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THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics
JPET 297:711–717, 2001
Vol. 297, No. 2
3387/901353
Printed in U.S.A.
Long-Term Effects of Olanzapine, Risperidone, and Quetiapine
on Dopamine Receptor Types in Regions of Rat Brain:
Implications for Antipsychotic Drug Treatment
FRANK I. TARAZI, KEHONG ZHANG, and ROSS J. BALDESSARINI
Mailman Research Center, McLean Division of Massachusetts General Hospital, Belmont, Massachusetts; and Consolidated Department of
Psychiatry & Neuroscience Program, Harvard Medical School, Boston, Massachusetts
Received September 29, 2000; accepted January 31, 2001
This paper is available online at http://jpet.aspetjournals.org
Dopamine (DA) exerts its effects in mammalian brain by
interacting with several DA receptor types that include D1like (D1, D5) and D2-like (D2, D3, D4) receptor families
(Baldessarini and Tarazi, 1996). DA receptors, and particularly the D2-like family, have been implicated in the pathophysiology of psychotic disorders and, more directly, in the
pharmacodynamic basis of beneficial effects of antipsychotic
drugs (Baldessarini and Tarazi, 2001). They are also implicated in centrally mediated adverse effects typical of most
neuroleptic-antipsychotics, including extrapyramidal neurological reactions (particularly, parkinsonism and tardive dyskinesia) and hyperprolactinemia (Baldessarini and Tarsy,
1980; Baldessarini and Tarazi, 2001).
The introduction of the prototype “atypical” antipsychotic
agent clozapine was a major step in developing drugs with
less risk of the adverse neurological effects that are typical of
This work was supported by National Alliance for Research on Schizophrenia and Depression Young Investigator Award, The Grable Foundation, and a
research award from Eli Lilly Corporation (F.I.T.), National Institutes of
Health Grants MH-34006 and MH-47370, a grant from the Bruce J. Anderson
Foundation, and funds of the McLean Private Donors Neuropharmacology
Research Fund (R.J.B.).
(65%, 32%), and HIP (61%, 37%). D1-like and D3 receptors in
all regions were unaltered by any treatment, suggesting their
minimal role in mediating actions of these antipsychotics. The
findings support the hypothesis that antipsychotic effects of
olanzapine and risperidone are partly mediated by D2 receptors
in MPC, NAc, or HIP, and perhaps D4 receptors in CPu, NAc, or
HIP, but not in cerebral cortex. Selective up-regulation of D2
receptors by olanzapine and risperidone in CPu may reflect
their ability to induce some extrapyramidal effects. Inability of
quetiapine to alter DA receptors suggests that nondopaminergic mechanisms contribute to its antipsychotic effects.
standard antipsychotics but with similar or even superior
beneficial effects. Clozapine is usually well tolerated, with
very limited adverse extrapyramidal signs (EPS) or hyperprolactinemia and substantial evidence of superior antipsychotic effectiveness (Baldessarini and Frankenburg, 1991;
Brunello et al., 1995). The pharmacological basis of the unusual clinical properties of this unique agent remains unclear. Clozapine interacts with high or moderate potency at
serotonergic (5-HT2A, 5-HT2C, and others), acetylcholinergic
(muscarinic), adrenergic (␣1, ␣2, ␤2), histaminic (H1), and
other neurohumor receptors. In contrast, it has only moderate affinity for both D1 and D2 DA receptors (Baldessarini
and Frankenburg, 1991; Brunello et al., 1995; Baldessarini
and Tarazi, 1996).
Clozapine also displays somewhat greater affinity for D4
than other DA receptors (Van Tol et al., 1991), suggesting
that these receptors may represent potential sites of action of
clozapine and perhaps other antipsychotic agents. D4 receptors also may be increased in postmortem brain tissue of
schizophrenic patients (Seeman et al., 1993; Murray et al.,
1995), although these findings remain inconsistent (Lahti et
al., 1996). In addition, repeated administration of clozapine,
ABBREVIATIONS: DA, dopamine; CPu, caudate-putamen; DFC, dorsolateral-frontal cerebral cortex; EC, entorhinal cortex; HIP, hippocampus;
MPC, mesioprefrontal cortex; NAc, nucleus accumbens septi (core and shell subdivisions); EPS, extrapyramidal signs; 7-OH-DPAT, R(⫹)-[2,33
H]7-hydroxy-N,N-di-n-propyl-2-amino-1,2,3,4-tetrahydronaphthalene; DTG, 1,3-ditolylguanidine; RT, room temperature; SCH-23390, R(⫹)-[Nmethyl-3H]7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
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ABSTRACT
Changes in members of the dopamine (DA) D1-like (D1, D5) and
D2-like (D2, D3, D4) receptor families in rat forebrain regions
were compared by quantitative in vitro receptor autoradiography after prolonged treatment (28 days) with the atypical antipsychotics olanzapine, risperidone, and quetiapine. Olanzapine
and risperidone, but not quetiapine, significantly increased D2
binding in medial prefrontal cortex (MPC; 67% and 34%), caudate-putamen (CPu; average 42%, 25%), nucleus accumbens
(NAc; 37%, 28%), and hippocampus (HIP; 53%, 30%). Olanzapine and risperidone, but not quetiapine, produced even
greater up-regulation of D4 receptors in CPu (61%, 37%), NAc
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Tarazi et al.
