differential effects of typical and atypical antipsychotic drugs on striosome and matrix...

Differential effects of typical and atypical antipsychoticdrugs on striosome and matrix compartments of thestriatum

Michael Bubser and Ariel Y. DeutchDepartments of Psychiatry and Pharmacology and Center for Molecular Neuroscience, Vanderbilt University Medical Center,

Nashville, TN 37212, USA

Keywords: clozapine, Fos, haloperidol, rat

Abstract

Administration of typical antipsychotic drugs (APDs) is often accompanied by extrapyramidal side-effects (EPS). Treatment with

atypical APDs has a lower incidence of motor side-effects and atypical APDs are superior to typical APDs in treating the negative

symptoms of schizophrenia. Although typical APDs strongly induce the immediate-early gene c-fos in the striatum while atypicalAPDs do so only weakly, it is possible that the effects of atypical APDs are more pronounced within certain regions of the

striatum. The striatum contains two histochemically de®ned compartments, the striosome (patch) and the matrix. These

compartments have been well characterized anatomically but their functional attributes are unclear. We therefore examined the

effects of typical and atypical APDs on Fos expression in the striosome and matrix of the rat. Typical and atypical APDs weredistinguished by the pattern of striatal compartmental activation they induced: the striosome : matrix ratio of Fos-li neurons was

greater in rats treated with atypical APDs. Pretreating animals with selective antagonists of receptors that atypical APDs target

with high af®nity did not increase the striosome : matrix Fos ratio of typical APD-treated rats and thus did not mimic the ratioseen in response to atypical APDs. However, pretreatment with the atypical APD clozapine did recapitulate the characteristic

compartmental Fos pattern seen in response to typical APDs. These data suggest that some characteristics of atypical APDs,

such as the lower EPS liability and greater reduction of negative symptoms, may be linked to the coordinate regulation of thestriatal striosome and matrix.

Introduction

Administration of typical antipsychotic drugs (APDs) is accompanied

by extrapyramidal side-effects (EPS). These parkinsonian side-effects

are thought to be due to the blockade of striatal dopamine D2

receptors (Nordstrom et al., 1993). Acute administration of D2

antagonists, such as the APD haloperidol, results in diverse changes

in the striatal medium spiny neurons onto which dopaminergic axons

synapse, including the induction of several immediate-early genes

(IEGs). Expression of IEGs as an index of neuronal activation has

been widely used to reveal the sites and mechanisms of action of

APDs (Deutch, 1996). A large number of studies have revealed that

the ability of an APD to induce the IEG c-fos or its protein product

Fos in the striatum correlates well with EPS liability. Thus, typical

APDs, which have high EPS liability, markedly increase dorsal

striatal Fos expression, while atypical APDs that display low or

absent EPS liability result in a much weaker Fos response (Dragunow

et al., 1990; Deutch et al., 1992; Nguyen et al., 1992; Robertson &

Fibiger, 1992).

Two histochemically de®ned compartments can be distinguished in

the mammalian striatum (Olson et al., 1972; Graybiel & Ragsdale,

1978). Among the de®ning characteristics of these compartments is

the m opioid receptor (MOR), which is expressed in the striosome

(patch) but not in the matrix (Herkenham & Pert, 1981). Extensive

anatomical characterization of these compartments has revealed

differences in chemoarchitecture and connectivity (Graybiel, 1990;

Gerfen, 1992). However, the functional characterization of these

compartments remains in its infancy. Available data have led to the

heuristic that the striosome may be involved in affective processes

(reward) and the matrix compartment with sensorimotor integration

(Moratalla et al., 1992; White & Hiroi, 1998; Canales & Graybiel,

2000).

There have been no systematic studies of the degree to which

typical and atypical APDs activate the striosome and matrix, although

anecdotal observations suggest that typical APDs such as haloperidol

induce Fos to an equivalent degree in the striosome and matrix

(Deutch et al., 1996), while atypical APDs such as clozapine may

drive striosomal Fos expression to a greater degree (Hiroi & Graybiel,

1996; Bubser et al., 1999; Bubser & Deutch, 2000).

We therefore compared the effects of several atypical and typical

APDs on Fos expression in the striosome and matrix of the rat.

Atypical APDs such as clozapine have a rich pharmacology with high

af®nities for several receptors with which most typical APDs do not

interact (Fatemi et al., 1996; Schotte et al., 1993; Arnt & Skarsfeldt,

1998). We wished to determine if occupancy of these receptors can

account for the differences between typical and atypical APDs. We

therefore attempted to convert the pattern of Fos expression induced

by administration of the typical APD raclopride, a selective D2

Correspondence: Dr Ariel Y. Deutch, Psychiatric Hospital at Vanderbilt, Suite313, 1601 23rd Avenue South, Nashville, TN 37212, USAE-mail: [email protected]

Received 16 October 2001, revised 31 December 2001, accepted 7 January2002

European Journal of Neuroscience, Vol. 15, pp. 713±720, 2002 ã Federation of European Neuroscience Societies

receptor antagonist, to that of an atypical APD by pretreating rats

with ligands at receptors for which clozapine has a high af®nity.

