Possible implications of the dopamine D 3 receptor in schizophrenia and in antipsychotic drug...

Ž .Brain Research Reviews 31 2000 277–287www.elsevier.comrlocaterbres

Interactive report

Possible implications of the dopamine D receptor in schizophrenia and3

in antipsychotic drug actions 1

Jean-Charles Schwartz a,), Jorge Diaz b, Catherine Pilon a, Pierre Sokoloff a

a ( )Unite de Neurobiologie et Pharmacologie Moleculaire U.109 de l’INSERM, Centre Paul Broca, 2ter rue d’Alesia, 75014 Paris, France´ ´ ´b Laboratoire de Physiologie, Faculte des Sciences Pharmaceutiques et Biologiques, 4 AÕenue de l’ObserÕatoire, 75006 Paris, France´

Accepted 30 June 1999

Abstract

The D receptor may represent an important target for antipsychotic drugs which all bind with high affinity and do not induce upon3

repeated administration either tolerance or receptor upregulation. The D receptor is localized in brain areas, namely the nucleus3

accumbens and cerebral cortex, implicated in neural circuits believed to display defective functioning in schizophrenia. Overexpression ofthe D receptor, which accounts for the behavioral sensitization to levodopa in a rodent model of Parkinson’s disease, might also be3

responsible for the sensitization to dopamine agonists observed in schizophrenia. The appearance of the D receptor during brain3

development, early in proliferating neuroepithelia and later in neurons from limbic areas, suggests further studies to assess itsparticipation in the neurodevelopmental disorders of schizophrenia. Finally, meta-analysis of ;30 studies comprising over 2500 patientsindicate that a polymorphism in the coding sequence of the D receptor is associated with a small but significant enhancement of3

vulnerability to the disease. q 2000 Elsevier Science B.V. All rights reserved.

Keywords: Brain development; Neuroleptics; Schizophrenia; Molecular genetics; Behavioural sensitization; Nucleus accumbens

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278

2. D -receptor blockade by antipsychotic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3 278

3. Tolerance to the effects of antipsychotics at D but not at D receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2 3 279

4. Localisation of the D receptor: implications for schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3 279

5. D -receptor overexpression and behavioral sensitization: relevance to schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3 280

6. Patterns of D -receptor localisation during brain development: possible relevance to schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . .3 282

7. Association of D receptor gene polymorphism and schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3 283

8. Conclusions: the dopamine hypothesis of schizophrenia revisited to incorporate the D receptor . . . . . . . . . . . . . . . . . . . . . . . . . . .3 284

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285

) Corresponding author. Tel.: q33-1-40-78 92 83; Fax: q33-1-45-80 72 93; E-mail: [email protected] Published on the World Wide Web on 3 December 1999.

0165-0173r00r$ - see front matter q 2000 Elsevier Science B.V. All rights reserved.Ž .PII: S0165-0173 99 00043-0

( )J.-C. Schwartz et al.rBrain Research ReÕiews 31 2000 277–287278

1. Introduction

The implication of dopaminergic pathways in the etiol-ogy of schizophrenia and the mode of action of antipsy-chotic drugs has been studied extensively starting from theobservation that their activity was modified by these drugsw x4 . The more recent discovery of the existence of a largevariety of dopamine receptor subtypes has rekindled theinterest by providing new approaches to assess the validity

Žof the ‘dopamine hypothesis of schizophrenia’ reviewedw x.in 17,66 . Among the novel dopamine receptor subtypes

revealed by molecular approaches, the D receptor was,3

from the beginning, considered as potentially relevant tothe topic of schizophrenia, due to its localisation and

w xpharmacology 65 .In the present review, we will try to answer the follow-

ing questions: Is D receptor blockade and regulation3

important for the therapeutic activity of antipsychoticdrugs? Is the D receptor localisation in brain consistent3

with the neuropathology of the disease? Is the pattern ofD receptor expression during neurodevelopment or in the3

course of the disease consistent with its implication inschizophrenia? Is the D receptor gene a good candidate3

for being associated with vulnerability to schizophrenia?

2. D -receptor blockade by antipsychotic drugs3

Before the discovery of the ‘novel’ dopamine receptorsubtypes, it was clear that the therapeutic actions of an-tipsychotic drugs could be safely attributed to blockade ofD rather than D receptor subtypes. However, the recent2 1

cloning of several D -like receptors, i.e. the D , D and D2 2 3 4

receptors, has raised the question of the role of these threeproteins as a main target for antipsychotics. Initially, thepositive correlation between drug affinity at D -like recep-2

tor binding sites and drug plasma levels identified thesew xreceptors as a common target for all antipsychotics 61,63 .

This was apparently confirmed when D -receptor occu-2

pancy in striatum of patients receiving various antipsy-chotics at therapeutic dosage was determined by positronemission tomography and found to be G70–80% in most

Ž .cases Farde et al., this volume . It remains to be estab-lished whether successful treatment of schizophrenic pa-tients is also accompanied by significant occupancy of D3

or D receptors, a difficult task in view of their low4

relative abundance which could not be undertaken so fardue to the lack of a suitable PET scan probe.

