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Vol. 281, Issue 1, 597-603, 1997
Section of Neurobiology (M.S.L., P.S.G.) and Department of Pharmacology (J.D.L.), Yale University School of Medicine, New Haven, Connecticut
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Abstract |
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 Top
Abstract
Introduction
Methods
Results
Discussion
References
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D2 dopamine receptor antagonism is postulated to be the key to
antipsychotic efficacy in the treatment of schizophrenia. Yet the D1
dopamine family of receptors is far more prevalent in the cortical
areas of the brain, such as the prefrontal cortex, which have
frequently been implicated in schizophrenia. Moreover, the prefrontal
cortical D1 sites have recently been shown to be down-regulated by
chronic treatment with several commonly used antipsychotic drugs (Lidow
and Goldman-Rakic, 1994
). To provide further insight into the
pharmacological regulation of the D1 class of dopaminergic receptors,
we have now used ribonuclease protection assays to examine the
regulation of D1 and D5 dopamine receptor mRNAs in the prefrontal
cortex and the neostriatum of nonhuman primates after chronic treatment
with eight different drugs representing a wide structural and
pharmacological spectrum of antipsychotic medications. The medications
were administered for 6 months twice daily at doses that fall within
the therapeutic range recommended for human patients. The study also
included a substituted benzamide, tiapride, which is a D2 antagonist
like the eight aforementioned drugs but reportedly lacks antipsychotic
activity. Remarkably, all drugs used in this study, including tiapride,
down-regulated the levels of both D1 and D5 mRNAs in the prefrontal
cortex by 30% to 60% compared with a vehicle control group, whereas
mRNAs in the neostriatum were not affected. This observation indicates that a reduction in the levels of prefrontal cortical dopamine receptors of the D1 class may be an obligatory consequence of D2
receptor antagonism and thus may be a pharmacological property of
antipsychotic drugs.
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Introduction |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Since the late seventies, the
efficacy of antipsychotic drugs in the treatment of schizophrenia has
been generally attributable to their D2 dopamine receptor antagonism
(Seeman et al., 1975; Creese et al., 1976), and
new drug development has largely focused on this class of receptors and
on their regulation in subcortical structures where they are present in
the high density (Creese et al., 1990; Angulo et
al., 1991; Matsunaga et al., 1991; Xu et
al., 1991; Kopp et al., 1992; Egan et al.,
1994; Fishburn et al., 1994; Fox et al., 1994).
In light of the mounting evidence for the involvement of the cerebral
cortex in schizophrenia (Weinberger, 1988; Davies et al.,
1991; Goldman-Rakic, 1987; 1991; Goldman-Rakic et al., 1992;
Selemon et al., 1995), we recently used quantitative autoradiography to examine the regulation of dopaminergic receptors in
the cortex of nonhuman primates after chronic treatment with three
different antipsychotic drugs: haloperidol, remoxipride and clozapine
(Lidow and Goldman-Rakic, 1994). These drugs were found to have a
common regulatory effect on dopaminergic receptors in the cortex but
not on those in the caudate nucleus. In particular, 6 months of daily
treatment with all three antipsychotics resulted in a substantial
decrease in the density of dopaminergic receptors of the D1 class in
the prefrontal and temporal cortices, the two regions often implicated
in schizophrenia (Goldman-Rakic, 1991; Shenton et al., 1992;
Selemon et al., 1995). On the basis of this finding we
suggested that the down-regulation of cortical D1 sites may be an
important component of response to antipsychotic drugs (Lidow and
Goldman-Rakic, 1994).
In order to gain further insight into D1 receptor regulation by antipsychotic medications, we have expanded our analysis to establish whether down-regulation of the D1 receptor class is a characteristic of all antipsychotic agents or is specific to the three drugs previously examined. We also wished to determine whether both the D1 and the D5 subtypes of the D1 receptor class are equally affected. Finally, we were interested in learning whether drug-induced down-regulation of cortical D1 receptors reflects changes in the level of receptor mRNAs. To achieve these goals, we used ribonuclease protection assays to measure levels of cortical and neostriatal mRNAs encoding the D1 and D5 receptors after chronic treatment with an array of drugs representing a wide structural and pharmacological spectrum of antipsychotic medications.
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Material and Methods |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Drugs.