Finally, we determined the effect of pretreatment with two atypical

APDs, clozapine and risperidone, on the compartmental pattern of

raclopride-induced Fos expression.

Materials and methods

Subjects

Adult male Sprague±Dawley rats (Harlan, Birmingham, AL) were

group-housed under a 12 h light : 12 h dark cycle with food and

water available ad libitum. All experiments were performed in the

light phase and were carried out in accord with the Guide for Care

and Use of Laboratory Animals as promulgated by the National

Institutes of Health, and reviewed and approved by the Vanderbilt

University Medical Center Institutional Animal Care Committee.

Drugs

The various APDs and the doses used are shown in Table 1. The high

dose of each drug was determined with reference to a dose of 1.0 mg/

kg (s.c.) of haloperidol. We set the high doses of other APDs based on

the ratio of their average clinical daily dose to that of haloperidol

(»15 mg). Thus, the dose of clozapine (which in clinical use averages

»450 mg/day) is 30 times greater than the reference clinical dose of

haloperidol (15 mg/day), leading to a dose in the rat of 30 mg/kg (30

fold higher than the arbitrary reference value of 1 mg/kg haloperidol).

Separate groups of animals were challenged with drug doses set at

20% of the high dose (e.g. 0.2 mg/kg haloperidol); the exception was

clozapine, which does not induce striatal Fos at such a low dose. In

addition, in order to determine if low D2 receptor occupancy

contributes to the pattern of compartmental activation, we examined

the effects of administration of 0.1 mg/kg haloperidol, which results

in < 50% in vivo occupancy of D2 receptors (Schotte et al., 1996).

Finally, we examined the effects of another typical APD, chlorpro-

mazine, which differs from haloperidol and racopride by displaying

high af®nities for several receptors in addition to the D2 site (Peacock

& Gerlach, 1996).

Five rats per treatment group (with the exception of clozapine,

which was tested in ten rats) received subcutaneous injections of

APDs. In most cases, acidi®ed water (pH 5.5±6) was used to dissolve

the APDs (haloperidol, clozapine, raclopride, chlorpromazine, and

olanzapine); risperidone and ziprasidone were prepared in a DMSO

solution. For each APD tested, corresponding animals were injected

with the appropriate vehicle on the same day. The injection of

different vehicles did not result in different degrees or patterns of

striatal Fos expression.

We also assessed the effects of pretreating animals with drugs that

bind to receptors targeted by clozapine; these pretreatments were

administered 30 min prior to injection of the typical APD raclopride

(1.0 mg/kg, sc). These antagonist studies had four experimental

groups: vehicle-vehicle, drug-vehicle, vehicle-raclopride, and drug-

raclopride. We examined the effects of pretreatment with the

following antagonists: the 5-HT2A/2C antagonist ritanserin, the

dopamine D1 antagonist SCH 23390, and the noradrenergic a1 and

a2 antagonists prazosin and idazoxan (Schotte et al., 1993; Fatemi

et al., 1996; Arnt & Skarsfeldt, 1998). In the case of idazoxan, two

different doses corresponding to a2-autoreceptor selective or

nonselective doses were tested. We also determined the effects of

the competitive N-methyl-D-aspartate (NMDA) receptor antagonist

(+/±)-CPP and the noncompetitive NMDA antagonist MK-801

because these drugs alter corticostriatal transmission and dampen

the ability of typical APDs to induce Fos in the striatum (Boegman &

Vincent, 1996). Because CLZ is a partial agonist at serotonin 5-HT1A

and muscarinic cholinergic m4 sites (Zorn et al., 1994; Newman-

Tancredi et al., 1998), we examined the effects of the 5-HT1A agonist

8-OH-DPAT and the m1/4 agonist oxotremorine on raclopride-

elicited compartmental Fos expression. Finally, in order to determine

if occupancy of the multiple receptors that are targeted by atypical

APDs can shift a typical APD pro®le to that of an atypical agent, we

TABLE 1. List of antipsychotic drugs and pretreatments used in this study

and their respective doses

Drugs used Type Dose (mg/kg)