Nevertheless comparing the affinity of antipsychotics atŽ .recombinant D and D receptors Table 1 indicates that2 3

these compounds generally show some but very limitedpreference for the D receptor. Hence, assuming an equal2

access of the drugs to brain regions where each receptorw xsubtype is mostly expressed, as it seems likely 21 , and

neglecting any possible difference in competition by en-

Table 1Compared potencies of various antipsychotic drugs at recombinant humanD and D receptors2 3

Ž .Drug K values nM K rKi iŽD2. iŽD3.

D receptor D receptor2Žs . 3

Amisulpride 1.3 2.4 0.53U UAmperozide 322 235 1.37

Carpipramine 8.7 15 0.58Chlorpromazine 2.3 5.9 0.39Clozapine 69 479 0.14Haloperidol 0.6 2.9 0.21Iloperidone 3.5 4.8 0.73Pimozide 9.8 11 0.88Pipotiazine 0.20 0.28 0.72Prochlorperazine 0.40 1.8 0.22Raclopride 1.8 3.5 0.51Remoxipride 198 2,300 0.09Risperidone 1.0 5.4 0.19

U USertindole 0.38 1.6 0.24Ž .- Sulpiride 10 20 0.50Sultopride 4.5 8.1 0.55Thioridazine 3.3 7.8 0.42

w125 xValues derived from studies of the inhibition of I iodosulpride bindingŽto hD and hD receptors expressed by transfected CHO cells. Data2Žs . 3

w x Ufrom Ref. 64 and Sokoloff et al., unpublished data, except from Ref.w x.42 .

dogenous dopamine, it can be estimated that significant D3Ž .receptor occupancy generally around 60% occurs during

antipsychotic treatments resulting in 70–80% D receptor2

occupancy. Presumably higher D receptor occupancy can-3

not be achieved with available antipsychotics since itwould result in parkinsonian-like side-effects occurring at

Ža D receptor occupancy above 80% Farde et al., this2.volume . Hence the idea that selective blockade of the D3

receptor is sufficient to afford antipsychotic efficacy re-mains to be tested.

CommentariesØ In contrast with D or D , D receptor occupancy2 3 4

cannot account for the antipsychotic activity of alldrugs since effective compounds such as the benzamidederivatives show low affinity at the recombinant D4

receptor. In addition, recent clinical trials with D -re-4

ceptor selective antagonists have shown their lack ofw xantipsychotic activity 28 .

Ø Remoxipride apparently shows marked preference forthe D over the D receptor but it seems likely that the2 3

compound acts indirectly, by generating much moreactive metabolites which display an inverse pharmaco-

w x Žlogical profile 47 P. Sokoloff, unpublished observa-.tions .

Ø In the case of clozapine only limited D receptor3

occupancy can be expected in view of the drug prefer-ence for the D over the D receptor and of the2Žs. 3

relatively low D receptor occupancy at effective thera-2Ž .peutic dosage Farde et al., this volume . However a

higher affinity of clozapine for the D over the D3 2ŽL.

( )J.-C. Schwartz et al.rBrain Research ReÕiews 31 2000 277–287 279

w xisoform was described 42 . In addition, it has beensuggested that the ‘atypical’ c-fos response to clozapinein islands of Calleja and, to a certain extent, in frontal

w xcortex is selectively mediated by the D receptor 22 .3

Ø Some antipsychotic drugs, e.g. haloperidol, display in-verse agonist properties at the recombinant D receptor3

but this occurs only at relatively high concentrations sothat the therapeutic relevance of this observation is

w xdoubtful 20 .

3. Tolerance to the effects of antipsychotics at D but2

not at D receptors3

Following repeated administration of antipsychotics su-persensitivity to dopamine and, its counterpart, tolerance todopamine antagonists develops, a process partly at-

Ž .tributable to an enhanced expression upregulation of theD receptor. In patients while such process accounts for2

the progressive reduction in parkinsonian-like side-effectsoccurring at the beginning of treatment and the appearanceof tardive dyskinesias after several years, it does not seem

Ž . Ž .to occur at the level of the dopamine receptor subtype sinvolved in the antipsychotic activity since this activitydoes not diminish upon long term treatment. It is thereforenoteworthy that repeated administration of haloperidol fortwo weeks to rats failed to trigger any significant upregula-tion in D receptor mRNA or binding in various brain3

areas, whereas in the same rats D -receptor mRNA and2Ž .binding were enhanced by up to more than 50% Fig. 1 .