Experimental Procedures
Materials and Animal Subjects
Radioligands were from NEN Life Science Products, Inc. (Boston,
MA): R,S(⫾)-[N-methyl- 3 H]nemonapride (86 Ci/mmol), S(⫺)[methoxy-3H]raclopride (74 Ci/mmol), and R(⫹)-[N-methyl-3H]7-chloro8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine
(SCH-23390; 81 Ci/mmol); or from Amersham (Arlington Heights, IL):
R(⫹)-[2,3-3H]7-hydroxy-N,N-di-n-propyl-2-amino-1,2,3,4-tetrahydronaphthalene (7-OH-DPAT; 116 Ci/mmol). Tritium-sensitive Hyper-
films were from Amersham. D-19 photographic developer and fixative
were from Eastman Kodak (Rochester, NY).
Donated drugs included olanzapine (Eli Lilly, Indianapolis, IN),
risperidone (Janssen, Beerse, Belgium), and quetiapine fumarate
(Zeneca, Cheshire, UK). 1,3-Ditolylguanidine (DTG), S(⫺)-eticlopride hydrochloride, cis-flupenthixol dihydrochloride, fluphenazine
dihydrochloride, ketanserin tartrate, pindolol, and S(⫺)-sulpiride
were purchased from RBI-Sigma (Natick, MA). Cation hydrochlorides, guanosine-5⬘-triphosphate sodium (GTP), and tris-(hydroxymethyl)-aminomethane (Tris) hydrochloride were from Sigma (St.
Louis, MO).
Animals were male Sprague-Dawley rats (Charles River Laboratories, Wilmington, MA), initially weighing 200 to 225 g, maintained
under artificial daylight (on, 7:00 AM–7:00 PM) in a temperatureand humidity-controlled environment with free access to standard
rat chow and tap water in a USDA-inspected, veterinarian-supervised, small-animal research facility of the Mailman Research Center of McLean Hospital. Animal procedures were approved by the
Institutional Animal Care and Use Committee (IACUC) of McLean
Hospital, in compliance with pertinent federal and state regulations.
Drug Treatment and Tissue Preparation
Four groups (N ⫽ 7) of rats received control vehicle, olanzapine
(5.0 mg/kg/day), risperidone (3.0 mg/kg/day), or quetiapine fumarate
(10.0 mg/kg/day) by osmotic minipumps (Alzet, Palo Alto, CA) implanted subcutaneously to ensure continuous and steady infusion of
drugs and overcome variations in tissue drug levels that would result
from daily injections. Doses are based on typical behaviorally active
doses in rats (Moore et al., 1992; Ellenbroek et al., 1996). After 4
weeks of treatment, rats were decapitated; brains were removed,
quick-frozen in isopentane on dry ice, and stored at ⫺80°C until
autoradiographic analysis. Frozen coronal sections (10 ␮m) were cut
in a cryostat at ⫺20°C, mounted on gelatin-coated microscopic slides,
and stored at ⫺80°C until use. Tissue sections were obtained from
CPu, NAc, hippocampus (HIP); areas of cerebral cortex including
dorsolateral-frontal (DFC) and mesioprefrontal (MPC), and entorhinal (EC) regions; islands of Calleja including the major island, and
the olfactory tubercle. These selected cortical, limbic, and extrapyramidal brain regions mediate cognitive, emotional, and motor behaviors that are typically disturbed in patients with psychotic disorders and altered by antipsychotic drug treatment (Benes, 2000;
Baldessarini and Tarazi, 2001).