Antipsychotic drugsHaloperidol Typical 0.2/1.0Raclopride Typical 0.2/1.0Chlorpromazine Typical 5.0/25.0Risperidone Atypical 0.4/2.0Olanzapine Atypical 1.0/5.0Ziprasidone Atypical 2.5/12.5Clozapine Atypical 30.0

PretreatmentsSCH 23390 D1 0.3Ritanserin 5-HT2A/2C 3.08-OH-DPAT 5-HT1A agonist 0.25Prazosin a1 noradrenergic 1.0Idazoxan a2 noradrenergic 0.2/1.0Scopolamine mAChR 1.0Oxotremorine m1/4 AChR agonist 0.5(+/±)CPP NMDA (competitive) 30.0MK-801 NMDA (non-competitive) 1.0Risperidone Atypical antipsychotic drug 0.4/2.0Clozapine Atypical antipsychotic drug 6/30

Controls received injections of the respective vehicle as outlined in Materialsand methods. Drugs used in the pretreatment paradigm are antagonists exceptwhen noted otherwise. The dose of raclopride used in the pretreatment studieswas 1.0 mg/kg. 5-HT, serotonin; mAChR, muscarinic cholinergic receptor;NMDA, N-methyl-D-aspartate.

FIG. 1. Schematic illustration of the striatal areas in which Fos-li neuronswere counted. Areas in the dorsomedial and dorsolateral striatum in whichthe striosome : matrix ratio of Fos-li cells were determined are illustratedby dashed lines, and the boxes mark where the densities of Fos-li neurons,irrespective of striosomal (light grey patches) and matrix boundaries, werecounted.

714 A. Y. Deutch et al.

ã 2002 Federation of European Neuroscience Societies, European Journal of Neuroscience, 15, 713±720

examined the effects of clozapine (6 and 30 mg/kg) and risperidone

(0.4 and 2.0 mg/kg) pretreatments on raclopride-elicited Fos expres-

sion.

Immunohistochemistry

Two hours after APD injection, rats were deeply anaesthetized with

iso¯uorane and transcardially perfused with 4% paraformaldehyde.

Brains were cryoprotected and coronal sections were cut through the

striatum and stored in glycerine/sucrose/phosphate at ±20 °C until

processed for immunohistochemical detection of Fos- and MOR-like

immunoreactivity (± li). A sequential dual immunoperoxidase

method was followed as previously described (Deutch et al., 1992),

using a goat anti-Fos antibody (1 : 4000; Santa Cruz

Biotechnologies, Santa Cruz, CA) and a rabbit anti-MOR antibody

(1 : 20 000) (Arvidsson et al., 1995).

Data acquisition

The densities of Fos-li cells in two closely matched sections from

each animal at levels corresponding to AP 0.2 and 0.5 (Paxinos &

Watson, 1986) were measured in the dorsolateral and dorsomedial

striatum (see Fig. 1) by counting the number of Fos-li neurons

within MOR-de®ned striosome and matrix compartments. The

microscopic image was imported to a computer using NIH Image

1.6 (developed at the US National Institutes of Health and

available on the internet at http://rsb.info.nih.gov/nih-image). The

number of Fos-li cells within an outlined MOR-li striosome was

®rst counted and the density of Fos-li cells/mm2 within the

striosome was calculated. We then moved the outline overlaying

the striosome to de®ne the exact same area and shape in the

contiguous matrix, and determined the density of Fos-li neurons

in this matrix area. For each animal a total of four striosomal and

eight matrix areas (one matrix area lateral to a given striosome

and one medial to the striosome, in order to avoid any potential

lateralization bias in Fos expression) were analyzed in both the

medial and lateral striatum, and the ratios between the density of

Fos-li cells in the striosome and matrix (striosome : matrix ratio,

SMR) were determined. In order to measure the overall density of

Fos-li cells in the dorsolateral or dorsomedial striatum, irrespect-

ive of compartmental distribution, we counted the number of Fos-

li cells within a rectangular grid measuring 280 3 375 mm size

(see Fig. 1).

Because recent reports have suggested that there may be core and

peripheral regions of the striosome (Jakab et al., 1996; Prensa et al.,

1999), we also measured the intrastriosomal distribution of Fos-li

nuclei in haloperidol- and clozapine-treated rats. The distance of Fos-

li nuclei in the striosome to the closest striosome±matrix border was

measured and the frequency distributions of these values compared

statistically.

Statistical analyses

The density of Fos-li neurons (number of Fos-li cells/mm2) in the

striosome and matrix compartments and the SMR were used in

statistical analyses. In the analysis comparing the SMRs of typical

and atypical APDs, we ®rst determined if there was any difference in

the ratio between the low and high doses of each APD; no such

differences were uncovered, and the SMR data from the low and high

doses were therefore pooled for subsequent analysis. The data were

analyzed by appropriate ANOVAs with subsequent posthoc tests when

indicated. The distributions of the distances of Fos-li neurons within a

given striosome to the closest border of a matrix compartment were

compared using a nonparametric (Kolmogorov±Smirnov) ANOVA.