The absence of upregulation of D -receptor mRNA and3

binding following repeated antipsychotic treatment is inw xagreement with other studies 14,23,70 . In addition, the

decrease in neurotensin gene transcripts in ventromedialshell of nucleus accumbens, a characteristic response to

w xD -receptor blockade 9 , does not show tolerance follow-3

ing repeated administration of haloperidol, whereas thereverse response in the core of nucleus accumbens, medi-ated by D receptors, diminishes upon repeated haloperi-2

Ž .dol administration Fig. 2 . These observations tend to

Fig. 1. Chronic treatment with haloperidol upregulates D receptor but2

not D receptor expression in nucleus accumbens. Rats received haloperi-3Ž .dol 20 mgrkg, i.p., b.i.d. for two weeks before sacrifice. D and D2 3

receptor mRNA and binding site levels were evaluated by quantificationof in situ hybridization and radioligand binding autoradiographic pictures

w x Uas described in 36 . P -0.01 vs. saline-treated animals.

Fig. 2. Contrasted effects of a repeated treatment with haloperidol onneurotensin gene expression in subareas of the shell of nucleus accum-

Ž .bens expressing preferentially the D receptor cone ShCo or the D2 3Ž .receptor ventromedial part ShV . Rats were killed 7 h after either a

Ž .single administration 5 mgrkg, i.p. or the last administration ofŽ .haloperidol 5mgrkg, i.p., b.i.d. for 5 days. Neurotensin mRNA levels

w xwere quantified on in situ hybridization pictures as described in 9 .U P -0.05 vs. saline-treated animals; a P -0.05 vs. Hal 7 h.

support the idea that the antipsychotic activity of neurolep-tic drugs is related to D - rather than D -receptor blockade.3 2

CommentaryØ The development of supersensitivity depends not only

on the receptor subtype considered but also on the typeof neurons which express it. Since the neuronal popula-

Ž .tion s involved in the antipsychotic activity of drugs isnot known, it cannot be excluded that a restrictedpopulation of such neurons does not develop D recep-3

tor supersensitivity.

4. Localisation of the D receptor: implications for3

schizophrenia

A link between the D receptor and schizophrenia was3

suggested from not only its pharmacology but also theinitial observation that, in rat brain, the receptor is mainly

w xexpressed in forebrain limbic areas 65 that may be di-Žrectly or indirectly involved in schizophrenia Andreasen,

.this volume .In rat brain, in which the phenotypes of neurons ex-

pressing the D receptor have been characterized, the3

largest receptor densities occur in granule cells of theislands of Calleja and in medium-sized spiny neurons ofthe rostral and ventromedial shell of nucleus accumbenswhich co-express the D receptor, substance P, dynorphin1

w xandror neurotensin 9,10,35 . These output neurons fromthe nucleus accumbens receive their dopaminergic innerva-tion from the ventral tegmental area and reach the entorhi-nal and prefrontal cortex after relaying in the ventralpallidum and mediodorsal thalamus. In turn the shell ofnucleus accumbens receives projections from the cerebral

Žcortex infralimbic, ventral, agranular, insular and piriform.areas , hippocampus and amygdala and also projects to the

ventral tegmental area from which originate its dopaminer-w xgic afferents 50,76 . These various specific connections of

the shell of nucleus accumbens, a part of the ‘extendedŽ .amygdala’ see Heimer, this volume , suggest that this area


is involved in a series of feedback or feed-foreward loops,involving namely the prefrontal cortex and ventral tegmen-tal area. Many functional imaging and neuropsychologicalstudies have implicated the heteromodal association neo-cortex, comprising several interconnected association areasŽdorsal, prefrontal cortex, Broca’s area and inferior parietal

. Žcortex , in higher integrative functions memory, speech,.focused attention and in the disorders of these functions

w xthat are observed in schizophrenia 54 . In agreementsubtle neuropathological abnormalities were also described

Žin these brain areas of schizophrenic patients or those to. w xwhich they are connected 52 . Its seems likely that

dopamine plays a modulatory role on the efficiency ofthese heteromodal cortico-ventrostriatal circuits, in analogywith the role dopamine plays on motor cortico-dorsostriatalcircuits. A dysfunction of these former circuits with func-tional dopamine deafferentation of the prefrontal cortexand enhanced dopamine subcortical tone was proposed to

w xoccur in schizophrenia 8,72 . It is noteworthy thatdopamine seems to control these circuits not only at thelevel of the nucleus accumbens but also at their variousrelays and that the D receptor is also expressed in the3

corresponding areas of the rat brain, e.g. in the ventralpallidum, mediodorsal thalamus, cerebral cortex, ventral

w xtegmental area, amgydala, etc. 3,10 .Using a recently developed and reliable D receptor3

Ž .antibody Fig. 3 , the phenotypes of neurons in these areasare progressively identified, e.g. pyramidal cells in layer 5of parietal and fronto-lateral cortice. In the human brainthe phenotype of neurons expressing the D receptor are3

not yet identified but several studies show their distribu-Žtion to be rather similar to that in the rat highest levels in

.islands of Calleja and nucleus accumbens, see Fig. 4 with,however, a larger distribution in the ventral part of the

wcaudate putamen and the cerebral cortex 24,30,31,44,x49,69 .