The eight antipsychotic drugs examined in this study
were selected to represent the major chemical classes of antipsychotic drugs, including those with both typical [such as haloperidol, chlorpromazine, molindone (Physicians' Desk Reference., 1996)] and
atypical [such as clozapine, olanzapine, risperidone (Physicians' Desk Reference., 1996; Moore et al., 1994; Janssen et
al., 1988)] profiles. Whereas all of these drugs have high
affinities for the dopamine receptor subtypes that belong to the D2
class (Janssen et al., 1988; Seeman, 1992), some of them,
such as olanzepine, also have high affinities for the receptors of the
D1 class (Moore et al., 1994). In addition to the
above-mentioned antipsychotic drugs, tiapride was included in the study
as a drug that has high affinity for receptors of the D2 class but
reportedly exhibits little or no antipsychotic activity at conventional
doses (table 1) (Eggers et al., 1988).
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).
Drug treatment.
A total of 22 rhesus monkeys (Macaca
mulatta), 3 to 5 years of age, were studied. Each of the nine drugs
examined in this study was given to two monkeys at daily doses that
fell within the common therapeutic range (table 1) (Physicians' Desk
Reference., 1996; Moore et al., 1994; Burma et
al., 1982; Pflug et al., 1990)]. The drugs were given
p.o. (in fruit treats) twice a day for 6 months to approximate
maintenance regimens in clinical practice (Hyman and Arana, 1987). The
same treatment period was used in our previous study (Lidow and
Goldman-Rakic, 1994). Four animals constituted a control group that
received daily fruit treats only. During the entire 6 months of
treatment, none of the animals displayed behavioral abnormalities
attributable to the actions of the drugs. Neither did we observe drug
effects on blood hematocrit, total white cell count or hemoglobin
level.
)] and the neostriatum (head and body of
the caudate nucleus and putamen) were dissected out and immersed in
liquid nitrogen for storage.
Synthesis of the riboprobes. The D1 and D5 riboprobes employed in this study and the tests of their specificity are described in detail in Lidow et al. (in press). They were fragments of the 32P-RNA complementary to the 228- and 335-base-long sequences from the third cytoplasmic loop of D1 and D5 dopamine receptor mRNAs, respectively.
The radiolabeled riboprobes were produced by in vitro transcription of linearized plasmids containing fragments of D1 or D5 receptor cDNA using an Ambion MAXIscript Kit (Ambion, Inc., Austin, TX). In brief, 1 µg of linearized plasmid DNA was added to a tube containing 2 µl 10X transcription buffer, 1 µl 200 mM dithiothretol, 1 µl RNase inhibitor (12.5 U/µl), 3 µl nucleotide mix (10 mM each of ATP, GTP and UTP), 5 µl 32P-CTP (800 Ci/mM, 10 mCi/ml; Du Pont, Inc., Wilmington, DE). RNase-free sterile water was added to bring the final volume to 20 µl. Finally, 1 µl (10 U) of T7 RNA polymerase was added. The mixture was vortexed, incubated for 1 hr at 37°C and then added to an equal volume of solution containing 80% formamide, 0.1% xylene cyanol, 0.1% bromophenol blue and 2 mM EDTA. The resulting solution was heated at 90°C for 5 min and loaded on a 5% polyacrylamide gel in order to separate the full-length riboprobes, which were eluted from the gel at 37°C overnight with buffer containing 0.5 M ammonium acetate, 1 mM EDTA and 0.2% SDS. Riboprobes for human
-actin mRNA and 18S rRNA
(183 bases long and 82 bases long, respectively), employed as loading
standards, were produced using vectors obtained from Ambion, Inc.
(Austin, TX). The protocols for their synthesis and purification were
similar to those described above. The only exceptions were that in the
case of the -actin riboprobe, 1.5 µl 32P-CTP (800 Ci/mM, 10 mCi/ml) and 2 µl 1 mM cold CTP, and in the case of the 18S
riboprobe, 4 µl 32P-CTP (800 mCi/µM, 100 µCi/ml) and
1 µl 10 mM cold CTP, were added to the synthetic mixture.
32P-RNA molecular weight markers were synthesized using a
Century Marker Template Set (Ambion, Inc.) according to the protocol described in the instruction supplied with this set. Upon completion of
the synthetic reaction, the marker template DNA was digested with 2 U
DNase at 37°C (15 min), and 32P-RNA markers were
extracted with phenol-chloroform and precipitated with ethanol.