Results

APD-elicited Fos expression in striatal compartments

In the medial striatum, most APDs tested caused a signi®cant increase

in the density of Fos-li neurons in the striosome relative to vehicle-

injected controls (see Table 2); however, ziprasidone did not effect an

increase in this area. Although visual inspection of the histological

material suggested that ziprasidone increased the density of Fos-li

neurons in the striosome, statistical evaluation revealed no signi®cant

effect for ziprasidone because of the distribution of variance across

the many cells in the ANOVA. Similar results were seen in the

dorsolateral striatum, where most APDs increased the density of Fos-

li cells in the striosome, the exceptions being clozapine and the low

dose of ziprasidone (Fig. 3 and Table 2).

TABLE 2. Effects of acute administration of antipsychotic drugs on the density of Fos-li cells in striatal striosome and matrix compartments

DrugDose(mg/kg) n

Number of Fos-li cells/mm2, medial Number of Fos-li cells/mm2, lateral

Striosome Matrix Striosome Matrix

Vehicle ± 14 19.9 6 8.2 30.6 6 12.6 0.8 6 0.8 0.0 6 0.0

Haloperidol 0.1 4 384.0 6 48.2** 380.5 6 105.1** 823.8 6 86.6** 688.8 6 5.7**0.2 5 327.0 6 30.8** 269.2 6 26.3** 713.0 6 58.8** 582.0 6 16.4**1.0 5 355.2 6 38.1** 262.4 6 40.7** 694.4 6 106.9** 620.6 6 66.8**

Raclopride 0.2 5 412.8 6 81.1** 427.8 6 79.0** 470.8 6 95.8** 469.6 6 100.3**1.0 5 658.0 6 52.3** 587.8 6 27.5** 913.8 6 66.2** 758.2 6 43.8**

Chlorpromazine 5.0 5 464.2 6 66.0** 367.0 6 42.4** 864.2 6 108.1** 713.0 6 90.4**25.0 5 471.8 6 101.9** 375.2 6 47.9** 1038.0 6 141.5** 950.8 6 136.3**

Risperidone 0.4 5 271.8 6 63.4** 128.0 6 33.3 237.6 6 24.7* 131.4 6 13.12.0 5 262.4 6 34.1** 136.6 6 9.6 387.4 6 30.5** 241.8 6 17.3**

Olanzapine 1.0 5 216.6 6 32.1** 129.0 6 18.5 312.2 6 37.6** 202.4 6 58.1*5.0 5 222.4 6 25.4** 125.0 6 17.6 366.0 6 73.3** 226.4 6 32.3**

Ziprasidone 2.5 5 131.6 6 29.3 64.0 6 12.2 219.2 6 54.5 108.4 6 34.912.5 5 173.8 6 14.8 83.2 6 3.7 242.4 6 34.4* 109.8 6 15.9

Clozapine 30.0 10 218.6 6 27.7** 105.0 6 14.6 211.3 6 34.4* 79.7 6 15.6

Data are presented as mean 6 SEM. *P < 0.05, **P < 0.01 vs. vehicle.

Atypical APDs and striatal compartments 715


None of the atypical APDs signi®cantly increased the density of

Fos-li cells in the medial striatal matrix, although all three typical

APDs robustly increased Fos expression in this compartment (Fig. 2

and Table 2). There were no signi®cant differences between

haloperidol, raclopride, and chlorpromazine in the degree to which

they altered total Fos expression, the density of striosomal or matrix

Fos-li neurons, or the Fos SMR. In contrast to the effects of APDs on

matrix Fos expression in the medial striatum, in the matrix of the

dorsolateral striatum the three typical APDs and certain atypical

APDs (olanzapine and the high dose of risperidone) signi®cantly

increased the density of Fos-li cells (see Table 2).

Typical and atypical APDs had strikingly different effects on the

relative abundance of Fos-li cells in the striosome and matrix.

Administration of all three typical APDs (haloperidol, raclopride, and

chlorpromazine) resulted in SMRs of »1.0, re¯ecting comparable

densities of Fos in the two compartments (see Figs 2 and 3). In

contrast, all atypical APDs resulted in SMRs in the dorsolateral

striatum that were signi®cantly greater than 1.0 (Figs 3 and 4); in the

dorsomedial striatum all atypical agents except olanzapine increased

the SMR relative to haloperidol.

