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Vol. 288, Issue 2, 774-781, February 1999
Department of Psychiatry, Saga Medical School, Nabeshima, Saga, Japan (T.K.); and Department of Psychiatry, Psychopharmacology Division, Vanderbilt University School of Medicine, Nashville, Tennessee (H.Y.M., J.I.).
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Abstract |
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 Top
 Abstract
 Introduction
Materials and methods
Results
Discussion
References
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The present study was designed to compare the effects of typical and
atypical antipsychotic drugs on extracellular dopamine (DA) levels in
the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAC),
using in vivo microdialysis with dual probe implantation in awake,
freely moving rats. Amperozide (2 and 10 mg/kg), clozapine (5 and 20 mg/kg), and olanzapine (10 mg/kg), all of which are atypical
antipsychotics, produced greater increases in extracellular DA levels
in the mPFC than in the NAC. Olanzapine (1 mg/kg), risperidone (0.1 and
1 mg/kg), also an atypical antipsychotic, and
S-(
)-sulpiride (25 mg/kg), a typical antipsychotic,
produced comparable increases in extracellular DA levels in the mPFC
and the NAC. S-()-sulpiride (10 mg/kg) and haloperidol
(0.1 and 1 mg/kg), another typical antipsychotic, significantly
increased extracellular DA levels in the NAC but not in the mPFC. The
effects of the six antipsychotic drugs to increase extracellular DA
levels in the mPFC relative to those in the NAC was positively
correlated with the difference between their pKi values for serotonin
(5-hydroxytryptamine, 5-HT2A) and DA-D2
receptors and was inversely correlated to their pKi values for
D2 or D3 receptors, but was not for
5-HT2A receptors alone. These results are consistent with
the hypothesis that the ability of antipsychotic drugs to produce a
greater increase in prefrontal compared with NAC extracellular DA
levels may be related, in part, to weak D2 and
D3 receptor affinity relative to 5-HT2A receptor antagonism.
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Introduction |
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Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
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Antipsychotic
drugs such as haloperidol (HAL) and S-()-sulpiride (SUL)
increase dopamine (DA) release in the striatum (STR) and the nucleus
accumbens (NAC), most likely due to the blockade of presynaptic
DA-D2-like autoreceptors (Westerink and DeVries, 1989
). The atypical antipsychotics clozapine (CLOZ) and amperozide (APZ), both of which have greater affinities for serotonin
(5-hydroxytryptamine, 5-HT)2A receptors relative
to D2 receptors (Meltzer et al., 1989; Leysen et
al., 1993), have been reported to produce greater increases in
extracellular DA levels in the medial prefrontal cortex (mPFC) compared
with the STR and the NAC (Moghaddam and Bunney, 1990; Nomikos et al.,
1994; Pehek and Yamamoto, 1994; Volonté et al., 1997). By
contrast, HAL has a limited effect on extracellular DA levels in the
mPFC. Compounds like CLOZ and APZ that are relatively more potent as
5-HT2A than as D2 receptor
antagonists, e.g., melperone, olanzapine (OLAN), risperidone (RISP),
quetiapine, sertindole, and ziprasidone (Meltzer et al., 1989; Leysen
et al., 1993), have been commonly referred to
5-HT2A/D2 receptor
antagonists (Meltzer, 1995). Therefore, it is of interest to test the
hypothesis that all antipsychotic drugs of the
5-HT2A/D2 receptor
antagonist type produce a greater increase in extracellular DA levels
in the mPFC compared with the NAC.
Dopaminergic hypofunction in the prefrontal cortex has been suggested
to be related to the etiology of negative symptoms (Davis et al., 1991;
Weinberger and Lipska, 1995) and cognitive dysfunction of schizophrenia
(Sawaguchi and Goldman-Rakic, 1991). A number of the
5-HT2A/D2 receptor
antagonists, e.g., CLOZ, RISP, OLAN, and sertindole, have been reported
to have a greater ability to improve negative symptoms than do
neuroleptics such as HAL or chlorpromazine (Kane et al., 1988;
Chouinard et al., 1993; Meltzer, 1995; Tollefson and Sanger, 1997).