Extraction of the total RNA. Total RNA was extracted from the prefrontal cortical and the neostriatal tissue with an RNA STAT-60 reagent (TEL-TEST"B", Inc., Friendswood, TX). For this purpose, the tissue was homogenized in the above-mentioned reagent (1 ml per 100 mg tissue). Then chloroform was added (0.2 ml of chloroform per milliliter of homogenate), and the mixture centrifuged for 15 min at 12,000 × g and 4°C. After the centrifugation, the upper aqueous phase was precipitated with isopropanol (0.5 ml of isopropanol per milliliter of the aqueous phase) at room temperature for 5 min. After another centrifugation (15 min, 12,000 × g; 4°C), the RNA pellet was washed with 75% ethanol and dissolved in diethylopyrocarbonate-treated distilled water. The RNA was quantitated by measuring its absorbance at 260 nm. The ratios of 260/280 nm were usually over 2.0.
Ribonuclease protection assay.
The ribonuclease protection
assay was performed using an Ambion RPAII Kit. For both the neostriatum
and the cortex of every animal, the assay was performed in triplicate.
For the assay, 80,000 cpm of D1 32P-riboprobe, 80,000 cpm
of D5 32P-riboprobe, 10,000 cpm of
32P--actin riboprobe and 10,000 cpm 18S
32P-riboprobe were added to 80 µg of total RNA in water.
The mixture was precipitated by adding 0.1 volume of 5.0 M ammonium
acetate and 2.5 volumes of ethanol at 
20°C (15 min) and centrifuged
(15 min; 12,000 × g; 4°C). The pellet was hybridized
in 20 µl of buffer containing 80% deionized formamide, 100 mM sodium
citrate, 300 mM sodium acetate and 1 mM EDTA (pH 6.4) for 16 hr at
45°C. After hybridization, 0.5 U RNase A and 20 U RNase T1 were
added. Samples were incubated at 37°C for 30 min to digest
unhybridized RNA. The protected RNA fragments were precipitated,
denatured by heating at 90°C for 5 min and separated on a 5%
polyacrylamide gel. The 3000 cpm of 32P-RNA marker was
loaded on the same gel. To make possible a comparison of the data
obtained from different runs, one of the samples on each gel was a
repeat from another gel. The negative control consisted of 80 µg of
east RNA processed as described for total brain RNA. The gels were
dried for 1 hr at 70°C on a Drygel Sr. Vacuum Gel Drier (Hoefer
Scientific Instruments, San Francisco, CA). They were then placed in a
PhosphorImager SI (Molecular Dynamics, Sunnyvale, CA) for 8 hr, and the
radioactivity of each line containing D1, D5, -actin and 18S
riboprobes was measured. After that, the gels were apposed for 2 days
at 70°C to X-OMAT AR film (Eastman Kodak Co., Rochester, NY) with
intensifying screen in order to obtain a permanent visual record of the
results.
-actin and 18S
riboprobes. The final results were the mean values ± S.E.M. of
all repeats within each animal group (n = 6 for
drug-treated groups and n = 12 for control group). The
data for control and for each of the treated groups were compared with
two-tailed Student's t tests.
HPLC.
A single tissue sample from the neostriatum and a
single tissue sample from the prefrontal cortex of each animal were
sonicated in ice-cold 0.1 M perchloric acid containing 0.13 mM
EDTA and dihydroxybenzylamine as internal standard. They were than
centrifuged at 23,000 × g for 20 min at 4°C. The
pellets were saved for protein determination by the method of Lowry
et al. (1951). The supernatants were removed and analyzed by
HPLC. An aliquot (50 µl) of each sample was separated on
reverse-phase column (10 cm × 3.2 mm Phase II ODS-3,
Bioanalitical Systems Inc., West Lafayette, IN) under isocratic
conditions. The mobile phase, delivered at 0.3 ml/min, comprised sodium
citrate (30 mM), sodium dihydrogen phosphate (14 mM), sodium
octanesulphonate (2.3 mM), EDTA (0.025 mM), acetonitrile (6.5%),
tetrahydrofuran (0.6%) and diethylamine (0.1%) at pH 3.1. An
electrochemical detector (Bioanalitical Systems Inc.) was used at a
potential of 0.7 V, and the retention time was 20 min to resolve
dopamine and HVA. Quantification was achieved by dividing the peak
height of the unknown by that of the internal standard and referring
this ratio to an external standard.