Receptor Autoradiography
Brain sections from all drug-treated rats were evaluated at the
same time in each radioreceptor assay to minimize experimental
variability. Sections were first preincubated for 1 h at room temperature (RT) in 50 mM Tris-HCl buffer (pH 7.4) containing (mM): NaCl
(120), KCl (5), CaCl2 (2), and MgCl2 (1), for the D1-like, D2, and D4
assays, or with slight modification for D3 assays (with 0.3 mM GTP,
40 mM NaCl, and no MgCl2 added).
D1-Like Receptors. Rat forebrain sections were incubated for 1 h
at RT in the incubating buffer containing 1 nM [3H]SCH-23390 with
100 nM ketanserin to block 5-HT2A/2C receptors. Nonspecific binding
was determined with excess (1 ␮M) cis-flupenthixol. After incubation, slides were washed twice for 5 min in ice-cold buffer, dipped in
ice-cold water, and dried under a stream of air (Florijn et al., 1997;
Tarazi et al., 1997a, 1998).
D2 Receptors. Sections were incubated for 1 h at RT in the same
buffer containing 1.0 nM [3H]nemonapride with 0.5 ␮M DTG and 0.1
␮M pindolol to mask sigma (␴1,2) and 5-HT1A sites, respectively.
Nonspecific binding was determined with 10 ␮M S(⫺)-sulpiride.
After incubation, slides were washed twice for 5 min in ice-cold
buffer, dipped in ice-cold water, and air-dried (Tarazi et al., 1997b,c,
1998). Although the resulting radioligand binding may include
traces of binding to D3 or D4 sites, most of the signal is believed to
represent D2 receptors.
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as well as other typical and atypical antipsychotics, increased
D4 receptor abundance in rat caudate-putamen (CPu) and
nucleus accumbens septi (NAc) (Schoots et al., 1995; Florijn
et al., 1997; Tarazi et al., 1997a,c, 1998) and enhanced D4
mRNA expression in monkey striatum (Lidow and GoldmanRakic, 1997). These agents also up-regulated D2 receptors in
rat and monkey prefrontal cortex (Lidow and Goldman-Rakic, 1994; Florijn et al., 1997; Tarazi et al., 1997c, 1998). The
findings support the view that D4 receptors in CPu and NAc,
as well as D2 receptors in prefrontal cerebral cortex, are
common sites of action of both typical and atypical antipsychotics, although the physiological consequences of these molecular changes remain incompletely defined. In contrast,
typical neuroleptics, but not clozapine, also increased D2
receptor binding and expression in rat and monkey CPu
(Lidow and Goldman-Rakic, 1997; Tarazi et al., 1997a,c,
1998). This selective increase in D2 receptor labeling in the
extrapyramidal CPu probably reflects higher average occupancy of such receptor sites by typical neuroleptic agents and
appears to parallel the risk of acute EPS as well as lateremerging tardive dyskinesia.
Despite its favorable characteristics, clinical use of clozapine is complicated by its high risk of potentially fatal bone
marrow toxicity, as well as excessive sedation and dosedependent risk of epileptic seizures (Baldessarini and Frankenburg, 1991). There is a keen interest in developing novel
drugs with less adverse risk than clozapine but comparable
antipsychotic effects. Several newer agents have emerged
(Arnt and Skarsfeldt, 1998; Waddington and Casey, 2000;
Baldessarini and Tarazi, 2001). Among them are the clozapine analogs olanzapine and quetiapine and the benzisoxazole derivative risperidone. Like clozapine, these compounds have multiple sites of molecular interaction and
greater affinity for serotonin 5-HT2A than DA D2 receptors
(Bymaster et al., 1996; Schotte et al., 1996; Gunasekara and
Spencer, 1998). This receptor-interaction pattern may contribute to low EPS risk (Meltzer et al., 1989).
Olanzapine, quetiapine, and risperidone have undergone
extensive pharmacological and behavioral characterization
in animals (Arnt and Skarsfeldt, 1998; Tarazi et al., 2000;
Waddington and Casey, 2000), but their long-term effects on
DA receptors in mammalian forebrain are not well defined or
quantitatively compared with those of other antipsychotics.
Accordingly, we applied quantitative in vitro receptor autoradiography to assess regulation of D1-like, D2, D3, and D4
receptors in different forebrain regions following long-term
infusion of olanzapine, quetiapine, or risperidone in rats. Our
working hypothesis was that these novel atypical antipsychotics would induce regionally selective changes in tissue
levels of specific DA receptors more closely resembling those
of clozapine than typical neuroleptics.
