gy 534 (2006) 108–114www.elsevier.com/locate/ejphar

European Journal of Pharmacolo

Dopamine D3 receptor modulation of dopamine effluxin the rat nucleus accumbens

Claire Roberts ⁎, Robert Cummins, Zaira Gnoffo, James N.C. Kew

Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK

Received 26 May 2005; received in revised form 9 January 2006; accepted 11 January 2006Available online 21 February 2006

Abstract

The effect of antipsychotics on electrically evoked dopamine efflux in the rat nucleus accumbens core and shell was investigated, using in vitro fastcyclic voltammetry. In the nucleus accumbens core, the dopamine D2/D3 receptor agonist, (±)7-OH-DPAT ((±)-2-dipropylamino-7-hydroxy-1,2,3,4-tetrahydronaphthalene), inhibited dopamine efflux with a pEC50 of 8.1. Clozapine, haloperidol, sulpiride and the selective dopamine D3 receptorantagonist, SB-277011-A, had no effect on dopamine efflux per se but all attenuated the (±)7-OH-DPAT-induced-inhibition of dopamine efflux,with pA2

values of 6.6, 7.9, 7.0 and 7.6, respectively. In the nucleus accumbens shell, (±)7-OH-DPAT inhibited dopamine efflux with a pEC50 of 8.3. Clozapineand SB-277011-A had no effect on dopamine efflux. In contrast, haloperidol and sulpiride significantly increased dopamine efflux through aD2 receptor-mediated mechanism. Clozapine, haloperidol, sulpiride and SB-277011-A attenuated the (±)7-OH-DPAT-induced inhibition with pA2 values of 7.3, 8.6,7.6 and 8.2, respectively. These data demonstrate that dopamine efflux ismodulated by both dopamineD2 andD3 receptors in the rat nucleus accumbens.© 2006 Elsevier B.V. All rights reserved.

Keywords: Dopamine; Nucleus accumbens shell and core; SB-277011-A

1. Introduction

Dopamine projections to the forebrain arise from two mainregions in the brain: the substantia nigra (A9) and the ventraltegmental area (A10). There are 3 main dopaminergic pro-jections arising from the substantia nigra and ventral tegmentalarea, classified as nigrostriatal (substantia nigra to striatum),mesocortical (ventral tegmental area to cortex) and mesolimbic(ventral tegmental area to nucleus accumbens).

It has been proposed that the positive symptoms of schizo-phrenia (delusions, hallucinations and thought disorders) resultfrom overactivity of the mesolimbic dopaminergic systemwhich is thought to be the major pathway at which neurolepticsexert their antipsychotic effect (Weinberger, 1987). In contrast,drug effects on the nigrostriatal dopaminergic system arethought to be responsible for the generation of adverse sideeffects, such as extrapyramidal symptoms and tardive dyskine-sias (Baldessarini, 1985).

⁎ Corresponding author. Tel.: +44 01279 622 684; fax: +44 01279 875 389.E-mail address: Claire_2_Roberts@gsk.com (C. Roberts).

0014-2999/$ - see front matter © 2006 Elsevier B.V. All rights reserved.doi:10.1016/j.ejphar.2006.01.014

Of the areas associated with the mesolimbic pathway, thenucleus accumbens is of particular interest because it is a con-vergent site for inputs from the amygdala, hippocampus, en-torhinal area, anterior cingulate area and parts of the temporallobe (Groenewegan et al., 1999). The nucleus accumbens thenprojects to the hypothalamus, septum, anterior cingulate areaand frontal lobes.

In respect to dopaminergic inputs the nucleus accumbensreceives projections predominantly from the ventral tegmentalarea, as part of the mesolimbic system and predominantly fromthe substantia nigra, as part of the nigrostriatal system. Theseprojections have discrete localisations within the nucleusaccumbens termed the shell and core regions (Zaborszky etal., 1985) which receive projections from the ventral tegmentalarea and substantia nigra, respectively (Groenewegan et al.,1999; Csernansky and Bardgett, 1998). Therefore, the nucleusaccumbens is a useful brain region in which to study drugeffects on both the mesolimbic and nigrostriatal dopaminergicpathways, which are believed to reflect antipsychotic activityand motor side effect liability, respectively.