CLOZ and RISP also improve some aspects of cognitive function (Hagger
et al., 1993; Green et al., 1997) which may be related to
frontal lobe function. Thus, the greater ability of
5-HT2A/D2 receptor
antagonists to increase extracellular DA levels in the cortical regions
compared with subcortical regions may contribute to their ability to
improve negative symptoms (Deutch et al., 1991). This hypothesis is
consistent with preferential in vivo and in vitro binding of
5-HT2A/D2 receptor antagonists to cortical 5-HT2A compared with
striatal D2 receptors (Meltzer et al., 1989;
Leysen et al., 1993; Stockmeier et al., 1993).
Recently, evidence for the modulation of the activity of
mesolimbocortical DA neurons by 5-HT2A receptors
has been reported. Systemic administration of the
5-HT2A/2C receptor antagonist ritanserin has been
demonstrated to enhance the activity of midbrain DA neurons (Ugedo et
al., 1989). Ritanserin has also been reported to potentiate the ability
of the selective D2/3 receptor antagonist
raclopride to increase DA release in the mPFC but not in the STR,
whereas ritanserin alone had no effect on DA release in either region (Andersson et al., 1995). These data suggest that the
5-HT2A receptor antagonism, together with
blockade of D2-like receptors
(D2, D3, and perhaps
D4 subtype), may contribute to the preferential
increase in extracellular DA levels in the mPFC compared with the NAC
and the STR produced by APZ and CLOZ. However, this hypothesis is not
consistent with the reports that RISP and OLAN, which are more potent
as 5-HT2A than as D2
receptor antagonists (Bymaster et al., 1996a; Schotte et al., 1996),
produced comparable increases in extracellular DA levels in the mPFC
and the NAC or the STR (Hertel et al., 1996; Volonté et al.,
1997).
The present study was designed to characterize antipsychotic drugs of
the 5-HT2A/D2 receptor
antagonist type in terms of their relative ability to produce a greater
increase in extracellular DA levels in the mPFC compared with the NAC.
Importantly, antipsychotic drugs differ in their affinities for
D1, D3,
D4, 5-HT2C,
5-HT6, and 5-HT7 receptors
(Meltzer et al., 1989; Roth et al., 1992; Schotte et al., 1996). These
affinities may also influence their effects on extracellular DA levels
in the mPFC, the NAC, and the STR. Therefore, this study also
investigated the relationships between relative potency to increase
extracellular DA levels and in vivo affinities for multiple 5-HT and DA
receptors as indicated by pKi values obtained from published sources
(Table 1). Six antipsychotic drugs were chosen on the basis of the
difference in in vitro and in vivo affinity between rat cortical
5-HT2A and striatal D2
receptors in the following rank order: APZ > CLOZ > RISP > OLAN > HAL > SUL.
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Materials and Methods |
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Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
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Animals. Male Sprague-Dawley albino rats (Zivic-Miller, Pittsburgh, PA) weighing 250 to 300 g were used throughout the study. Rats were housed two or three per cage and were maintained on a 12-h light/dark cycle and under constant temperature at 22°C, with ad libitum access to food and water.
Surgery and Microdialysis.
Rats were anesthetized with a
combination of xylazine (Rompun, 6 mg/kg, i.p.; Miles, Kansas City, KS)
and ketamine hydrochloride (Ketaset, 70 mg/kg, i.p.; Fort Dodge Lab.,
Fort Dodge, IA) and mounted in a stereotaxic frame (David Kopf
Instruments, Tujunga, CA). Two stainless guide cannula (21 gauge) with
a dummy probe were placed and fixed by cranioplastic cement onto the
cortex dorsal both to the right mPFC and the left NAC (dual probe
implantation). Stereotaxic coordinates of each probe when implanted
were A +3.2, L +0.8 (10° inclination), V 5.5 mm for the mPFC and A
+2.0, L +1.7, V 7.5 mm for the NAC, respectively, relative to bregma; incision bar level: 3.0 mm, according to the atlas of Paxinos and
Watson (1986).