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Results |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Evaluation of the levels of mRNAs encoding D1 and D5 dopamine
receptors with ribonuclease protection assay.
Observation of the
film autoradiograms and of images generated by the PhosphoImager
revealed that the ribonuclease protection assay of the brain RNAs
employed in this study generated gels with four major bands with
molecular weights corresponding to those of the D1, D5, -actin and
18S riboprobes (fig. 1). Identical assays of yeast RNA
resulted in gels without bands (the negative control is not shown).
These results indicate that our riboprobes are appropriate for the
ribonuclease protection assay of macaque RNA and can be used for
quantitative analysis of their specific targets in tissue.
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-actin mRNA as well as to 18S
rRNA. The data obtained by both of these methods showed that all
drug-treated animals expressed 30% to 60% lower levels of D1 receptor
mRNA than animals in the control group (fig. 2A).
Similar decrements were also observed for D5 receptor mRNA (fig. 2B).
Among the drugs examined, risperidone produced the greatest decrease in
both dopamine receptor mRNAs, and olanzepine produced the least
reduction (fig. 2). The nonantipsychotic D2 antagonist tiapride
down-regulated D1 and D5 mRNAs to levels comparable to those in
remoxipride- and molindone-treated animals (fig. 2). For all drugs, the
decrease in the levels of cortical D1 and D5 receptor mRNAs was
statistically significant (P < .05).
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Evaluation of the dopamine turnover with HPLC.
In order to
evaluate dopamine turnover, we calculated levels of HVA and
HVA/dopamine ratios in the neostriatum and prefrontal cortex (Scatton,
1977; Bacopoulos et al., 1979; Essig et al., 1991). Table 2 shows the data obtained from each animal
used in this study. It is clear from this table that the drugs examined in the present study did not produce similar changes in either HVA
levels or HVA/dopamine ratios. Rather, the effects on basal dopamine
turnover in both the neostriatum and the prefrontal cortex were
variable. For example, in the neostriatum, molindone increased the HVA
level and the HVA/dopamine ratio in both treated animals compared with
controls, whereas exposure to pimozide decreased these parameters. In
the cortex, all the animals of the chlorpromazine-treated group had
increased dopamine turnover, whereas animals in the haloperidol-exposed
group had decreased dopamine turnover.
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Discussion |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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D1 and D5 mRNA regulation in the prefrontal cortex and
neostriatum.
This study provides strong support for our earlier
proposal that down-regulation of D1 dopamine receptors in the primate
prefrontal cortex is a highly consistent consequence of prolonged
treatment with antipsychotic drugs (Lidow and Goldman-Rakic, 1994). It
clearly demonstrates that chronic treatment with the multiple
antipsychotic drugs tested in this study produces a down-regulation of
the levels of both D1 and D5 dopamine receptor mRNAs in the monkey
prefrontal cortex. The very similar levels of down-regulation of
cortical D1 and D5 mRNAs, whether calculated using dopamine receptor
mRNA/-actin mRNA ratios or dopamine receptor mRNA/18S rRNA ratios,
make it unlikely that the detected changes are related to unexpected
drug regulation of the levels of the loading standard RNAs rather than the levels of D1 and D5 mRNA. Further, the reliability of the present
results is not compromised by the small number of monkeys that received
each drug, because all drug-treated animals showed a very clear
decrease in the level of prefrontal cortical D1 and D5 messages
relative to the control group.
; MacKenzie and Zigmond, 1985; Hess et
al., 1988; Lappalainen et al., 1990). There are
several reports that clozapine can up-regulate neostriatal D1 sites
(Rupniak et al., 1985; O'Dell et al., 1990; See
et al., 1990). Our results support the studies that show no
clozapine-related effects at these sites (Ashby et al.,
1989; Jiang et al., 1990). However, it is possible that
clozapine up-regulates subcortical D1 sites only under specific
conditions not fulfilled in our study. Furthermore, the possibility
that clozapine regulates the synthesis and degradation of D1 and D5
proteins in the basal ganglia without affecting mRNA levels cannot be
ruled out; such an effect would not be detected by the ribonuclease
protection assay.