In addition to the anatomical divisions, many physiologicaldifferences also exist between the shell and the core. For

Fig. 1. Waveforms of fast cyclic voltammetry. The top trace is the appliedvoltage waveform (−1.0 to±1.0 V, 1.5 cycles at a rate of 480 V/s) and thebottom trace the background current generated at the working electrode while inartificial CSF.

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example, many reports in the literature demonstrate differencesin dopamine levels in the shell and core. Deutch and Cameron(1992) reported that ex-vivo dopamine tissue levels were higherin the shell than the core with 110 and 78 ng/mg protein, res-pectively. In vivo basal levels of extracellular dopamine werereported to be higher in the shell than the core, using differentialpulse voltammetry (Marcus et al., 1996) but higher in the corethan the shell while using microdialysis (Cadoni and Di Chiara,2000; Zocchi et al., 2003). More relevant to this study, there isevidence that electrically evoked dopamine efflux is greater inthe core than the shell (Jones et al., 1996). In addition, it hasbeen demonstrated that dopamine re-uptake following electri-cal stimulation is greater in the core than the shell, presumablybecause of the increased density of re-uptake sites in the core(Jones et al., 1996). As a consequence, dopamine re-uptakeinhibitors, e.g. nomifensine, have larger effects on extracellulardopamine levels in the core compared to the shell (Jones et al.,1996).

Differences in the acute effects of antipsychotic drugs be-tween these two regions have also been observed. Thus, hal-operidol and olanzapine increase extracellular dopamine levelsto a greater extent in the core than the shell, whilst quetiapineand low doses of clozapine have larger effects in the shell(Marcus et al., 1996; 2000). However, care must be taken whencomparing evoked responses from varying basal levels ofdopamine (Zocchi et al., 2003).

All of the above mentioned compounds have affinity for bothdopamine D2 and D3 receptors, which are differentially dis-tributed in the core and shell subregions of the nucleusaccumbens. Localisation of both dopamine D2 and D3 receptorson dopaminergic terminal fields (such as the nucleus accum-bens) and dopaminergic cell bodies (substantia nigra and ventraltegmental area) have led to proposals that these receptorsfunction as dopaminergic autoreceptors. In support of this, invitro (Tang et al., 1994; Gainetdinov et al., 1996) and in vivostudies (Gobert et al., 1995; Millan et al., 2000; Reavill et al.,2000) have demonstrated both dopamine D2 and D3 receptormodulation of dopamine release.

There is evidence for a higher dopamine D3 receptor densityin the mediolateral shell than the core while D2 receptors arefound at equivalent levels in both regions (Schwartz et al.,2000). Thus, dopamine D3 receptor activation could differen-tially modulate dopamine release in the nucleus accumbensshell over the core.

In the literature, knock-out (KO) studies have thrown intoquestion the importance of dopamine D3 receptors in the mod-ulation of dopamine release. L'hirondel et al. (1998) demon-strated that, in D2 receptor KO mice, evoked [3H]dopaminerelease from striatal slices was not modulated by dopamine D3

receptor agonists. In addition, Koeltzow et al. (1998) suggestedthat in vivo dopamine release in ventral striatum of dopamineD3 receptor KO mice was primarily under D2 receptor-mediatedcontrol. However, both studies used agonists that are nowthought to be non-selective in native tissue preparations to reachtheir conclusions (Levesque, 1996; Xu et al., 1999). Morerecently, Zapata and Shippenberg (2005) also failed todemonstrate any dopamine D3 receptor modulation of dopa-

mine release in the nucleus accumbens or caudate of D2 receptorKO mice. In contrast to these findings, both Zapata et al. (2001)and Joseph et al. (2002) demonstrated decreased effects ofdopamine D3 receptor agonists in dopamine D3 receptor KOmice and concluded that the dopamine D3 receptor had a smallbut significant role as a dopamine autoreceptor.