Fig. 3. Immunohistochemical localisation of the D receptor in rat brain.3Ž .Superimposable distributions of anti-D receptor immunoreactivity left3

w125 xand binding of I trans-7-OH-PIPAT, a D receptor-selective ligand,3Ž .with highest levels in the islands of Calleja IcjM and IC and moderate

Ž .levels in the shell of nucleus accumbens AccSh and ventral pallidumŽ .VP . ac, anterior commissura.

Fig. 4. D receptor mRNA distribution in the human brain. In situ3

hybridization signals were quantified form 3 individuals and expressed asŽ .percentage of the level in nucleus accumbens N. accumbens . Frontal

Cx, frontal cortex; Occ. Cx, occipital cortex; Cing. Cx, cingulate cortex;Caudate N., caudate nucleus; Isl of Calleja, islands of Calleja; Subthal N.,subthalamic nucleus; Sub. Nigra comp., substantia nigra pars compacta.Ž w x.Data from Ref. 69 .

Taken together these observations are consistent with.the hypothesis that i schizophrenia might be associated

Ž .with caused by a defective functioning of the circuits.linking the extended amygdala an limbic cortices, ii

dopamine regulates the gain factor of these circuits viainteracting with the D receptor.3

CommentariesØ The effect of D -receptor activation on these circuits is3

still largely conjectural.Ø Via the D receptor, dopamine may exert a tonic activa-3

tion of accumbo-pallidal GABA neurons as suggestedby the decreased expression of neurotensin gene thatD -receptor blockade triggers in some of these neurons3w x9 . However, this conclusion must be considered withcaution as it is derived from studies performed withrather unselective pharmacological tools.

Ø In all parts of these circuits the D receptor is also2

expressed, often in higher abundance than the D recep-3

tor, and its role might be similar to that put forwardhere for the latter.

5. D -receptor overexpression and behavioral sensitiza-3

tion: relevance to schizophrenia

That the expression of the D receptor is not regulated3

in the same manner as that of the D receptor was already2

evidenced by the lack of effect of chronic antipsychoticdrug treatments. Furthermore, ablation of dopaminergicneurons following unilateral injections of 6-hydroxy-dopamine results in a dramatic but paradoxical decrease inD receptor expression in the ipsilateral nucleus accum-3

bens, as assessed by in situ hybridization studies as well asw xautoradiography of radioligand binding sites 36 . Repeated


intermittent treatment of these hemiparkinsonian rats withlevodopa induces a progressive enhancement of D recep-3

tor mRNA and binding in the whole striatal complexw xwhich occurs selectively on the lesioned side 2 . While the

induction was the most dramatic in the dorsal striatumŽfrom which the D receptor is almost absent in control3

animals or on the control side of unilaterally-lesioned.animals , it was also robust in the nucleus accumbens. In

these animals, the treatment with levodopa was followedby a progressive development of behavioral sensitizationto this drug, as demonstrated in the Ungerstedt’s rotationalmodel.

Several observations indicate that the process of lev-odopa-induced D receptor induction is causally related3

Ž .with the development of behavioral sensitization: i bothŽ . Ž .processes occur with a similar time course Fig. 5 ; ii

both require previous dopaminergic denervation and de-pend on repeated intermittent stimulation of the D recep-1

Žtor hence D receptor induction occurs in D -receptor3 1. Ž .expressing neurons ; iii development of both processes

can be prevented by treatment with MK-801, a NMDAŽ .receptor antagonist; iv the expression of behavioral sensi-

tization, i.e. the enhanced rotational response to levodopa,is blocked by co-administration of nafadotride, a preferen-tial D -receptor antagonist, and is mimicked by administra-3

tion of BP897, a recently designed and highly selectiveŽD -receptor agonist together with a D -receptor agonist3 1

which, alone, does not induce increased rotational re-. Ž w xsponse Ref. 2 and R. Bordet, S. Ridray, P. Sokoloff,

.and J-C. Schwartz, unpublished observations . A similarprocess seems to occur in another model of Parkinson

w xdisease, i.e. in MTP-treated monkeys 48 . It is noteworthythat whereas overexpression of the D receptor occurs as a2

result of dopamine denervation and may be related todisuse hypersensitivity, chronic levodopa treatment doesnot result in any further enhancement in this receptorabundance.

Fig. 5. Parallel changes in D -receptor binding and levodopa-induced3

rotations in hemiparkinsonian rats during and after repeated administra-tion of levodopa. Rats with an unilateral 6-hydroxy dopamine-inducedlesion of the ascending mesencephalic dopaminergic pathways placed 3

Ž .weeks earlier, received levodopa 50 mgrkg, i.p., b.i.d. for up to 15 daysand were challenged with a single same dose of levodopa. Contralateralrotations were counted 35 min after and animals killed 4 h after thechallenge and D -receptor binding quantified on autoradiograms using3w3 x Ž w x.H 7-OH-DPAT as the ligand. Data from Ref. 2 .