Effects of Novel Antipsychotics on Dopamine Receptors
D3 Receptors. Sections were preincubated for 1 h in Tris buffer
modified as stated to minimize labeling of the high-affinity agonist
binding state of D2 receptors, then incubated for 1 h in the same
buffer containing 3 nM [3H]7-OH-DPAT, with 5 ␮M DTG to mask
sigma sites. Nonspecific binding was determined with 1 ␮M S(⫺)eticlopride. After incubation, slides were washed twice for 3 min in
ice-cold fresh buffer and dried (Tarazi et al., 1997c, 1998).
D4 Receptors. Tissue sections were preincubated for 1 h at RT in
the D2 assay buffer, and then for 1 h with 1.0 nM [3H]nemonapride,
300 nM S(⫺)-raclopride to occupy D2/D3 sites, and other masking
agents (0.5 ␮M DTG and 0.1 ␮M pindolol) used in the D2 assay.
Nonspecific binding was determined with 10 ␮M S(⫺)-sulpiride. The
highly D4-selective ligands L-745,870 and RBI-257 displaced approximately 80% of binding remaining in the presence of raclopride in
adult CPu and NAc tissue, indicating that most of the racloprideinsensitive binding sites are D4 receptors (Tarazi et al., 1997b,c,
1998).
Autoradiography and Image Analysis
Given overall significance of effects for drug or brain region, post hoc
Dunnett t tests were used to test for significant differences due to
each drug treatment in preselected anatomical areas. Unless stated
otherwise, data are presented as means ⫾ S.E.M. Comparisons were
considered significant at p ⬍ 0.05 in two-tailed tests, with degrees of
freedom (df) based on N ⫽ 7 subjects/treatment group.
Results
Four weeks of continuous infusion of all test agents failed
to alter tissue concentrations of D1-like receptors in any
brain region (Table 1). In contrast, olanzapine and risperidone significantly increased labeling of D2 receptors in several forebrain areas, including MPC (by 67 and 34%, respectively), NAc (37 and 28%), CPu (by a lateral and medial
average of 42 and 25%), and HIP (53 and 30%), but did not
alter D2 binding in DFC or EC (Table 2). Similar to D1-like
receptors, there were no changes in D3-selective labeling in
any brain region analyzed or with any agent (Table 3). Even
more than signals representing mainly D2 receptors (uncorrected for overlap with D3 or D4 receptors), D4 labeling was
up-regulated in several regions by treatment with olanzapine
and risperidone, including NAc (by 65 and 33%, respectively),
CPu (average of 61 and 37%), and HIP (61 and 37%), with no
significant changes in several regions of cerebral cortex (Table 4). It is particularly noteworthy that quetiapine was
anomalous and the only tested antipsychotic that did not
alter expression of any DA receptor type in any brain region
examined.
Discussion
Statistical Analysis
Long-Term Effects of Newer Antipsychotics on the D1
Receptor Family
Two-way analysis of variance (ANOVA) was employed to evaluate
overall changes across treatments and brain regions for each assay.
Continuous subcutaneous infusion of olanzapine, quetiapine, or risperidone did not alter binding of [3H]SCH-23390 in
Fig. 1. Sites of autoradiographic analyses of rat brain regions sampled in
10-␮m coronal sections from A (A 3.2–
4.2), B (A 1.7–2.2), C (A 0.7–1.2), and
D [A 0.2– 0.7 mm anterior to bregma,
according to Paxinos and Watson
(1982)]. CP, caudate-putamen (L, lateral; M, medial); ICj, islands of
Calleja; ICjM, major island of Calleja;
Olf Tub, olfactory tubercle.
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Radiolabeled slides and calibrated 3H-standards (Amersham)
were exposed to Hyperfilm (Eastman Kodak) for 2 to 5 weeks at 4°C.
[3H]SCH-23390- and [3H]nemonapride-labeled brain sections were
exposed for 2 (CPu and NAc) or 5 weeks (cortex and HIP) and
[3H]7-OH-DPAT for 4 weeks. Films were developed in Kodak D-19
developer and fixative. Optical density (O.D.) in brain regions of
interest was measured with a computerized densitometric image
analyzer (MCID-M4, Imaging Research, St. Catharines, ON, Canada). Brain regions of interest were outlined (Fig. 1), and their O.D.
was measured. Left and right sides of two contiguous sections represented total binding, and two other sections represented nonspecific binding; the four determinations were averaged for each subject
(N ⫽ 7 rats/treatment). O.D. was converted to nanocuries per milligram of tissue with calibrated 3H-standards, and after subtracting
nonspecific from total binding, specific binding was expressed as
femtomoles per milligram of tissue.
713
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Tarazi et al.