In light of the contradictory data arising from KO animals, inthis study we examined the role of dopamine D3 receptors in themodulation of dopamine efflux in the nucleus accumbens coreand shell using a highly selective dopamine D3 receptorantagonist. More specifically, using the technique of in vitro fastcyclic voltammetry we have investigated the modulation ofelectrically evoked dopamine efflux from the nucleus accum-bens core and shell using the dopamine D2/D3 agonist (±)7-OH-DPAT, with mixed dopamine D2/D3 receptor antagonistantipsychotic drugs, and the selective dopamine D3 receptorantagonist, SB-277011-A (Reavill et al., 2000). Preliminaryresults were reported previously at the British NeuroscienceAssociation (Roberts et al., 2003).

2. Materials and methods

2.1. Materials

Haloperidol, sulpiride, clozapine and (±)7-OH-DPAT werepurchased from Tocris. GBR-12909 (1-(2-[bis(4-Fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine) was purchasedfrom Sigma. SB-277011-A (trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinoline car-boxamide) was synthesised at GlaxoSmithKline. Compoundswere dissolved in dimethylsulphoxide (DMSO) to generate astock solution of 1 mM. Subsequent dilutions were made intoartificial cerebrospinal fluid (CSF: NaCl 120 mM; KCl 2.5 mM;NaHCO3 26 mM; NaH2PO4 1.2 mM; MgCl2 1.3 mM; CaCl22.4 mM; glucose 10 mM) and the final slice exposure to DMSOduring the experiment was less than or equal to 0.1%. Con-centrations of antagonists used within the study were 3 fold

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higher than their binding affinity at human cloned dopamine D3

receptors.

2.2. In vitro fast cyclic voltammetry

Male Sprague–Dawley rats (100–150 g) were sacrificedusing terminal anaesthesia (halothane) followed by decapita-tion. The brain was rapidly removed and a coronal 400 μm brainslice containing the nucleus accumbens prepared in ice-cold“slicing” buffer (KCl 2.5 mM; NaHCO3 26 mM; MgCl2 5 mM;NaH2PO4 1.2 mM; CaCl2 0.1 mM; sucrose 189 mM; glucose10 mM). The slice was allowed to recover in oxygenatedartificial CSF at room temperature for 60 min. The slice wasthen transferred to a brain slice chamber where it was perfusedat 2.5 ml/min with oxygenated artificial CSF at 32 °C. Astimulating (bipolar tungsten, 100 μm tip diameter, 150 μm tipseparation) and voltammetric carbon fibre electrode were placedin the nucleus accumbens, shell or core, at a depth of 100 μm.The voltammetric electrode tip was positioned equidistantbetween those of the stimulating electrode and about 1 mm tothe right, just off linearity. Carbon fibre electrodes were madein-house according to Armstrong-James and Millar (1979). Asingle carbon fibre (8 μm diameter) was inserted into a glasscapillary (GC200-10, 2 μm o.d.×1.16 μm i.d., HarvardApparatus Ltd.) and pulled in an Ealing microelectrode puller(Harvard Apparatus Ltd.). The carbon fibre connecting the 2resulting micropipettes was then cut and trimmed to a length of50–100 μm. Electrical connection to the carbon fibre was madevia a silver paint coated wire. The paint was allowed to dryovernight before use. Carbon fibre electrodes were calibratedwith standards before the experiment. There did not appear to beany significant deterioration of sensitivity of the carbon fibreelectrode for up to a month of use.

A triangular voltage waveform (−1.0 to +1.0 V, 1.5 cycles ata rate of 480 V/s) was applied to the carbon fibre electrode at afrequency of 2 Hz (Fig. 1). Dopamine efflux was evoked bytrains of 20 electrical stimuli at 20 Hz, with each pulse deliveredat 10 mA for 0.1 ms. To aid identification of the dopamine,initially a background scan (Fig. 1, average of 10 scans) wassubtracted from those obtained during calibration and stimula-

Fig. 2. Faradaic currents for dopamine after subtraction of background current. (A) It=0, 5 and 10 min. (B) Increasing currents generated following electrical stimulation−200 mV, respectively.

tion to generate a faradaic current. An oxidation and reductionpeak around 600 and −200 mV, respectively, confirmed theexistence of dopamine (Fig. 2). Throughout the experiment thecurrent was then sampled at 600 mV and fed into a chartrecorder and a CED 1401 AD interface. Data captured with theCED 1401 were analysed using CED “Signal” software.