Since D -receptor overexpression in hemiparkinsonian3

rats occurred not only in striatal areas involved in motorcontrol but also in shell of nucleus accumbens, we haveproposed that this process might underlie not only thedevelopment of abnormal involuntary movements but alsoof psychotic manifestations, e.g. hallucinations, which areobserved in a high proportion of parkinsonian patientssubmitted to long-term treatment with levodopa.

Behavioral sensitization, also called behavioral facilita-tion or reverse tolerance, i.e. the enhanced responsivenessto dopamine agonists, is a process which develops afterlong-term administration of not only levodopa but also

Ždrugs like apomorphine, amphetamine or cocaine re-w x.viewed in 27,59 .

Various lines of evidence suggest the potential contribu-tion of sensitization as a pathophysiologic mechanism in

w xschizophrenia 18,38 . Administration of psycho-stimulantssuch as amphetamine to healthy subjects can producepsychotic symptoms including delusions, hallucinations anda thought disorder which mimic schizophrenia and can be

w xreversed by administration of antipsychotic medication 1 .Administration of such psycho-stimulants at low doses,which do not produce psychotic symptoms in healthysubjects, exacerbate psychotic symptoms in a substantial

w xproportion of patients with schizophrenia 26,37 . This hasbeen interpreted as evidence that schizophrenic patientsdisplay enhanced responsiveness to dopamine agonists.The heightened inhibition in D -like receptor binding2

elicited by amphetamine, almost twice higher in drug-freeschizophrenic patients than in controls, is interpreted as an

Ž w xenhanced dopamine release in these patients Ref. 33 and.this symposium . Although its mechanism remains conjec-

tural, this enhanced responsiveness to amphetamine couldbe considered as reflecting a sensitized dopaminergic state,perhaps via a higher setting point of the feedback loopscontrolling dopamine release.

In addition, the repeated intermittent use of psychostim-ulants in low to moderate doses produces a delayed onsetpsychosis in a significant proportion of stimulant abuserswho, like schizophrenic patients, seem to display a low

w xthreshold to the induction of psychotic symptoms 25,57 .Whereas in rodents overexpression of the D receptor as a3

mechanism of behavioral sensitization is, so far, substanti-ated only in the case of levodopa, a post-mortem study hasevidenced D receptor overexpression in the ventral stria-3

tum of 6 subjects who died after a cocaine overdosew x62,67 .

It is noteworthy that overexpression of the D receptor3

in the ventral striatum was also evidenced in a carefullyperformed radioligand binding study with post-mortembrain samples of schizophrenic patients which were nottaking antipsychotics for at least one month prior to deathw x23 . In contrast, in patients that had been treated withantipsychotics up to the time of death, D receptor levels3

did not differ significantly from those of controls. Theelevation of D receptor binding in drug-free schizophrenic3


patients was region-specific and not accompanied by anysignificant change in D receptor abundance. These data2

were interpreted as indicating that antipsychotics activelydownregulate the D receptor in schizophrenic patients3

that, otherwise, have a higher density of this receptor inthe ventral striatum.

Taken together these various observations may tenta-tively indicate that overexpression of the D receptor in3

schizophrenia is responsible for the dopaminergic sensi-tized state observed in this disease and accounts for a largepart of its neuroleptic-sensitive symptomatology. Thiswould indicate the importance of factors and mechanismscontrolling D -receptor expression in brain, namely during3

development. In the adult rat brain, D -receptor expression3

in medium spiny neurons of the ventral striatum criticallydepends upon the activity of afferent dopamine neuronsaffecting their target cells via release of an unknown factor

w xdistinct from dopamine and cotransmitter peptides 36 .The identification of this factor could be important tounderstand the mechanisms of sensitization, including inschizophrenia.

CommentariesØ The D receptor overexpression in schizophrenia was3

w xreported in a single study with 15 patients 23 , aninteresting finding which remains to be confirmed inother studies. Furthermore, in post-mortem brain sam-ples from schizophrenic patients, D -receptor mRNA3

abundance was decreased in the Brodmann area 11 ofw xthe orbitofrontal cortex 45 and in the parietal and

motor cortice, the latter change attributed to an in-w xcreased splicing of the pre-mRNA 58 . In addition,

neonatal lesion of the ventral hippocampus in rats, amodel of schizophrenia, because these animals showpost-pubertal hypersensitivity to stress and dopaminethat can be reversed by antipsychotic drug treatmentw x39 , is accompanied by a strong reduction of D -recep-3

w xtor binding, namely in nucleus accumbens 15 .Ø The postulated antipsychotic drug-induced decrease in

w xD receptor expression in schizophrenic patients 23 is3

not paralleled by any similar change in the normal ratw xreceiving haloperidol for 5 days 36 .