The marked similarity between the nonhuman primate brain and the human
brain suggests that the results obtained in the present study may be
relevant to chronic antipsychotic treatment of patients suffering from
schizophrenia. Indeed, the somewhat faster metabolism and excretion of
antipsychotic drugs in monkeys than in humans (Stafford et
al., 1981; Lidow and Goldman-Rakic, unpublished) suggest that the
same doses of drugs may produce greater changes in the dopamine
receptor mRNA levels in humans than in monkeys. Additionally, it should
be emphasized that down-regulation of D1 and D5 mRNA was produced not
only by the antipsychotically active drugs but also by the presumably
nonantipsychotic D2 antagonist tiapride. This finding indicates that
the regulation of mRNAs encoding the D1 dopamine receptor class in the
prefrontal cortex may be more a function of D2 antagonism than of the
ability of these drugs to counteract the florid symptoms of
schizophrenia. This down-regulatory activity is apparently quite
powerful, because it is capable of overriding the D1 up-regulatory
potential of drugs such as olanzapine that have a high affinity not
only for the D2 but also for the D1 receptor class (Moore et
al., 1994). It is of interest that the observed decrease in the
level of cortical D1 sites appears to require prolonged treatment with
D2 antagonists; we have not observed down-regulation of these receptors
after only 1 month of exposure to haloperidol, remoxipride and
clozapine (Lidow and Goldman-Rakic, in preparation).
Possible mechanisms of drug-induced down-regulation of cortical D1
receptors.
All drugs used in this study are antagonists of the D2
receptor class and have been shown to up-regulate cortical D2 sites (Janssen et al., 1988; Seeman, 1992; Lidow and
Goldman-Rakic, 1994). A plausible mechanism by which D2 antagonists
used in this study could reduce the levels of the prefrontal cortical
D1 and D5 receptors is a compensatory reaction of these receptors to an
increase in cortical dopamine release resulting from the blockade of D2
pre- and postsynaptic sites (Lidow and Goldman-Rakic, 1994). The
neostriatal D1 and D5 receptors may not be down-regulated, because, in
contrast to the cortical dopaminergic system, the neostriatal
dopaminergic innervation quickly develops tolerance to chronic D2
antagonist treatment (Scatton, 1977; Bacopoulos et al.,
1979; Lappalainen et al., 1990; Essig et al.,
1991; Parsons et al., 1993). However, we failed to find a
consistent pattern of change in either cortical or neostriatal basal
dopamine turnover resulting from chronic treatment with the drugs used
in this study. This may indicate that in monkey, both neostriatal and
cortical dopaminergic systems develop tolerance to prolonged drug
treatment (Bacopoulos et al., 1979) and that the
down-regulation of cortical D1 sites may not be a response to an
increase in dopamine levels in this tissue. This conclusion must be
tempered, however, by the fact that animals sacrificed 18 hr after the
last drug administration can provide only a measure of basal dopamine
turnover (Grace, 1991). An in vivo examination of changes in
levels of dopamine and its metabolites within several hours after daily
drug treatments may be more relevant for understanding whether D2
antagonists can affect cortical D1 sites through regulation of dopamine
release.
; Creese and Hess, 1986). A strong interaction
between D1 and D2 second messenger systems is well established (Seeman
et al., 1989; Strange, 1991), so it is conceivable that an
increase in the sensitivity of D2-associated adenylate cyclase would be
accompanied by an increase in the sensitivity of the D1-coupled enzyme,
which, in turn, would constitute a signal for down-regulation of the D1
receptor class (Lidow and Goldman-Rakic, 1994; Creese and Hess, 1986).
D1 receptor regulation and cognition.
The present findings may
be pertinent to understanding the effect of antipsychotic drugs on the
cognitive impairments that are characteristic of schizophrenia (Taylor
and Abrams, 1984; Goldman-Rakic, 1987; 1991; Weinberger, 1988; King,
1990). It is widely believed that antipsychotic drugs have little
impact on cognitive function in schizophrenia (Berman et
al., 1986; Classen and Laux, 1988; Tomer and Flor-Hendry, 1989).