2.3. Data analysis and statistics

Carbon fibre electrode's were calibrated before use bymeasuring current generated to 100 nM and 1 μM dopaminestandards. Data were expressed as a percentage of their res-pective control levels prior to drug perfusion and summarised asmean area under the curve (AUC) post drug perfusion. All datawere expressed as mean±S.E.M. The minimum number ofobservations were ascertained by power analysis (Roberts et al.,2004). That is, the variance inherent in the experiment was usedto calculate a graph relating sample number with magnitude ofresponse. Statistical analysis was performed on the AUCsummary data using a one-way analysis of variance (ANOVA);factor=group) followed by a post hoc t-test (least squares dif-ference). Comparisons of pEC50 values were obtained usingindependent Student t-tests. Significance was taken at Pb0.05in all cases.

Concentration–response curves were generated from thedata for (±)7-OH-DPAT, in the absence and presence ofantagonist, by taking the mean AUC for the last 3 samples ateach concentration. These curves were then utilised to calculatepA2 values from the equation: pA2= log [EC50 of agonist inpresence of antagonists /EC50 agonist)−1]− log [antagonist].

3. Results

3.1. Nucleus accumbens core

The concentration of extracellular dopamine in the nucleusaccumbens core was raised to 200±15 nM (n=5) in response toeach train of 20 electrical stimuli delivered at 20 Hz. Clozapine(300 nM), haloperidol (30 nM), sulpiride (300 nM) and theselective dopamine D3 receptor antagonist, SB-277011-A

ncreasing currents generated after perfusion of a 100 nM dopamine standard atof DRN at t=0.5 and 1 s. Oxidation and reduction peaks occur at around 600 and

Fig. 3. Effect of clozapine, haloperidol, sulpiride and the selective D3 receptorantagonist, SB-277011-A, on dopamine efflux from the rat nucleus accumbenscore. In this and all subsequent figures, data are mean±S.E.M. and numbers inparentheses denote number of slices tested per group.

Table 1pKi values, generated from binding at recombinant human dopamine receptors(GSK unpublished data), compared with pA2 values, generated by fast cyclicvoltammetry, in the nucleus accumbens shell and nucleus accumbens core

Compound pKi pA2

D1 D2 D3 Nucleusaccumbens shell

Nucleusaccumbens core

(±)7-OH-DPAT

6.1 7.0 8.6

Haloperidol 7.8 8.8 8.1 8.6 7.9Sulpiride 4.4 7.9 7.4 7.6 7.0Clozapine 7.1 7.0 6.7 7.3 6.6SB-277011-A 6.0 (5.6) 8.0 (8.0) 8.2 7.6

Values in parentheses quote pKi affinity at rat cloned receptors (Reavill et al.,2000).

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(30 nM, 300 nM, 1 μM), had no significant effect on dopamineefflux (Fig. 3) (ANOVA details: PN0.05, F=2.4, df=4).

In contrast, (±)7-OH-DPAT (10 nM–100 nM) inhibiteddopamine efflux in a concentration-dependent manner (Fig. 4),reaching a minimum mean AUC of 30±5% of control (n=3) at100 nM, with a pEC50 of 8.1±0.1 (n=3). Subsequent ex-

Fig. 4. Effect of (+)7-OH-DPAT on dopamine efflux from the rat nucleusaccumbens core, in the presence and absence of SB-277011-A.

periments demonstrated that (±)7-OH-DPAT had no effect ondopamine efflux at 1 nM and effect at 100 nM was significantlylower than that at 10 nM (Pb0.05). SB-277011-A (300 nM and1 μM), haloperidol (30 nM), sulpiride (300 nM) and clozapine(300 nM) all attenuated the (±)7-OH-DPAT-induced-inhibitionof dopamine efflux, with pA2 values of 7.6 (Fig. 3, n=4–5), 7.9,7.0 and 6.6 (n=4), respectively (Table 1).