. Briefly, the probe was a
concentric design consisting of 25-gauge stainless steel tubing (460 µm o.d.) connected to PE20 tubing as an inlet. The outlet
consisted of a fused silica capillary (150 µm o.d.; Polymicro
Technologies, Phoenix, AZ) passed through the wall of the PE20,
threaded down through the stainless steel tubing and into a 2-mm length
of sealed dialysis tubing (polyacrylonitrile/sodium methalylsulfonate
polymer, 310 µm o.d., 220 µm i.d., 40,000 Da cutoff, AN69HF,
Hospal; CGH Medical, Lakewood, CO). PE10 tubing was attached to the
silica capillary where it exits the probe. All junctions were glued
with 2-ton Epoxy (Devon Bearings, Brooklyn Heights, OH). Because the
variability in percentage of recovery of DA between probes varied by
less than 10%, basal extracellular DA levels in each region were
expressed as absolute values and were not corrected by percentage of recovery.
Three to five days after cannulation, the microdialysis probes were
implanted into the mPFC and the NAC under slight anesthesia with
methoxyflurane (Metofane; Pitman-Moore, Chicago, IL). The probe was
perfused with modified Dulbecco's phosphate-buffered saline including
Ca++ (NaCl, 138 mM;
Na2HPO4, 8.1 mM; KCl, 2.7 mM; KH2PO4, 1.5 mM; MgCl2, 0.5 mM; and CaCl2,
1.2 mM, at pH = 7.4) at 0.2 µl/min through the night. After
overnight perfusion for approximately 15 h, the perfusion flow
rate was increased to 0.4 µl/min, and, beginning 1 h later,
dialysate samples (12 µl) were collected every 30 min. After
obtaining stable baseline values in the dialysate such that a
percentage of S.E.M. of the three consecutive DA values in the dialysate differed less than 10% of the mean values, each drug or
vehicle was administered s.c. to rats. The effect of the drug was
followed for at least another 180 min. After the completion of each
experiment, the rats were sacrificed with an overdose of chloral
hydrate. The brains were removed and cut coronally along the puncture
created by the probe. The location of the tip was then verified
macroscopically. All experiments were carried out between 10:00 and
16:00 h. The procedures applied in this study were in strict accordance
with the National Institutes of Health Guide for the Care and Use of
Laboratory Animals and were approved by the Institutional Animal Care
and Use Committee of Case Western Reserve University in Cleveland, OH,
where we completed these experiments.
Dual probe implantation into the mPFC and the NAC used in this study
was done to monitor cortico-subcortical interactions and to compare
drug effects on the two regions. It has been suggested that the shell,
but not the core, of the NAC, projects to the mPFC in the rat brain and
may be the target site for the antipsychotic action of antipsychotic
drugs (Deutch et al., 1993). In this study, dialysis probes were always
implanted above or on the medial side of the anterior limb of the
anterior commissure, a location which may indicates preference for the
shell of the NAC. However, because of the probe size used in this
study, the dialyzed area might also include, in part, the core of the NAC.
Biochemical Assay.
DA concentrations in dialysate samples
were determined by high-performance liquid chromatography with
electrochemical detection as described previously (Kuroki et al.,
1996). DA was separated on the reversed phase column (BDS Hypersil C18,
1.0 × 100 mm, 3 µm particle size; Keystone Scientific,
Bellefonte, PA). The composition of the mobile phase was 50 mM
NaH2PO4 (pH = 6.0), 20% (v/v) methanol,
8% (v/v) acetonitrile, 450 mg/liter SDS, 1 mM Na2EDTA, 10 mM NaCl, and 500 µl/liter triethylamine. Electrochemical detection
controllers (LC-4C; BAS, West Lafayette, IN) with unijet amperometric
detector cells (MF-9080; BAS) set at +550~580 mV versus Ag/AgCl
reference electrodes were used to detect DA. The column and detector
cell were placed within a column oven (831 temperature regulator;
Gilson, Middlestone, MA) at 35°C except for the experiment of OLAN
administration. Because an OLAN metabolite was coeluted with DA at the
same retention period of the chromatogram under the above-mentioned
conditions, the column temperature was lowered to 28°C to obtain
clear separation of DA for the experiment of OLAN injection. The data
were analyzed with an integrator (HP 3396 Series II; Hewlett-Packard,
Avondale, PA). The detection limit was 0.4 fmol for DA at a 3:1
signal-to-noise ratio. All reagents used for high-performance liquid
chromatography with electrochemical detection were purchased from
Fisher Scientific (Pittsuburgh, PA) and Sigma Chemical Co. (St. Louis, MO).