Intrastriosomal distribution of Fos-li neurons after haloperidoland clozapine treatments

The mean distance of Fos-li neurons in a striosome to the nearest

striosome : matrix border in the dorsolateral striatum of haloperidol-

treated animals was 18.9 6 1.0 mm (n = 113), while the mean

distance in clozapine-treated rats was 21.2 6 1.5 mm (n = 89).

Comparison of the distributions of these distances did not reveal

any signi®cant difference (Z = 0.769).

Pretreatment of raclopride with selective antagonists

Administration of the competitive and noncompetitive NMDA

antagonists CPP and MK-801 signi®cantly reduced raclopride-

elicited Fos expression in the dorsolateral striatum, irrespective of

compartmental boundaries (see Fig. 5). The 5-HT1A agonist 8-OH-

DPAT and the muscarinic m1/4 agonist oxotremorine also signi®-

cantly reduced the effects of raclopride in the dorsolateral striatum,

although the magnitude of these effects was quite small (Fig. 5).

None of the other pretreatments modi®ed raclopride-elicited Fos

expression.

Although some pretreatments modi®ed the overall number of

striatal Fos-li cells induced by raclopride, without respect to

compartmental boundaries, none of these pretreatments changed the

Fos SMR relative to the value obtained in rats treated with raclopride

alone (see Fig. 5).

Pretreatment of raclopride with atypical APDs

Both clozapine and risperidone signi®cantly reduced raclopride-

elicited Fos expression in the dorsolateral striatum, irrespective of

compartmental boundaries (see Fig. 6). This reduction was seen in

response to both low and high doses of clozapine, and in response to

the high (but not low) dose of risperidone.

Clozapine pretreatment increased the SMR relative to the

raclopride-elicited response (Fig. 6). In contrast, neither dose of

risperidone increased the raclopride-induced SMR.

Discussion

Typical and atypical APDs were readily distinguished on the basis of

the SMR. In contrast, one could not reliably distinguish typical from

atypical APDs based on the degree to which they increased Fos

expression in either striatal compartment alone. Among the various

pretreatments of raclopride, only clozapine was able to convert the

SMR to that of an atypical APD-like pattern.

Receptor pro®le subserving the atypical APD-elicited patternof striatal compartmental activation

The typical APDs haloperidol, raclopride, and chlorpromazine have

high EPS liability and striatal D2 receptor occupancy (Hall et al.,

0HPD RAC CPZ OLA RIS ZIP CLZ

1

2

3

4

**

**

** *

***

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Dorsomedial StriatumDorsolateral Striatum

FIG. 3. The striosome : matrix ratio (SMR) of Fos-like immunoreactive celldensities in the dorsomedial striatum (light columns, F6,73 = 12.2,P < 0.0001) and dorsolateral striatum (dark columns, F6,73 = 24.8,P < 0.0001) is higher in rats treated with atypical APDs than typical APDs.The data represent the SMRs collapsed across the low and high doses ofeach APD, as there was no signi®cant difference between the doses.Abbreviations: CLZ, clozapine; CPZ, chlorpromazine; HPD, haloperidol;OLA, olanzapine; RAC, raclopride; RIS, risperidone; ZIP, ziprasidone.*P < 0.05, **P < 0.01 vs. HPD

FIG. 2. Localization of Fos-li neurons in the striosome and matrix of thedorsolateral striatum in response to haloperidol (top panel) and clozapine(bottom panel). Fos-li neurons, which are seen as black dots, are expressedthroughout the striatum and are present in high density in both striosome(grey cloud of MOR-li) and matrix compartments of a haloperidol-treatedrat (top). In a section from a clozapine-treated animal (bottom), few Fos-licells are seen in the matrix, with most Fos-li neurons being present in theMOR-li striosome. Scale bar, 80 mm.



1989) while atypical APDs have low or absent EPS liability and

relatively low D2 receptor occupancy in vivo (Nordstrom et al.,

1993). Atypical APDs also differ from most typical APDs by

displaying high in vivo af®nities to multiple receptors (Schotte et al.,

1996; Zhang & Bymaster, 1999). Haloperidol and raclopride bind

almost exclusively in vivo to D2 receptors (Hall et al., 1989). All of

the atypical APDs that we studied have high af®nity for the 5-HT2A

receptor. They also interact in vivo with other receptors, including D1

(risperidone, olanzapine, and clozapine), muscarinic cholinergic

(olanzapine and clozapine), and a1 (clozapine) sites. In order to

determine if broad occupancy of receptors was suf®cient by itself to

confer an atypical APD-like SMR, we also examined the effects of

chlorpromazine, which has high af®nities for several receptors

(including D2, D1, 5-HT2A, a1, and muscarinic cholinergic sites)

but is a typical APD (Peacock & Gerlach, 1996).