TABLE 1
D1-like receptor binding after 4 weeks of continuous infusion of antipsychotic drugs
Data are mean ⫾ S.E.M. values (N ⫽ 7 rats/group) for binding [fmol/mg of tissue and (percentage of control)], determined by quantitative autoradiography following
continuous subcutaneous infusion of vehicle or antipsychotic drugs for 4 weeks, all as described under Experimental Procedures. No statistically significant drug effect was
found.
Brain Region
Cerebral cortex
Medial-prefrontal
Dorsolateral
Nucleus accumbens
Caudate-putamen
Medial
Lateral
Hippocampus
Entorhinal cortex
a
Controls
Olanzapine
Risperidone
Quetiapine
Clozapinea
Fluphenazinea
14.0 ⫾ 0.5 (100)
7.5 ⫾ 0.9 (100)
85.7 ⫾ 4.1 (100)
13.3 ⫾ 0.6 (95)
6.2 ⫾ 0.8 (82)
86.0 ⫾ 4.3 (100)
11.9 ⫾ 1.5 (85)
9.0 ⫾ 0.8 (120)
88.4 ⫾ 7.3 (103)
15.5 ⫾ 1.0 (107)
8.2 ⫾ 0.8 (109)
81.1 ⫾ 6.0 (95)
(93)
(100)
(92)
(102)
(96)
(96)
87.6 ⫾ 7.1 (100)
90.9 ⫾ 7.9 (100)
7.5 ⫾ 1.0 (100)
10.8 ⫾ 0.7 (100)
90.0 ⫾ 10.3 (103)
98.8 ⫾ 11.6 (109)
8.6 ⫾ 0.5 (115)
11.3 ⫾ 1.1 (105)
78.0 ⫾ 4.6 (99)
78.4 ⫾ 4.3 (103)
8.3 ⫾ 0.7 (111)
12.5 ⫾ 0.6 (116)
74.8 ⫾ 7.2 (85)
83.3 ⫾ 6.3 (92)
8.9 ⫾ 0.6 (119)
12.6 ⫾ 0.4 (117)
(99)
(91)
(101)
(104)
Data (percentage of control) for clozapine (40 mg/kg/day) and fluphenazine (1 mg/kg/day) were determined previously (Tarazi et al., 1998) and are shown for comparison.
TABLE 2
D2 receptor binding after 4 weeks of continuous infusion of antipsychotic drugs
Brain Region
Cerebral cortex
Medial-prefrontal
Dorsolateral
Nucleus accumbens
Caudate-putamen
Medial
Lateral
Hippocampus
Entorhinal cortex
a
Controls
Olanzapine
Risperidone
Quetiapine
Clozapinea
Fluphenazinea
18.4 ⫾ 0.6 (100)
13.0 ⫾ 0.7 (100)
153.3 ⫾ 7.2 (100)
30.8 ⫾ 1.0 (167)*
14.9 ⫾ 0.5 (107)
210.4 ⫾ 14.4 (137)*
24.7 ⫾ 1.3 (134)*
12.6 ⫾ 0.4 (91)
196.8 ⫾ 9.8 (128)*
20.1 ⫾ 0.5 (109)
14.7 ⫾ 0.5 (106)
164.4 ⫾ 6.3 (107)
(160)*
(111)
(103)
(146)*
(92)
(167)*
169.9 ⫾ 8.5 (100)
224.5 ⫾ 12.1 (100)
35.3 ⫾ 1.0 (100)
15.1 ⫾ 1.0 (100)
244.9 ⫾ 21.7 (144)*
311.4 ⫾ 16.3 (139)*
54.4 ⫾ 3.5 (153)*
16.4 ⫾ 1.1 (108)
215.9 ⫾ 12.6 (127)*
276.2 ⫾ 18.0 (123)*
46.0 ⫾ 2.1 (130)*
15.4 ⫾ 1.2 (102)
168.1 ⫾ 11.1 (99)
231.4 ⫾ 17.4 (103)
37.5 ⫾ 2.6 (106)
16.9 ⫾ 0.4 (112)
(104)
(109)
(126)*
(117)*
Data (percentage of control) for clozapine (40 mg/kg/day) and fluphenazine (1 mg/kg/day) were determined previously (Tarazi et al., 1997c) and are shown for comparison.
TABLE 3
D3 receptor binding after 4 weeks of continuous infusion of antipsychotic drugs
Data are mean ⫾ S.E.M. values (N ⫽ 7 rats/group) for binding [fmol/mg of tissue and (percentage of control)], determined by quantitative autoradiography following
continuous subcutaneous infusion of vehicle or antipsychotic drugs for 4 weeks, all as described under Experimental Procedures. No statistically significant drug effect was
found.