Drugs.
Six antipsychotic drugs were chosen on the basis of
the difference in in vitro and in vivo affinity between rat cortical
5-HT2A and striatal D2 receptors (Table
1). The doses of antipsychotic drugs
except OLAN were chosen on the basis of the ED50 values for
displacing in vivo [3H]N-methylspiperone
binding to cortical 5-HT2A/olfactory tubercle D2 receptors (Stockmeier et al., 1993). The choice of the
doses of OLAN was according to the ED50 values for
inhibition of ex vivo [3H]ketanserin binding to cortical
5-HT2A receptors and inhibition of
N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline-induced
inactivation of striatal D2 receptors (Bymaster et al.,
1996b). APZ, CLOZ, RISP, and OLAN at the doses used in this study may
predominantly occupy 5-HT2A receptors compared with
D2 receptors in rat brain, whereas SUL and HAL
predominantly occupy D2 receptors compared with
5-HT2A receptors, although discrepancies between in vivo and in vitro data have been reported for some antipsychotic drugs, e.g., racemic SUL (Meltzer et al., 1989; Stockmeier et al., 1993).
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Data Analysis. The mean value of three consecutive samples before drug injection was set at 100% as the predrug basal value. The percentage of net area under the curve (% net AUC) was obtained from the net increase for a 180-min period after drug or vehicle over each predrug basal level, and expressed as percentage of predrug basal levels. All data were statistically evaluated with StatView 4.50 (Abacus Concepts Inc., Berkeley, CA). Basal extracellular DA levels in the mPFC and the NAC in the various treatment groups were subject to one-way analysis of variance (ANOVA). The time-dependent effects of drugs were analyzed by repeated-measure ANOVA followed by the Fisher's protected least significant difference post hoc pairwise comparison procedures. Spearman rank correlation was analyzed to examine the relationship between the greater effect on extracellular DA levels in the mPFC compared with the NAC, as indicated by the difference between the values of log[mPFC] and log[NAC], and the pKi values of antipsychotic drugs for 5-HT and DA receptor subtypes. The values of log[mPFC] and log[NAC] are the logarithms of the % net AUC in the mPFC and the NAC. A probability of less than 0.05 (p < .05) was considered significant in the present study.
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Results |
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Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
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Basal Extracellular DA Levels in the mPFC and the NAC. Basal extracellular DA levels (mean ± S.E.M. fmol/10 µl/30 min, not corrected by % recovery) in the dialysates obtained from all rats used in this study were 1.72 ± 0.09 (n = 71) for the mPFC and 11.04 ± 0.46 (n = 77) for the NAC, respectively. The basal extracellular DA levels in the NAC were about 6-fold higher than in the mPFC (F1,146 = 370.90, p < .001 by one-way ANOVA). There was no significant difference in basal extracellular DA levels in each brain region between the various treatment groups. In a preliminary experiment, the injection of either 0.1 M tartaric acid, deionized water, or physiological saline (0.9% NaCl) had no significant effect on extracellular DA levels in either region. Therefore, the combined data of the effects of both 0.1 M tartaric acid and deionized water on extracellular DA levels were used as the vehicle control (VEH) for the statistical analysis and the graphic presentation (n = 6 for each region).
Time-Dependent Effects on Extracellular DA Levels in the mPFC and the NAC during the 180-min Period after Drug Injections Compared With VEH. Repeated-measure ANOVA for each treatment group in both regions with post hoc comparison, as compared with VEH, is indicated as follows: APZ (10 mg/kg) produced time-dependent effects on extracellular DA levels in the mPFC and the NAC, whereas APZ (2 mg/kg) had no time-dependent effect in either region. Both doses of CLOZ (5 and 20 mg/kg), OLAN (1 and 10 mg/kg), and RISP (0.1 and 1 mg/kg) had significant time-dependent effects in both regions. SUL (25 mg/kg) significantly increased extracellular DA levels in both regions, whereas SUL (10 mg/kg) had a significant effect in the NAC but not in the mPFC. Both doses of HAL (0.1 and 1 mg/kg) increased extracellular DA levels in the NAC but not in the mPFC (Figs. 1 and 2).