The fact that atypical APDs all displayed high af®nities for

multiple receptors suggested that we might be able to mimic the high

SMR seen after atypical APD challenge by treating rats with both the

D2-selective typical APD raclopride and selective antagonists to

receptors to which many atypical APDs bind. These pretreatments

with selective antagonists uniformly failed to increase the raclopride-

induced SMR, although in several cases they did modify overall Fos

expression without respect to compartmental boundaries. Neither

ritanserin nor prazosin changed overall D2 antagonist-elicited Fos

expression, consistent with previous reports (Fink-Jensen et al.,

1995), as is our observation that the 5-HT1A agonist 8-OH-DPAT

slightly but signi®cantly decreased overall raclopride-elicited Fos

expression (Tremblay et al., 1998). Because clozapine is an agonist at

the m4 receptor but an antagonist at other muscarinic sites (Zorn et al.,

1994), we examined the effects of the m1/4 agonist oxotremorine,

which has been reported to increase Fos in the striosome (Bernard

et al., 1999). However, we saw no increase in the SMR of animals

treated with oxotremorine and raclopride relative to animals treated

with raclopride alone. It seems unlikely that selective m4 agonism

accounts for the high SMR seen with atypical APDs, as risperidone

and ziprasidone have low m4 af®nity (Zeng et al., 1997). High

(3.0 mg/kg) doses of scopolamine attenuate the ability of typical

APDs to induce striatal Fos (Guo et al., 1992). However, at the lower

dose (1.0 mg/kg) that we used, which blocks diverse cholinergic

functions (Meltzer et al., 1994; Delfs et al., 1995), there was no

change in either overall raclopride-elicited striatal Fos or the SMR.

This observation is consistent with early data indicating that addition

of an anticholinergic to a typical APD does not yield an atypical

APD-like pro®le (Ljungberg & Ungerstedt, 1979).

150

100

50

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(% o

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150

100

50

0.1

0

0.3

0

3.0

0

0.2

5

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0

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(% o

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SCH RIT 8-OH PRZ IDA SCO OXO CPP MK

+ Raclopride

* **

***

***

FIG. 5. The effects of pretreatment of raclopride-injected rats with selectiveagonists and antagonists. Various drugs that are selective agents at receptorsfor which clozapine displays high af®nity do not alter the dorsolateral striatalstriosome : matrix ratio of Fos cell densities seen in response to raclopride(top panel), even though the overall density of Fos-li cells, without respect tostriatal compartments, was changed by some drug pretreatments.Abbreviations: 8-OH, 8-OH-DPAT; IDA, idazoxan; MK, MK-801; OXO,oxotremorine; PRZ, prazosin; RAC, raclopride; SCH, SCH 23390; SCO,scopolamine; VEH, vehicle. *P < 0.05 **P < 0.01 vs. VEH-RAC.

*** ****

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5

4

3

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Fos

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TypicalAPDs

AtypicalAPDs

FIG. 4. Scatter plot of the mean Fos striosome : matrix ratios in thedorsolateral striatum of individual animals of all APD treatment conditions.Note that there is virtually no overlap between the SMRs of typical andatypical APDs. The overall mean of typical and atypical APDs is indicatedby the horizontal line in each group of points. j, haloperidol; .,raclopride; m, chlorpromazine; n, ziprasidone; s, risperidone; h,olanzapine; :, clozapine.



APDs lack signi®cant af®nity for the NMDA receptor, although at

micromolar concentrations haloperidol can in¯uence NMDA receptor

function (Coughenour & Cordon, 1997). NMDA antagonists signi®-

cantly reduce haloperidol-elicited striatal Fos expression, presumably

by dampening corticostriatal glutamatergic transmission and modi-

fying intracellular Ca2+ concentrations in striatal medium spiny

neurons (Boegman & Vincent, 1996; Leveque et al., 2000). However,

neither competitive (CPP) nor noncompetitive (MK-801) NMDA

antagonists altered the raclopride-elicited SMR, despite signi®cantly

decreasing overall Fos expression.

Clozapine, risperidone, and olanzapine share high af®nity for the

5-HT7 receptor, and all but risperidone have high af®nity for the 5-

HT6 receptor (Schotte et al., 1993; Roth et al., 1994). Unfortunately,

we were unable to assess the role of these receptors because of the

lack of available selective antagonists.