6. Patterns of D -receptor localisation during brain3

development: possible relevance to schizophrenia

It has progressively become clear that schizophreniashould be considered as a neurodevelopmental disorder inwhich the primary brain insult or pathological processoccurs during brain development, long before the illness is

w xclinically manifest 72,73 .There are two main reasons to study D receptor on-3

togeny in relationships with schizophrenia pathophysiol-ogy. The first one is that the dopaminergic system appears

w xearly in brain development in higher species 71 and aneurodevelopmental role for dopamine has been suggestedw x46,53 . The second one is that the hypothesized role of

D -receptor overexpression in the etiology of schizophre-3

nia raises the question of mechanisms governing this re-ceptor expression during development.

D -receptor expression during embryonic and early3

post-natal development was mainly studied in the rodentw xbrain and characterized by several original features 7,11 .

The first one is the detection of D -receptor mRNA at an3

early stage, in higher abundance than in the adult brain andin proliferating neuroepithelia but not, like the D or D1 2

receptor mRNAs, in neuroblasts or migrating neurons: atE14 in striatal, rhinencephalic and tectal neuroepithelia andfrom E16 to E19 in neuroepithelia of the olfactory bulb,

w xnucleus accumbens, amygdala and septum 11 . We haverecently confirmed this selective expression of the D3

receptor in proliferative zones during early development ofthe human brain in which it was already detected at week6. There was, however, a striking difference between thetwo species: the cortical neuroepithelium giving rise to thecerebral neocortex was heavily labeled in the human but

Ž .not in the rat embryo Fig. 6 . This localisation of the D3

Fig. 6. Expression of the D receptor mRNA in the human brain at 203

weeks of gestation. An in situ hybridization image was obtained from ahalf coronal section of foetal brain hybridized with a specific probe forhuman D receptor mRNA. Cd, caudate nucleus; FrCx, frontalcortical3

plate; Ne, neuroepithelium; SVZ, subventricular zone.


receptor invites speculations about its participation in neu-ropathological abnormalities in schizophrenia.

Tentatively, the D receptor expressed in neuroepithe-3

lial cells lining the cerebral ventricles might regulate theirmitotic activity since, in NG108-15 cells, activation of therecombinant receptors enhances MAP kinase activity andw3 xH thymidine incorporation via a pathway independentfrom cAMP and involving tyrosine kinases and phos-

w xphatidyl 3-kinase 51,60 . Putative dopaminergic neuronswere seen in the human brain, adjacent to the ventricle,presumably in the germinal zone at 16 days of gestationw x16 . Being the only dopamine receptor subtype expressedin these dividing neuroepithelial cells and owing to its high

Žsensitivity to dopamine allowing dopamine to act at a.certain distance from its release , the D receptor could3

have a role in the control of their proliferation elicited bydopamine and, therefore, in the number of neurons of theirprogeny. Among the cerebral morphometric abnormalitiesdetected in either in vivo or post-mortem studies, ventricu-lar enlargement, reduction in neocortical and hippocampalneuronal density could result from an abnormal control oftheir progenitors in the neuroepithelium during early devel-opment.

w xFrom our study in rats 11 , it appears that the expres-sion of the D receptor mRNA is not continuous during3

cell differentiation and migration from the neuroepithe-lium: in this species whereas D and D receptors are1 2

already present in nucleus accumbens in E18, it is onlyduring the first post-natal week, i.e. at the time of theirinnervation by dopamine axons, that the D receptor starts3

to be expressed in spiny neurons of this area. This mayw xindicate that, like in the adult brain 36 , these neurons

require the trophic influence of a factor emanating fromdopamine axons to express the D receptor. In the human3

brain, the D receptor is detected in the putamen and3

nucleus accumbens at 14 weeks of gestation or earlierwhereas the dopaminergic innervation of the area is settled

w xfrom 9 weeks 16 . Hence a trophic role of dopaminergicneurons similar to that postulated in rats could also takeplace in the developing human brain and defects of thisprocess be at the origin of the overexpression of the D3

w xreceptor in schizophrenia, as observed in one study 23 .Commentary

Ø These postulated roles of the D receptor during brain3

development remain to be assessed experimentally.

7. Association of D receptor gene polymorphism and3

schizophrenia

Family, twin and adoption studies suggest that geneticfactors play a significant role in schizophrenia with esti-mates of the proportion of variance in the liability of the

w xdisorder accounted by genes of 63–85% 43 . With theadvent of molecular genetics approaches, many attemptshave been made during the last decade to identify genesinvolved in the disease, which have so far met limited

Ž .success, however see Owen, this volume . Indeed thedisorder appears genetically complex, being unlikely to bedue to a single major gene, the mode of transmission of thedisorder is still unknown and environmental factors appearto play important roles. Hence the most current view isthat several genes of minor effect interact or co-act with agene of major effect and relevant developmental or envi-ronmental factors to account for the etiology of the dis-ease.