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Effects on the Percentage of Net AUC of Extracellular DA Levels in the mPFC and the NAC. Both doses of antipsychotic drugs studied except HAL produced significant increases in the % net AUC in the mPFC compared with VEH. APZ (2 mg/kg) showed a significant increase in the % net AUC in the mPFC when determined by one-way ANOVA despite nonsignificant time-dependent effects determined by repeated-measure ANOVA with post hoc comparison. HAL (1 but not 0.1 mg/kg) had a significant effect in the mPFC. APZ (10 but not 2 mg/kg) produced a significant increase in the % net AUC in the NAC. Both doses of all of the other antipsychotic drugs had significant effects in the NAC (Table 2).
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Relationship Between the Affinities (pKi Values) for Receptor
Subtypes and the Ability to Increase Extracellular DA Levels in the
mPFC Compared With the NAC.
To determine the relationship between
pKi values and regional effects of antipsychotic drugs on extracellular
DA levels, the difference in the values of log[% net AUC of DA]
between the mPFC and the NAC (log[mPFC] log[NAC]) was determined
in this study (Table 2). This measure is more appropriate for this
purpose than the comparison of absolute extracellular DA levels in each region between the mPFC and the NAC because basal extracellular DA
levels are significantly different (6-fold) between these regions, and
the % net AUC values are less affected by the difference in basal levels.
log[NAC]) significantly correlated with the difference in the pKi
values between 5-HT2A and
D2 receptors (r = 0.79, p < .01) and inversely correlated with their pKi
values for D2 (r = 0.89, p < .01) and D3 receptors
(r = 0.86, p < .01) (Fig.
3). However, the log[mPFC] - log[NAC]
values had no significant correlation with the pKi values for
5-HT2A receptors (r = 0.23) or
other receptor subtypes (D1,
D4, 5-HT1A, and
5-HT2C receptors, r = 0.24,
0.04, 0.31 and 0.51, respectively). The log[mPFC] or log[NAC]
values alone were not significantly correlated with the pKi values for DA and 5-HT receptor subtypes, except for the log[NAC] versus D2 (r = 0.79, p < .01) or D3 receptors (r = 0.81, p < .01). The difference in the pKi values
between D2 and 5-HT2A
receptors was not significantly correlated with the pKi values for
D2 (r = 0.60, p > .1) or D3 (r = 0.64, p > .1) receptors (Table 1).
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Discussion |
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Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
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The major findings of the present study are: 1) at certain doses, some but not all atypical antipsychotic drugs have preferential effects to increase extracellular DA levels in the mPFC compared with the NAC; and 2) the ability of antipsychotic drugs to increase extracellular DA levels in the mPFC compared with the NAC is positively correlated with the difference in the affinities of antipsychotic drugs for 5-HT2A and D2 receptors. It is also inversely correlated with the affinities for D2 or D3 receptors. There is no correlation between the affinities for 5-HT2A receptors alone and the preferential effects in the mPFC.
This study was undertaken to clarify the importance of the affinities
of antipsychotic drugs for 5-HT2A and
D2 receptors for the differential clinical and
biochemical effects of typical and atypical antipsychotic drugs. It was
previously postulated that the difference in pKi values for these two
receptors was relevant to their ability to produce minimal
extrapyramidal symptoms and might also contribute to their possible
advantages as antipsychotic drugs (Meltzer et al., 1989). These drugs
may also differ with regard to their ability to treat negative symptoms
and to improve cognitive function. Negative symptoms and cognitive
impairment have been suggested to be related to frontal lobe function
and, in particular, to the alteration of cortical dopaminergic activity (Sawaguchi and Goldman-Rakic, 1991; Murphy et al., 1996).
5-HT2A receptors located on pyramidal cells in
the cerebral cortex may also be the site of action of antipsychotic
drugs (Jakab and Goldman-Rakic, 1998). Therefore, it is of importance
to determine whether typical and atypical antipsychotic drugs differ
with regard to their ability to increase extracellular DA levels in the
mPFC relative to the NAC. If so, this difference may be related to
their affinities for 5-HT2A and
D2 receptors.