Risperidone
Quetiapine
Clozapinea
Fluphenazinea
32.8 ⫾ 1.9 (89)
17.9 ⫾ 1.7 (96)
34.5 ⫾ 1.7 (93)
20.0 ⫾ 1.3 (108)
36.5 ⫾ 1.8 (99)
18.8 ⫾ 1.0 (101)
(97)
(102)
(100)
(102)
17.9 ⫾ 0.7 (100)
7.9 ⫾ 0.5 (100)
18.7 ⫾ 1.3 (104)
8.5 ⫾ 0.4 (108)
17.4 ⫾ 0.6 (97)
9.0 ⫾ 0.6 (114)
19.7 ⫾ 0.8 (110)
8.8 ⫾ 0.3 (112)
(93)
(97)
(108)
3.4 ⫾ 0.2 (100)
3.7 ⫾ 0.3 (100)
3.3 ⫾ 0.2 (97)
3.2 ⫾ 0.2 (86)
3.3 ⫾ 0.1 (97)
3.3 ⫾ 0.1 (89)
3.4 ⫾ 0.2 (100)
3.6 ⫾ 0.1 (97)
(100)
(100)
(118)
(118)
Brain Region
Controls
Islands of Calleja
Olfactory tubercle
Nucleus accumbens
Shell
Core
Caudate-putamen
Medial
Lateral
36.9 ⫾ 1.9 (100)
18.6 ⫾ 0.7 (100)
a
Olanzapine
Data (percentage of control) for clozapine (40 mg/kg/day) and fluphenazine (1 mg/kg/day) were determined previously (Tarazi et al., 1997c) and are shown for comparison.
any region of rat forebrain considered (Table 1). This radioligand labels both highly abundant D1 receptors and rarer D5
sites (Baldessarini and Tarazi, 1996). Lack of adaptive
changes in D1-like binding with the three newer antipsychotic agents tested agrees with similar previous findings
following treatment with dissimilar agents including haloperidol, fluphenazine, raclopride, and clozapine (Florijn et
al., 1997; Tarazi et al., 1997a, 1998).
Interest in D1-like receptors as potential targets for novel
antipsychotic drugs was encouraged by findings in positron
emission tomography studies that clozapine in clinically relevant doses occupied D1-like sites more than typical neuroleptics did, suggesting that D1-like receptors may contribute
to the unique clinical properties of clozapine (Farde et al.,
1989). However, clinical trials have yielded no support for the
hypothesis that D1 antagonists may exert antipsychotic activity (Debeaurepaire et al., 1995). Lack of adaptive changes
in D1-like receptor levels after prolonged administration of
olanzapine, risperidone, or quetiapine (Table 1) as well as
clozapine and typical neuroleptics (Florijn et al., 1997; Tarazi
et al., 1997a, 1998) adds to the impression that these receptors are not likely to play a major role in mediating effects of
antipsychotic agents. Nevertheless, open-minded caution is
required concerning the pharmacological potential of D1 antagonists since current understanding of the physiology of
these most abundant of the cerebral DA receptors remains
remarkably limited (Baldessarini and Tarazi, 1996).
Long-Term Effects of Olanzapine, Risperidone, and
Quetiapine on the D2 Receptor Family
D2 Receptors. D2 receptor potency of tested agents ranks
risperidone (Ki ⫽ 6.0 nM) ⬎ olanzapine (Ki ⫽ 31 nM) ⬎
quetiapine (Ki ⫽ 380 nM) (Schotte et al., 1996). Infusion of
olanzapine and risperidone, but not quetiapine, increased
binding of [3H]nemonapride in MPC (Table 2). Such increases mainly reflect up-regulation of D2 receptors since
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Data are mean ⫾ S.E.M. values for binding [fmol/mg of tissue and (percentage of control)], determined by quantitative autoradiography following continuous subcutaneous
infusion of vehicle or antipsychotic drugs for 4 weeks, with significant differences from controls indicated in bold (* p ⬍ 0.05, N ⫽ 7 rats/group), all as described under
Experimental Procedures.
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Effects of Novel Antipsychotics on Dopamine Receptors
TABLE 4
D4 receptor binding after 4 weeks of continuous infusion of antipsychotic drugs
Data are mean ⫾ S.E.M. values for binding [fmol/mg of tissue and (percentage of control)], determined by quantitative autoradiography following continuous subcutaneous
infusion of vehicle or antipsychotic drugs for 4 weeks, with significant differences from controls indicated in bold (* p ⬍ 0.05, N ⫽ 7 rats/group), all as described under
Experimental Procedures.