However, a review of the literature (King, 1990; Hindmarch, 1994) shows
rather that neuroleptics have inconsistent effects on cognitive
performance, often either improving or worsening it. The poor or
inconsistent outcomes of antipsychotic treatment may perhaps be
explained by taking into account their effect on D1 receptors as well
as D2 receptors, particularly because the levels of D1 receptors have recently been reported to be lowered in drug-naive schizophrenics (Sedvall and Farde, 1996). If D1 sites are further reduced because of
drug treatment, as the present experimental study in nonhuman primates
shows, it is possible that the number of D1 sites is suboptimal for
cortical function. D1 stimulation in a narrow range of occupancy has
recently been shown to optimize physiological signaling in prefrontal
neurons engaged by working memory in nonhuman primates, whereas too
little D1 stimulation (due to excessive blockade of the receptor)
resulted in diminished neuronal activation (Williams and Goldman-Rakic,
1995). Because there are strong indications that impairment of working
memory is one of the major deficits underlying the cognitive
impairments of schizophrenia (Goldman-Rakic, 1987, 1991; Weinberger,
1988), these various findings raise the possibility that antipsychotics
may either improve, worsen or have no effect on cognitive performance
in schizophrenia, depending on how they regulate the levels of
prefrontal cortical D1 sites in relation to the optimal range. Similar
considerations could be raised with regard to the action of
antipsychotic drugs on the negative symptoms of schizophrenia, which,
according to a number of investigators (Johnstone et al.,
1978; Andreasen and Olsen, 1982; Bilder et al., 1985;
McKenna et al., 1989; Meltzer and Zureick, 1989), are
closely associated with cognitive abnormalities and which, like
cognitive deficits, do not show consistent improvement with presently
available drug treatments (Moller, 1993; Lindenmayer, 1995).
Furthermore, D1-specific drugs have been reported to affect the
negative symptoms without having any significant influence on the
positive symptoms of the disease (Davidson, et al., 1990; De Boer, 1995; Karle et al., 1995). Altogether, these
findings suggest that, although the ability to down-regulate cortical
D1 receptors may not be a unique feature of antipsychotic drugs, but
rather an effect associated with D2 antagonism, this ability is
nevertheless common to all presently effective antipsychotic agents and
so may have important implications for their therapeutic effects. In
evaluating the regulatory actions of antipsychotic treatments,
investigators should therefore give greater consideration to changes in
prefrontal cortical D1 receptors, and future antipsychotic treatments
might be designed to provide optimal stimulation of cortical D1 sites
as well as to antagonize D2 receptors.
| |
Acknowledgments |
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We thank Yang Cao for her excellent technical assistance.
The following drugs were kindly provided by the sources indicated: chlorpromazine (Smith Kline Beecham Pharmaceuticals, Pittsburgh, PA), clozapine (Sandoz Pharmaceutical Co., East Hanover, NJ), haloperidol (McNeil Pharmaceutical Co., Spring House, PA), molindone (Du Pont Co., Wilmington, DE), olanzapine (Eli Lilly Co., Indianapolis, IN), pimozide (Gate Pharmaceuticals, Sellersville, PA), remoxipride (Astra Pharmaceutical Co., Sodertalje, Sweden), risperidone (Janssen Pharmaceutical Co., Titusville, NJ) and tiapride (Synthelabo Co., Secaucus, NY).
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Footnotes |
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Accepted for publication December 10, 1996.
Received for publication August 5, 1996.
1 This work was supported by the NIMH Center Grant P50-MH44866.
Send reprint requests to: Michael S. Lidow, Ph.D., Department of Oral and Craniofacial Biological Sciences, University of Maryland at Baltimore, 5-A-12, HHH, 666 West Baltimore Street, Baltimore, MD 21201.
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Abbreviations |
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mRNA, messenger ribonucleic acid; rRNA, ribosomal ribonucleic acid; cDNA, cloned deoxyribonucleic acid; UTP, uridine triphosphate; CTP, cytidine triphosphate; RNase, ribonuclease; DNase deoxyribonuclease, SDS, sodium dodecyl sulfate; HVA, homovanillic acid.
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References |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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M. A. Kelly, M. Rubinstein, T. J. Phillips, C. N. Lessov, S. Burkhart-Kasch, G. Zhang, J. R. Bunzow, Y. Fang, G. A. Gerhardt, D. K. Grandy, et al. Locomotor Activity in D2 Dopamine Receptor-Deficient Mice Is Determined by Gene Dosage, Genetic Background, and Developmental Adaptations J. Neurosci., May 1, 1998; 18(9): 3470 - 3479. [Abstract] [Full Text] [PDF]
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and one
nonantipsychotic drug 
. The main graphs represent dopamine receptor
mRNA/