The identification of polymorphisms in the humanŽ . w xdopamine D receptor gene DRD 32,56 allowed to3 3

Žstart a very large series of studies nearly 50 published so.far to assess its implication in schizophrenia and other

psychiatric disorders. The DRD is located to chromosome3w x3q13.3 34 . The firstly described and most commonly

analyzed polymorphism is a Ser9 to Glycine9 substitution,taking place in the putative N-terminal extracellular do-

w xmain of the receptor, in exon 1 of the gene 19,32 . Thiscreates a Bal I restriction enzyme site, allowing a simple

Ž . Ž .genotyping of alleles 1 Ser or 2 Gly by combining PCRamplification and restriction analysis, a method used inmost studies.

The first studies consisted in linkage analysis and didnot favor a non-random segregation of either allele and

w xschizophrenia 5,74 , leading to the suggestion that theDRD gene does not play a major role in the susceptibility3

to schizophrenia, a conclusion also reached in severaladditional linkage studies. However, linkage may not bedetectable if the mode of inheritance is mis-specified or ifgenetic and clinical heterogeneity is present. Hence it hasbeen repeatedly proposed that, in presumably polygenicdiseases such as schizophrenia, the minor contribution of asusceptibility allele to genetic predisposition might be

Ž .more reliably detected in association case control studies.Crocq and coworkers were the first to detect, in a

limited French population, evidence for an association ofŽ . Žhomozygosity of either allele 1 Ser-Ser or allele 2 Gly-

.Gly with schizophrenia, immediately confirmed in anindependent study performed by McGuffin and Owen at

w xCardiff, UK, and published together 6 . These initialstudies were followed by a flurry of association studies ina variety of populations that have been split into confirma-tion and non-replications. While most studies were unableto replicate the first positive association between the ho-mozygosity of any alleles and schizophrenia, some studiesreported positive association for the 1-1 genotype in sub-

Ž w x.groups of patients or ethnicities reviewed in 13,75 .These discrepancies between studies might have arisen

Ž .from various causes including i an insufficient number ofŽ .patients lack of statistical power in each study to lead to

Ž .a reliable conclusion regarding a gene of minor effect, iiŽ .heterogeneity within and between samples, iii imperfect

matching between patients and controls leading to stratifi-cation.

ŽTwo independent meta-analysis of a large number 29–.30 of association studies were recently performed in an


attempt to minimize these factors in a total population ofover 2500 patients and 2500 controls and convergent

w xconclusions were obtained 13,75 . The heterogeneity be-tween studies was stressed by the high variations of geno-type frequencies among controls belonging to various eth-

Žnicities e.g. from 2% in Japanese to 52% in Italians.regarding the 1-1 genotype , which led Dubertret and

w xcolleagues 13 to perform separate analysis for distinctŽ .ethnic groups Table 2 . Whereas in the whole sample no

Ž .significant difference was found, a significant P-0.05Ž .excess of either homozygosity 1-1 plus 2-2 genotypes or

1-1 genotype was found in the caucasian group, with oddsratios of 1.25 and 1.23, respectively, corresponding to anestimated role of 8.6 and 11.1%, respectively, of the D3

receptor gene in the susceptibility to the disease. Theassociation of the Bal I polymorphism and the disease wasnot found in any other ethnic group except the Africans.

w xThe meta-analysis by Williams and colleagues 75 con-Ž .cluded to a highly significant P-0.0009 excess of

Žhomozygotes in their sample slightly different from thatw x.of Dubertret and colleagues 13 .

Ž .The low odds ratios ;1.2 in both analysis of largeŽcohorts i.e. the limited influence of the gene upon the

.vulnerability to disease may largely explain the discrepan-cies between various studies. Nevertheless this clearly

Ž .suggests that having the 1-1 allele or the 2-2 allele of theD receptor gene slightly enhances susceptibility to the3

disease over having the 1-2 allele.The functional significance of the Ser9-Gly 9 mutation

Žis not clear. It takes place in a region of the protein the.N-terminal extracellular tail which is not likely to be

involved in either ligand binding or signal generation. Inagreement only minor differences were detected betweenthe dopamine binding affinities of the homozygous andheterozygous recombinant receptors expressed in a cell

w xline 40 . Nevertheless, a point mutation in the same regionof rhodopsin, which also belongs to the superfamily of

Table 2Meta-analysis of association studies between the Bal I polymorphism ofthe dopamine D receptor gene and schizophrenia3

Whole European Africansample caucasian sample

sample

Number of studies 29 13 1Number of patients 2,619 982 65Number of controls 2,517 1,013 63Frequency of 1-1 genotype

In patients 0.44 0.47 0.20In controls 0.48 0.42 0.04

U U2x 0.92 5.07 5.80Odds ratio 1.06 1.23 5.00

The meta-analysis was performed according to the Woolf method. AŽ .significant P s0.002 difference in 1-1 genotype frequency between

Žfive ethnic subgroups was detected among which only two European.caucasians and Africans led to a significant difference between patients

and controls. U P -0.05.

heptahelical signaling proteins, is responsible for one ofw xthe most common forms of retinitis pigmentosa 68 . The

mutation could affect the level of membrane expression ofthe D receptor via changes in cell processing or, even3

more likely, via a linkage disequilibrium with other geneticvariations in its promoter region. The latter view is partlysupported by the observation that the association ofschizophrenia was significant with the Bal I polymor-

Ž .phism but not with another polymorphism MspI situatedw x;35 kb downstream in the same sample of subjects 19 .