Brain Region
Cerebral cortex
Medial-prefrontal
Dorsolateral
Nucleus accumbens
Caudate-putamen
Medial
Lateral
Hippocampus
Entorhinal cortex
a
Controls
Olanzapine
Risperidone
Quetiapine
Clozapinea
Fluphenazinea
10.0 ⫾ 0.6 (100)
6.3 ⫾ 0.3 (100)
29.3 ⫾ 1.1 (100)
11.3 ⫾ 0.8 (113)
6.8 ⫾ 0.4 (108)
48.2 ⫾ 2.8 (165)*
11.1 ⫾ 0.7 (111)
6.4 ⫾ 0.5 (102)
38.9 ⫾ 3.3 (133)*
10.8 ⫾ 0.3 (108)
6.0 ⫾ 0.6 (95)
28.6 ⫾ 3.3 (98)
(117)
(97)
(171)*
(106)
(75)
(224)*
31.4 ⫾ 2.4 (100)
37.8 ⫾ 1.6 (100)
18.0 ⫾ 0.5 (100)
6.9 ⫾ 0.6 (100)
50.2 ⫾ 3.6 (160)*
61.4 ⫾ 1.3 (162)*
29.0 ⫾ 1.6 (161)*
7.4 ⫾ 0.5 (107)
42.7 ⫾ 1.8 (136)*
51.6 ⫾ 2.6 (137)*
24.7 ⫾ 0.9 (137)*
7.3 ⫾ 0.5 (106)
29.1 ⫾ 2.9 (93)
41.9 ⫾ 4.6 (111)
19.1 ⫾ 1.5 (106)
8.2 ⫾ 0.3 (119)
(143)*
(143)*
(160)*
(163)*
Data (percentage of control) for clozapine (40 mg/kg/day) and fluphenazine (1 mg/kg/day) were determined previously (Tarazi et al., 1997c) and are shown for comparison.
well below risperidone and probably also olanzapine (Gunasekara and Spencer, 1998; Leucht et al., 1999; Baldessarini
and Tarazi, 2001; Tarsy et al., 2001). The lack of clinical EPS
with quetiapine is paralleled by its low D2 affinity (Schotte et
al., 1996) and weak antagonism of behavioral effects of DA
microinjected directly into rat CPu (Campbell et al., 1991).
Risperidone shares many characteristics of typical neuroleptics, including severe hyperprolactinemia and dose-dependent EPS risk (Fleischhacker and Marder, 2000; Baldessarini and Tarazi, 2001; Tarsy et al., 2001). In addition to its
ability to occupy striatal D2 receptors, olanzapine has relatively potent antimuscarinic properties compared with risperidone or quetiapine (Bymaster et al., 1996; Schotte et al.,
1996) that probably limits its risk of EPS effects.
Other studies using low daily doses of olanzapine (0.35–2
mg/kg) or risperidone (0.25– 0.5 mg/kg) did not find D2 receptor up-regulation in rat or monkey striatum (Kuoppamaki et
al., 1995; Lidow and Goldman-Rakic, 1997; Kusumi et al.,
2000). In addition, long-term treatment with low doses of
olanzapine (0.5–2 mg/kg) resulted in lesser oral chewing
movements (a proposed animal model of tardive dyskinesia)
than did haloperidol (Gao et al., 1998). Nevertheless, the
present findings with higher doses of constantly infused olanzapine and risperidone did include significant apparent upregulation of D2 receptors. Moreover, the present and previous results are consistent with clinical evidence that risks of
acute EPS and of tardive dyskinesia with risperidone and
olanzapine are substantially greater than with either quetiapine or clozapine (Tarsy et al., 2001).
D3 Receptors. These low-abundance proteins have a restricted distribution, with notable levels of expression in
mammalian basal forebrain, most prominently in the islands
of Calleja, followed by olfactory tubercle and NAc shell, with
very low levels in CPu (Sokoloff et al., 1990; Levant, 1997;
Table 3). Binding of [3H]7-OH-DPAT under D3-selective conditions was unchanged after prolonged exposure to all test
agents in all regions examined. Even risperidone, which has
relatively high D3 affinity (Schotte et al., 1996), failed to alter
expression of D3 receptors, even in the islands of Calleja and
NAc (Table 3), as was found with various other antipsychotics (Levésque et al., 1995; Florijn et al., 1997; Tarazi et al.,
1997a,c, 1998).