The six antipsychotic drugs studied included four atypical
antipsychotic drugs (CLOZ, APZ, RISP, and OLAN) and two typical antipsychotic drugs (HAL and SUL) (Meltzer, 1995). Despite the fact
that only six drugs were studied, the range of the differences in their
relative affinities for 5-HT2A and
D2 receptors was 1000-fold. Because the
D2 and D3 receptor
affinities of the six drugs are highly correlated, it was not possible
to separate out the importance of D2 versus
D3 receptor blockade with regard to the effect on extracellular DA levels in the mPFC and NAC. Further study is needed to
determine the relative importance of D2 and
D3 receptors to the ability to increase
extracellular DA levels in the two regions.
Both doses of APZ, CLOZ, OLAN, and RISP had greater or comparable
effects on extracellular DA levels in the mPFC compared with the NAC.
By contrast, SUL (10 mg/kg) and both doses of HAL had much greater
effects on extracellular DA levels in the NAC than in the mPFC, leaving
open the possibility that an equal or greater effect on extracellular
DA levels in the mPFC compared with the NAC may be characteristic of an
atypical antipsychotic drug. These results are generally consistent
with previous reports by others (Moghaddam and Bunney, 1990; Nomikos et
al., 1994; Hertel et al., 1996). Volonté et al. (1997) reported a
greater effects of OLAN (0.3, 1 and less than 3 mg/kg) in the STR than
in the mPFC, whereas we found a greater effect of OLAN (10 but not 1 mg/kg) in the mPFC than in the NAC. It should be noted that SUL (25 mg/kg) produced a comparable increase in extracellular DA levels in the
mPFC relative to the NAC. This effect may be related to the reported
beneficial effects of SUL to decrease negative symptoms (Mauri et al.,
1996). HAL, which has minimal beneficial effect on negative symptoms,
produced the smallest increase in extracellular DA levels in the mPFC
at both doses studied. These data support the possibility that there
could be a relationship between extracellular DA levels in the mPFC and
improvement in negative symptoms.
Quetiapine, another
5-HT2A/D2 receptor
antagonist, has a low extrapyramidal symptoms profile similar to that
of OLAN, yet there is no evidence that it has beneficial effects on
negative symptoms or cognition in schizophrenia (Arvanitis et al.,
1997). Recently, quetiapine was reported not to increase extracellular DA levels in the mPFC (Volonté et al., 1997). These findings may
be consistent with the hypothesis that increased prefrontal extracellular DA levels may be important to the ability of
5-HT2A/D2 receptor
antagonists to improve negative symptoms. The lesser ability of
quetiapine to increase DA levels in the mPFC may be due to much weaker
affinity of quetiapine for 5-HT2A and
D2 receptors than any other atypical
antipsychotic drug studied here (Schotte et al., 1996). More typical
and atypical antipsychotic drugs need to be studied to further clarify
this relationship between prefrontal extracellular DA levels and
negative symptoms. It will also be important to determine the effect of
chronic administration of these agents on extracellular DA levels
because the effect of chronic treatment would be expected to have
greater clinical relevancy.
Although there was a strong inverse correlation between
D2 (or D3) receptor
affinities and the ability to increase extracellular DA levels in the
mPFC compared with the NAC, it is most likely that the relationship
determining the preferential effect on extracellular DA levels in the
mPFC is 5-HT2A relative to
D2 receptor affinity. The Spearman rank
correlation coefficient of the difference in pKi values for the two
receptors and the logarithm of the % net AUC for the mPFC and the NAC
was 0.79, accounting for 62% of the variance in the dependent measure.
