygote genotypes
(Jonsson et al., 1996). Although further study must support and extend
these observations, these studies, combined with studies of linkage and
association of D3 receptor alleles in
neuropsychiatric disorders, may ultimately contribute to our
understanding of the mechanism(s) by which certain genotypes may
contribute to the predisposition to diseases.
B. Receptor Alterations in Neuropsychiatric Disorders
Investigation into alterations in the expression of the
D3 receptor in disease is still in the early
stages. Accordingly, data available at present are relatively limited.
Initial studies examining the densities of the
D2-like dopamine receptors in postmortem putamen
tissues from schizophrenic patients using relatively nonselective radioligands suggested an elevation in D4 sites
but not in D2 or D3 sites
(Seeman et al., 1993). Another postmortem study of schizophrenic brain
reported that whereas normal subjects express mRNAs for both the
D3 receptor and the truncated splice variant D3nf, the parietal and motor cortices of
schizophrenic patients exhibited a selective loss of expression of
D3 receptor mRNA (Schmauss et al., 1993).
Investigation into alterations in the D3 receptor
in Parkinson's disease suggests that whereas decreases in expression
of D3 receptor mRNA are observed in certain brain
regions, such as the olfactory tubercle during aging (Valerio et al.,
1994), densities of both D3 receptor mRNA and
D3 binding are not altered in postmortem brain of
patients afflicted with Parkinson's disease (Hurley et al., 1996).
Although no significant alterations in D3
receptor expression in brain of Parkinson's patients have yet been
reported, a decrease in D3 receptor mRNA
expression in lymphocytes of Parkinson's patients has been observed.
In fact, the magnitude of the decrease in D3
receptor mRNA expression correlated with the severity of the disease
suggests that this might serve as a marker for monitoring disease
progression (Nagai et al., 1996). The detection of
D3 receptor mRNA in human lymphocytes, however,
has not been observed in some studies (Vile and Strange, 1996).
Finally, cocaine use has been reported to alter the density of the
D3 receptor. No changes in
D3 receptor mRNA expression were observed in the
dorsal or ventral striata of postmortem brain of chronic cocaine
abusers (Meador-Woodruff et al., 1995). However, the density of
D3 sites was observed to be increased from one to
three-fold in the caudate, nucleus accumbens, and substantia nigra of
persons who had died from cocaine overdose (Staley and Mash, 1996).
Clearly, investigation of alterations in the D3 receptor in disease is in the early stages. Further study must verify whether alterations in the density or the regulation of this receptor exist in various pathological conditions.
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IX. Conclusion |
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TopPreviousNextReferences
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In the short time since the identification of the 3rd dopamine receptor, considerable progress has been made toward understanding the function of this novel site. Although some avenues of investigation have yielded more definitive results than others, studies to date indicate the localization of the D3 receptor in limbic and vestibulocerebellar brain areas that affect locomotion and perhaps play a role in reinforcement and reward. A subpopulation of the receptors appears to be autoreceptors, which modulate dopamine synthesis, release, and neuronal activity. These observations have lead to the hypotheses that the D3 receptor may be an appropriate target in the treatment of neuropsychiatric disorders, such as schizophrenia and drug addiction. The role of D3 sites in disease, however, remains to be established. Genetic association of D3 receptor polymorphisms with neuropsychiatric disorders have been controversial. Nevertheless, alterations in expression of D3 sites may occur in some diseases. Though the study of this receptor is clearly in the early stages, these findings lay the foundation for future investigation. Further study may ultimately aid in the elucidation of the role of the D3 receptor in normo- and pathophysiology and its potential utility in the treatment of disease.
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Footnotes |
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a Address for correspondence: Beth Levant, Ph.D., Department of Pharmacology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160-7417.
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Abbreviations |
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CHO, Chinese hamster ovary; mRNA, messenger ribonucleic acid; 7-OH-DPAT, 7-hydroxy-dipropylaminotetralin; 7-OH-PIPAT, [125I](R)-trans-7-hydroxy-2-[N-propyl-N-]3'-iodo-2'-propenyl)amino]tetralin.
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both D2 and "silent" D3 autoreceptors control synthesis and release in mesolimbic, mesocortical and nigrostriatal pathways.
J. Pharmacol. Exp. Ther.
275: 899-913, 1995activation of postsynaptic D3 receptors mediates hypothermia, whereas blockade of D2 receptors elicits prolactin secretion and catalepsy.
J. Pharmacol. Exp. Ther.
275: 885-898, 1995b
receptor in the rat striatum and nucleus accumbens using (±)-7-hydroxy-N, N-di-n-[3H]propyl-2-aminotetralin and carbetapentane.
J. Neurochem.
64: 700-710, 1995[Medline].
0031-6997/97/4903-0231$03.00/0
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G. Di Giovanni, M. Di Mascio, V. Di Matteo, and E. Esposito Effects of Acute and Repeated Administration of Amisulpride, a Dopamine D2/D3 Receptor Antagonist, on the Electrical Activity of Midbrain Dopaminergic Neurons J. Pharmacol. Exp. Ther., October 1, 1998; 287(1): 51 - 57. [Abstract] [Full Text]
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V. Audinot, A. Newman-Tancredi, A. Gobert, J.-M. Rivet, M. Brocco, F. Lejeune, L. Gluck, I. Desposte, K. Bervoets, A. Dekeyne, et al. A Comparative In Vitro and In Vivo Pharmacological Characterization of the Novel Dopamine D3 Receptor Antagonists (+)-S 14297, Nafadotride, GR 103,691 and U 99194 J. Pharmacol. Exp. Ther., October 1, 1998; 287(1): 187 - 197. [Abstract] [Full Text]
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M. J. Millan, A. Gobert, A. Newman-Tancredi, V. Audinot, F. Lejeune, J.-M. Rivet, D. Cussac, J.-P. Nicolas, O. Muller, and G. Lavielle S 16924 ((R)-2-{1-[2-(2,3-Dihydro-Benzo[1,4] Dioxin-5-Yloxy)-Ethyl]-Pyrrolidin-3yl}-1-(4-Fluoro-Phenyl)-Ethanone), a Novel, Potential Antipsychotic with Marked Serotonin (5-HT)1A Agonist Properties: I. Receptorial and Neurochemical Profile in Comparison with Clozapine and Haloperidol J. Pharmacol. Exp. Ther., September 1, 1998; 286(3): 1341 - 1355. [Abstract] [Full Text]
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T. Ilani, D. Ben-Shachar, R. D. Strous, M. Mazor, A. Sheinkman, M. Kotler, and S. Fuchs A peripheral marker for schizophrenia: Increased levels of D3 dopamine receptor mRNA in blood lymphocytes PNAS, January 16, 2001; 98(2): 625 - 628. [Abstract] [Full Text] [PDF]
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