Some analyses have concluded that low D2 receptor occupancy

contributes to the clinical pro®le of atypical APDs. However, three

arguments suggest that low D2 receptor occupancy does not subserve

the high SMR seen in response to atypical but not typical APDs. First,

clozapine pretreatment of raclopride increased the SMR relative to

raclopride alone, despite the fact that the combined treatment results

in high occupancy of both D2 and 5-HT2A receptors. Second, low and

high doses of atypical APDs yielded comparable SMRs, despite the

fact that the higher doses more completely occupy D2 sites. Finally,

the SMR observed in rats treated with 0.1 and 1.0 mg/kg haloperidol

did not differ, even though the lower dose of this typical APD

occupies < 50% of striatal D2 receptors in vivo (Schotte et al., 1996).

The inability of selective receptor antagonists to convert the

raclopride pattern of compartmental Fos expression to that of an

atypical APD suggests that it is unlikely that only two receptors (such

as 5-HT2A and D2 sites) account for the atypical APD pattern.

However, because clozapine signi®cantly increased the raclopride-

elicited SMR, it is clear that an appropriate treatment can indeed

change Fos expression to the compartmental pattern seen after

atypical APD treatment.

Both clozapine and risperidone pretreatments decreased overall

raclopride-elicited Fos expression, but only clozapine signi®cantly

increased the raclopride-induced SMR. This was seen in animals

treated with either 30 or 6 mg/kg clozapine. Risperidone by itself

resulted in the characteristic high SMR seen with all the atypical

APDs but did not reverse the SMR elicited by the typical APD

raclopride. These ®ndings suggest that there are either receptors with

which clozapine (but not risperidone) interacts that do not reverse the

typical APD-like effect of raclopride, or alternatively that clozapine

targets an as yet unidenti®ed receptor. Although the latter argument is

possible, it is not tractable to experimental analysis. Based on the

testing of a large number of selective antagonists in combination with

raclopride, we suspect that there is a particular array of receptors that

collectively must be targeted to account for the difference between

clozapine and risperidone. Bolstering the contention that occupancy

of a particular combination of multiple receptors is required is the

observation that the typical APD chlorpromazine, which interacts

with multiple receptors, does not display an atypical APD-like SMR.

The function of striatal compartments and clinical relevance tothe actions of APDs

Although the compartmental organization of the striatum has been

appreciated for 30 years, the functional aspects subserved by the two

compartments remain poorly understood. There are no means

currently available to ablate selectively one compartment, and studies

probing compartmental function have therefore been correlative or

used electrical stimulation of the striatum with subsequent recon-

structions of electrode placement.

Several studies have linked the matrix compartment with motor

behaviour. Moratalla et al. (1992) reported that the dopamine

innervation of the matrix compartment degenerates preferentially in

primates treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,

the neurotoxin that results in parkinsonism. White (1989) has argued

that the matrix may be involved in reinforcement; the pairing of

individual components of a motor repertoire into a more complex

behaviour ®ts well with the concept that the matrix is involved in

stimulus-response strengthening. Less work has focused on the

functions of the striosome. Striosomes in the medial striatum have

been reported to sustain intracranial self-administration to a greater

degree than matrix areas (White & Hiroi, 1998), leading to the

suggestion that the striosomal compartment subserves reward.

It is dif®cult to place the therapeutic and side-effects of APDs into

the context of the function of individual striatal compartments.

Neuroleptic-elicited EPS and the motor de®cits of Parkinson's disease

may be linked to changes in the function of matrix neurons that result

from decreased dopamine function in this compartment (Moratalla

et al., 1992). However, Parkinson's disease is also marked by high

incidence of depression (Poewe & Luginger, 1999) and such affective

changes may be related to the striosome, particularly late in the course

0.5

1.5

VEH CLZ

+ RAC + RAC

CLZ VEH RIS RIS

6.0 30.0 0.4 2.0

1.0

2.0

200

400

600

800

Srt

rioso

me:

Mat

rix R

atio

Num

ber

of F

os-li

cel

ls/m

m2

*

* *

**

**

FIG. 6. Reversal of raclopride-induced Fos expression in the striatum byatypical APDs. Pretreatment with clozapine (CLZ; F2,14 = 10.3, P < 0.01)but not risperidone (RIS; F2,13 = 2.41, P > 0.05) increases the SMR relativeto animals pretreated with vehicle prior to raclopride (RAC) challenge (toppanel). In contrast, both clozapine (F2,14 = 36.6, P < 0.001) and risperidone(F2,13 = 6.36, P < 0.05) blunted the ability of raclopride to induce overallFos in the dorsolateral striatum (bottom panel). *P < 0.01 **P < 0.01 vs.VEH-RAC.



of the disease when striatal dopamine loss is more extensive and

impacts the striosome to a greater degree. In this vein, the proposed

association of the striosome and reward is in line with the ability of

atypical APDs to effectively target certain negative symptoms in

schizophrenia (Deutch et al., 1991).