3.2. Nucleus accumbens shell

The concentration of extracellular dopamine in the nucleusaccumbens shell was raised to 159±22 nM (n=5) in response toeach train of 20 electrical stimuli delivered at 20 Hz. Clozapine

Fig. 5. Effect of clozapine, haloperidol, sulpiride and the selective D3 receptorantagonist, SB-277011-A, on dopamine efflux from the rat nucleus accumbensshell. ⁎Pb0.05 when comparing AUC with control.

Fig. 6. Effect of SB-277011-A on dopamine efflux from the rat nucleusaccumbens shell, in the presence and absence of GBR-12909. In the groupGBR-12909±SB-277011-A, GBR-12909 was perfused for at least half an hourbefore recording and was present throughout the experiment: SB-277011-Awasadded after the third sample as indicated by the bar. ⁎Pb0.05 when comparingAUC with control.

Fig. 8. Effect of (±)7-OH-DPAT on dopamine efflux from the rat nucleusaccumbens shell, in the presence and absence of SB-277011-A.

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(300 nM) and SB-277011-A (30 nM, 300 nM) had no sig-nificant effect on dopamine efflux (Fig. 5). In contrast,haloperidol (30 nM) and sulpiride (300 nM) significantly(Pb0.05) increased dopamine efflux to 155±18% (n=4) and

Fig. 7. Effect of sulpiride on dopamine efflux from the rat nucleus accumbensshell, in the presence and absence of SB-277011-A. In the group SB-277011-A+Sulpiride, SB-277011-A was perfused for at least half an hour beforerecording and was present throughout the experiment: Sulpiride was added afterthe third sample as indicated by the bar. ⁎Pb0.05 when comparing AUC withcontrol.

190±15% of control (n=9), respectively (Fig. 5) (ANOVAdetails: Pb0.05, F=15.4, df=4).

To establish whether the selective dopamine D3 receptorantagonist, SB-277011-A, was able to increase dopamine effluxin the presence of an elevated dopamine tone, the effect of SB-277011-A was investigated in the presence of the dopamineuptake inhibitor, GBR-12909. GBR-12909 (1 μM) significantlyincreased (Pb0.05) dopamine efflux to a maximum of 195±16% of control (Fig. 6, n=3). In the presence of this uptakeinhibitor SB-277011-A (300 nM) produced no further increasein dopamine efflux (Fig. 6, n=3) (ANOVA details: Pb0.05,F=24.7, df=3).

To investigate whether the significant increase in dopamineefflux observed with sulpiride was due to dopamine D2 or D3

receptor antagonism, its effects were investigated in the pres-ence of the selective dopamine D3 receptor antagonist, SB-277011-A. The increase in dopamine efflux induced by 300 nMsulpiride was not significantly altered in the presence of 300 nMSB-277011-A, with dopamine efflux increasing to 184±21% ofcontrol (Fig. 7, n=4) (ANOVA details: Pb0.05, F=46.9,df=3).

(±)7-OH-DPAT (10 nM–100 nM) inhibited dopamineefflux in a concentration-dependent manner (Fig. 8), reachinga minimum mean AUC of 38±3% of control (n=7) at 100 nM,and a pEC50 of 8.3±0.2 (n=7). As in the core, no effect of(±)7-OH-DPAT on dopamine efflux was evident at 1 nM andeffect at 100 nM was significantly lower than 10 nM (Pb0.05).There was no significant difference in the maximum inhi-bition or the pEC50 value of (±)7-OH-DPAT in the nucleusaccumbens core compared to that obtained in the shell. SB-277011-A (Fig. 6; 30 nM, 300 nM), haloperidol (30 nM),sulpiride (300 nM) and clozapine (300 nM) all attenuated the(±)7-OH-DPAT-induced inhibition of dopamine efflux with

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pA2 values of 8.2, 8.6, 7.6 and 7.3 (n=4), respectively(Table 1).