Lack of response of D3 receptors to repeated antipsychotic
treatment may reflect their unique molecular mechanisms,
including absence of well defined interactions with G-proteins and signal transduction cascades (Sokoloff et al., 1990;
Downloaded from jpet.aspetjournals.org at ASPET Journals on June 14, 2017
cortical D4 receptors did not increase significantly (Table 4),
and D3 receptors are minimally expressed in rat frontal cortex (Sokoloff et al., 1990; Baldessarini and Tarazi, 1996).
Similar D2 receptor up-regulation and increased D2 mRNA
expression have been found in cerebral cortex of rats and
nonhuman primates after repeated treatment with typical
and atypical antipsychotics (Damask et al., 1996; Florijn et
al., 1997; Lidow and Goldman-Rakic, 1997; Tarazi et al.,
1997c, 1998). D2 receptor up-regulation in MPC by olanzapine and risperidone further supports the importance of D2
receptors in this region as a common target for both typical
and atypical antipsychotics.
Prolonged treatment with olanzapine and risperidone also
enhanced binding to D2 receptors in HIP but neither in DFC
nor EC (Table 2). Such enhancement of D2 expression in HIP
probably reflects an increase in the transcriptional activity of
the D2 receptor gene since repeated treatment with clozapine
increased D2 mRNA expression in HIP but not EC (Ritter
and Meador-Woodruff, 1997). D2 receptors in HIP, where DA
innervation is limited, evidently are regulated differently
from those in EC, where DA innervation is much denser
(Goldsmith and Joyce, 1994). D2 receptors in HIP, but not
EC, may act as additional common targets of olanzapine,
risperidone, and perhaps other antipsychotics. Blockade and
up-regulation of hippocampal D2 receptors by antipsychotics
may contribute to improvement of delusions and hallucinations of psychotic patients by ameliorating DA hyperactivity
postulated to occur in their HIP (Krieckhaus et al., 1992).
Repeated treatment with olanzapine and risperidone, but
not quetiapine, also increased D2 receptor labeling in CPu
(Table 2). Similar responses have been found after long-term
treatment with typical neuroleptics but not clozapine (Florijn
et al., 1997; Tarazi et al., 1997a,c, 1998). Up-regulation of D2
receptors in CPu may disturb neurotransmission in circuits
involved in regulating movement and posture (Albin et al.,
1989) and generally correlates with EPS risk. Similar responses to newer antipsychotics (olanzapine, risperidone)
with relatively low EPS risk were, therefore, unexpected.
Additional indications that these drugs can occupy D2 receptors in human basal ganglia come from positron emission
tomography studies showing that relatively high, but clinically encountered, doses of olanzapine and risperidone lead
to occupation of striatal D2 receptors similar to that produced
by typical neuroleptics and much more than that produced by
clozapine (Farde et al., 1989; Kapur et al., 1999) or quetiapine (Gefvert et al., 1998). Quetiapine has the most benign
clinical EPS risk of the three novel agents tested, ranking
716
Tarazi et al.
Conclusions
Similar to other typical and atypical antipsychotics, longterm treatment of rats with olanzapine and risperidone significantly up-regulated D2 receptors in MPC, as well as D4
receptors in NAc and CPu. These new findings add support to
the hypothesis that these receptors and brain regions may be
involved in the beneficial clinical effects of antipsychotics. In
addition, both olanzapine and risperidone increased levels of
D2 as well as D4 receptors in HIP (but not other cortical
areas, including DFC and EC), suggesting a third possible
site contributing to beneficial effects of atypical antipsychotics.
At behaviorally effective doses, olanzapine and risperidone
also increased abundance of D2 receptors in CPu, similar to
the effects of long-term treatment with typical, but not atypical, antipsychotics. This finding parallels the moderate,
dose-dependent risk of clinical EPS with these agents, consistent with their status as quantitatively atypical agents
(Baldessarini and Tarazi, 2001; Tarsy et al., 2001). Lack of
effects of olanzapine and risperidone on D1-like or D3 receptors in any brain region examined adds support to the view
that these receptors are probably not prominently involved in
the actions of various kinds of antipsychotics. Failure of
quetiapine to alter abundance of any DA receptor type in any
brain region examined is consistent with its low affinity for
all DA receptors and suggests that nondopaminergic, and
perhaps serotonergic or histaminergic, mechanisms may contribute to the clinical actions of this novel agent.
Acknowledgments
Drug substances were generous gifts of Lilly, Janssen, Lundbeck,
and Zeneca Corporations.
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