It is also dif®cult to associate the cognitive dysfunction of

schizophrenia (Meltzer et al., 1999; Green & Braff, 2001) with

striatal compartmental function if the crude heuristic that associates

motor function with the matrix and reward with the striosome is

correct. The striosome receives prominent inputs from association

cortex (Gerfen, 1992), raising the possibility that the striosome is

involved in cognition. Some atypical APDs improve certain cognitive

de®cits in schizophrenia, but such improvements are neither consist-

ent across different cognitive domains nor across different atypical

APDs (Meltzer & McGurk, 1999). Moreover, we did not ®nd any

consistent relationship between Fos induction in the striosome and

atypical APDs. It has been suggested that there are distinct

intrastriosomal territories (Jakab et al., 1996; Prensa et al., 1999),

but we did not see any clear indication of such a subcompartmental

organization using MOR-li to de®ne the striosome, nor did we ®nd a

signi®cant difference between the intrastriosomal distributions of

Fos-li neurons of rats treated with clozapine and haloperidol. Thus,

one cannot associate the ability of atypical or typical APDs to modify

the cognitive de®cits in schizophrenia with either the striosome (or

any subcompartmental organization therein) or matrix.

The dif®culties that confront attempts to relate distinct effects of

APDs to either the striosome or matrix compartment suggest that the

relative degree of activity between the two compartments is more

critical than activity in individual compartments.

Coordinate regulation of the striosome and matrix

We found that typical and atypical APDs could be differentiated on

the basis of the SMR in both the medial and lateral striatum. Canales

& Graybiel (2000) have reported a striking correlation between the

SMR and chronic psychostimulant-elicited motor stereotypies, but

not between stereotypy and activation of a single compartment alone.

Interestingly, both our data and those of Canales & Graybiel (2000)

suggest that various manipulations may readily alter the IEG response

in the matrix but that the striosomal response remains relatively

constant. As Fos induction in the matrix does not correlate directly

with the treatment condition but the SMR does, it follows that the

coordinate regulation of the two compartments determines functional

signi®cance.

The mechanisms that underlie coordinated regulation of the

striosome and matrix are not clear. Medium spiny neurons in the

rat have dendritic arbors that mainly conform to the boundaries of the

compartment in which the soma is located, i.e. dendrites of striosomal

cells remain in the striosome, matrix neuron dendrites in the matrix

(Penny et al., 1988; Kawaguchi et al., 1989). In contrast, the dendritic

arbors of many interneurons, whose perikarya are often situated near

striosome±matrix borders, cross compartmental boundaries and may

therefore coordinate activity across the compartments (Chesselet &

Graybiel, 1986; Kawaguchi et al., 1989). Although most medium

spiny neurons have low basal rates of discharge, certain striatal

interneurons are often tonically active (Aosaki et al., 1995). In

particular, parvalbumin-containing interneurons, which receive con-

vergent cortical and pallidal inputs (Bolam et al., 2000), are a

possible substrate for integrating activity between the compartments,

as cortical drive appears to preferentially activate striatal parvalbumin

interneurons (Berretta et al., 1997). Svenningsson et al. (2000)

suggested that the ability of combined D1±D2 receptor activation to

drive Fos expression in a striosome-enriched fashion may be related

to activation of cholinergic interneurons. One concern about a

proposed role for interneurons in subserving the observed differences

between typical and atypical APDs is that the degree to which

different types of interneurons are activated in the presence of APDs

is not clear; D2 receptor antagonists increase local release of GABA

from medium spiny neurons (Osborne et al., 1994) and might

therefore be expected to inhibit interneurons.

Future studies will be required to unravel the mechanisms

responsible for coordinate regulation of striosome and matrix. The

ability of different classes of antipsychotic drugs to differentially alter

the coordinated activity of neurons in the striosome and matrix

compartments provides an experimental manipulation to exploit in

such studies, and may help explain the origin of certain therapeutic

and side-effects of antipsychotic drugs.

Acknowledgements

We thank Tom A. Lanz and Charee M. Stanley for their help with theexperiments, Tamara L. Altman for preparing the illustrations, and Dr RobertElde for the generous gift of the m-opioid receptor antiserum. This study wassupported by a NARSAD Young Investigator Award (MB), NIH grantsMH 45124 and MH 57995 (AYD), the National Parkinson Foundation Centerof Excellence at Vanderbilt University, and support from Eli Lilly andCompany and P®zer, Inc.

Abbreviations

APD, antipsychotic drug; EPS, extrapyramidal side-effects; IEG, immediate-early gene; -li, -like immunoreactivity; MOR, m opioid receptor; NMDA, N±methyl-D-aspartate; SMR, striosome : matrix ratio.

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