Commentariesw xØ In the meta-analysis by Williams and colleagues 75 , a

Ž .highly significant P-0.001 excess of homozygotesfor either allele 1 or allele 2 was found in the whole

Žsample 30 studies with a total of 2722 patients and.2629 controls . This positive conclusion was reinforced

by the results of an additional Transmission Disequilib-Ž .rium Test TDT in which 57 schizophrenic patients

and their two parents were included: highly significantŽdifferences in the 1-1 genotype or in homozygosity 1-1

.plus 2-2 genotypes were detected with odds ratios of2.3 and 2.7, respectively. It would not be surprising thatan analysis tending to minimize ethnic and environmen-tal factors leads to a more significant result than currentassociation studies. However, in two other TDT analy-

w xsis, the association with schizophrenia 41,55 was notdetected.

Ø The excess homozygosity can be interpreted in differentways. It may only reflect the excess of the 1-1 geno-type, whose frequency is largely predominant over thatof the 2-2 genotype. Tentatively it may also reflect adifference in functionality of the D receptor operating3

as either homo- or hetero-dimer.Ø Taken together two recent studies suggest that the

association of the D receptor might relate to a subpop-3

ulation of schizophrenic patients with a propensity todrug abuse. Thus, on one side, homozygosity wassignificantly more frequent among opiate addicts with a

w xhigh sensation-seeking score 12 and, on the other side,it was more frequent in a subgroup of schizophreniapatients with a lifetime substance abuse comorbidity ascompared to patients with no history of substance abuseŽ . Ž . w xPs0.01 or controls P-0.05 29 . It is noteworthythat a variety of approaches suggests the participationof the D receptor in the effects of drugs of abuse in the3

shell of nucleus accumbens.

8. Conclusions: the dopamine hypothesis of schizophre-nia revisited to incorporate the D receptor3

It is always tempting and sometimes of heuristic valueto put together a variety of findings in order to draw acoherent hypothesis. Applying this principle to the dataobtained during the last decade concerning the dopamineD receptor leads to a tentative but rather coherent picture3


of its role in schizophrenia which can be summarized asfollows.

Dopamine, via the D receptor, regulates the gain of3

neural circuits involving the heteromodal association neo-cortex and controlling emotional and cognitive processes.The neural expression of the D receptor is triggered3

during development and regulated afterwards in a complexmanner, depending namely upon the activity of afferentdopamine and glutamate neurons. Hence the level of D3

receptor expression is controlled by neural loops, the activ-ity of which is, in turn, controlled by the D receptor3

abundance. The excessive expression of the D receptor3Ž .observed in one study in schizophrenia may result from

Žgenetic factors e.g. polymorphism in the promoter region. Žof its gene , developmental factors e.g. inadequate release

of a neurotrophic factor from dopamine neurons at the.critical period of dopaminergic synapse formation or ex-

Žternal factors e.g. emotional or hormonal influences af-.fecting the neural circuits involving the D receptor .3

Overexpression of the D receptor accounts for the be-3

havioural sensitization to psychostimulants observed inschizophrenia and at least a fraction of the psychoticsymptomatology of this disease. Antipsychotic drugs alle-viate this symptomatology by blocking the D receptor3

Žandror decreasing its expression as observed in one.study .

The outlined hypothesis is a re-formulation of previouspartial hypothesis, the so-called ‘dopamine hypothesis’,‘neurodevelopmental hypothesis’, ‘neurogenetic hypothe-sis’, ‘sensitization hypothesis’ of schizophrenia, a reformu-lation which incorporates a variety of findings about theD receptor. The ‘D receptor hypothesis’ has the advan-3 3

tage to put together a variety of recent and old observa-tions but, needless to say, it has still many weak points.For instance, the overexpression of the receptor inschizophrenia, shown in a single study, has to be con-firmed, the therapeutic effect of a selective D -receptor3

antagonist remain to be assessed, the exact role of the D3

receptor in circuits controlling cognitive process is almostentirely conjectural, etc . . . In addition, the widely admit-ted heterogeneity of the disease makes it unlikely that asingle common mechanism should be involved in its etiol-ogy.

Ongoing studies should help to evaluate the ‘D recep-3

tor hypothesis’ of schizophrenia, clarify the role ofdopamine in the disease and possibly provide novel thera-peutic approaches.

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