4. Discussion

In this study we have investigated the modulation of dopa-mine efflux in the nucleus accumbens, using in vitro fast cyclicvoltammetry. In the nucleus accumbens shell only compoundswith high D2 receptor affinity, i.e. sulpiride and haloperidol,increased dopamine efflux. Both these compounds also possesshigh dopamine D3 receptor affinity. However, the ability ofsulpiride to increase dopamine efflux in the presence of dopa-mine D3 receptor blockade confirmed that the observed in-creases were D2 receptor-mediated. We were unable to observea dopamine D3 receptor-mediated increase in dopamine effluxunder conditions of high endogenous dopamine tone, as shownby the lack of effect of SB-277011-A in the presence of do-pamine re-uptake blockade.

There are many literature reports confirming that sulpirideincreases dopamine efflux in vitro in rat nucleus accumbens(Chesi et al., 1995; Gobert et al., 1995; Yamada et al., 1995;Cragg and Greenfield, 1997) with smaller increases reported forhaloperidol and clozapine (Yamada et al., 1995). Although theseearly studies did not differentiate between shell and core regionsof the nucleus accumbens they also suggested that the sulpirideeffects were D2 receptor mediated. In a microdialyisis studywhich differentiated the two regions of the nucleus accumbens,Marcus et al. (1996) demonstrated that both clozapine andhaloperidol induced increases in dopamine levels in the nucleusaccumbens, with the atypical antipsychotic having a largereffect in the shell compared to the core. In contrast, in thepresent study, the effect of sulpiride and haloperidol on dopa-mine efflux was higher in the nucleus accumbens shell com-pared to the core with no significant effect of clozapine in eitherregion. This difference may be explained by the use of in vivoversus in vitro models where dopamine levels may beinfluenced by innervation from other brain structures, such asthe ventral tegmental area, substantia nigra and frontal cortex.

(±)7-OH-DPAT is a selective dopamine D3 receptor agonistwhen tested in binding assays in human cloned receptors (seeTable 1). However, when the assay conditions are altered toreflect those found in native tissue, i.e. in the presence ofsodium and magnesium ions, then its selectivity for dopamineD3 over D2 receptors is abolished (Levesque, 1996). Therefore,one would expect (±)7-OH-DPAT to be a mixed dopamine D2/D3 receptor agonist in this study. As previously reported, (±)7-OH-DPAT-induced a marked inhibition of dopamine efflux inboth the nucleus accumbens shell and core (Patel et al., 1995),which was attenuated by all antagonists. The rank order ofpotency of antagonism of the (±)7-OH-DPAT-induced inhibi-tion was: haloperidolNSB-277011-AN sulpirideNclozapine inboth brain regions, which paralleled their rank order of affinityat human dopamine D3 receptors and not human D2 receptors.Interestingly, the pA2 values calculated in the shell were 0.6–0.7of a log unit higher than the core. In addition, SB-277011-A didnot fully reverse the 7-OH-DPAT-induced inhibition in the core.Therefore, these differences may be an indication of additional

D2 receptor involvement in this brain region. Alternatively,evoked dopamine release was higher in the core than the shelland, therefore, may result in a higher dopamine tone in thecore which may reduce the apparent affinity of the antagonistin this tissue. In addition, the selective dopamine D3 receptorantagonist, SB-277011-A, reversed the (±)7-OH-DPAT-in-duced dopamine efflux with pA2 values comparable to itsaffinity at human dopamine D3 receptors. Importantly, there isa high degree of homology between the rat and humandopamine D2 and D3 receptor sequence and pharmacology(Gazi and Strange, 2002). Therefore, these data indicate thatthe (±)7-OH-DPAT-induced inhibition of dopamine efflux, inboth the nucleus accumbens shell and core, is a dopamine D3

receptor-mediated response. However, the involvement ofdopamine D2 receptors in the modulation of dopamine effluxcannot be ruled out due to the lack of appropriate selectivedopamine D2 receptor ligands.

In this study, using a selective dopamine D3 receptorantagonist, SB-277011-A, we have demonstrated that dopamineefflux is modulated primarily by dopamine D3 receptors in thecore and both dopamine D2 and D3 receptors in the shell of therat nucleus accumbens.

Acknowledgment

Thanks to Andrew Lloyd (GSK, Statistical Sciences) for hisstatistical advice for this study.

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