This correlation is unlikely due to the correlation with pKi values for
D2 or D3 receptors because
there was no significant correlation between these values and the
difference in pKi values for 5-HT2A and
D2 receptors. 5-HT2A
receptor affinities alone did not correlate with the greater ability to
increase extracellular DA levels in the mPFC relative to the NAC,
although the selective 5-HT2A receptor
antagonists such as M-100,907 were reported to increase extracellular
DA levels in the mPFC (Schmidt and Fadayel, 1995). It would appear that 5-HT2A receptor blockade, in the presence of
D2 receptor blockade that is relatively less
effective than that of 5-HT2A receptor blockade,
is able to increase extracellular DA levels in the mPFC more so than in
the NAC. This may be due to local effects of
5-HT2A receptor blockade in the mPFC and NAC
because the density of 5-HT2A receptors is much
higher in the former than the latter region (Jacobs and Azmitia, 1992).
This hypothesis is compatible with the data that ritanserin, a
5-HT2A receptor antagonist, potentiated the
D2-like receptor antagonist raclopride-induced DA
release in the mPFC but not in the STR, whereas ritanserin alone had no effect on DA release in either region (Andersson et al., 1995). However, this hypothesis does not explain why OLAN (10 mg/kg) was more
effective than OLAN (1 mg/kg) to increase extracellular DA levels in
the mPFC compared with the NAC. The occupancy of 5-HT2A relative to D2
receptors should be greater at OLAN, 1 mg/kg than 10 mg/kg (Bymaster et
al., 1996b).
The increase in extracellular DA levels in the NAC may be primarily the
result of blockade of presynaptic D2-like
receptors (Westerink and DeVries, 1989). This may contribute to the
strong correlation between D2 or
D3 receptor affinities of antipsychotic drugs and
their preferential effects on NAC extracellular DA levels. Because the
density of D2-like receptors has been reported to be low in the mPFC compared with the NAC (Bouthenet et al., 1991), D2 receptor antagonism may be more effective in
the NAC than in the mPFC. This hypothesis would not seem to explain the
marked effects of APZ to increase extracellular DA levels in the mPFC compared with the NAC. APZ, a weak D2 receptor
antagonist, is reported to inhibit the reuptake of DA (Pettersson,
1995). This effect might be expected to increase extracellular DA
levels in the NAC even more so than the mPFC because Cass and Gerhardt
(1995) reported that DA uptake is less efficient in the mPFC than in the NAC and STR. Moreover, local perfusion of APZ into the NAC has been
reported to produce a greater increase in DA release than in the mPFC
(Nomikos et al., 1994). Thus, it may not be excluded that the
combination of 5-HT2A receptor blockade and DA
reuptake inhibition produced by APZ contribute to the striking
preferential effect of APZ on extracellular DA levels in the mPFC.
Other factors not yet apparent may also be involved.
The present results suggest that antipsychotic drugs may be grouped on the basis of their ability to increase extracellular DA levels in the mPFC versus the NAC. Although the clinical relevance of such a classification is not clear at present, the assumption that the preferential activation of prefrontal dopaminergic neurotransmission may contribute, at least in part, to the efficacy in treating negative symptoms and cognitive impairment leads to testable hypotheses for developing new antipsychotic drugs.
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Footnotes |
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Accepted for publication September 14, 1998.
Received for publication April 10, 1998.
1 This work was supported in part by U.S. Public Health Services Grant MH 41684, Department of Veterans Affairs grant GCRC MO1RR00080, and the National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award grant, as well as grants from Elisabeth Severance Prentiss Foundation and Mr. Larry Freedman. Preliminary data from this study have been reported in abstract forms of the annual meetings of the Society for Neuroscience, 1995, and the Society of Biological Psychiatry, 1996.
Send reprint requests to: Toshihide Kuroki, M.D., Ph.D., Department of Psychiatry, Saga Medical School, Nabeshima 5-1-1, Saga 849-8501, Japan. E-mail: kurokit{at}post.saga-med.ac.jp
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Abbreviations |
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HAL, haloperidol;
SUL, S-()-sulpiride;
DA, dopamine;
STR, striatum;
NAC, nucleus accumbens;
CLOZ, clozapine;
APZ, amperozide;
mPFC, medial
prefrontal cortex;
OLAN, olanzapine;
RISP, risperidone;
5-HT, 5-hydroxytryptamine;
AUC, area under the curve;
VEH, vehicle control.
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Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
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1-adrenergic and muscarinic receptors in vivo in rats.
Psychopharmacology
124:
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