The cortical serotonin2A receptor and the pathology of schizophrenia: a likely accomplice

REVIEW The cortical serotonin2A receptor and the pathology

of schizophrenia: a likely accomplice

Brian Dean

The Rebecca L. Cooper Research Laboratories, The Mental Health Research Institute of Victoria,

Parkville, Victoria, Australia

Abstract

A large body of evidence shows that there is a change in the

density of cortical serotonin2A receptors (5HT2AR) in post-

mortem CNS from subjects with schizophrenia. Furthermore,

some antipsychotic drugs have also been shown to cause a

decrease in the density of 5HT2AR in the rat CNS. Thus, it

appeared possible that changes in this receptor in human

post-mortem CNS simply reflected an antipsychotic drug

effect. However, a great deal of research on the 5HT2AR and

schizophrenia now suggests that the changes in this receptor

are complex and may be involved in both the pathology of the

disorder and the effects of some antipsychotic drugs. More-

over, recent advances in basic research on the role of the

5HT2AR in the CNS add further support to the hypothesis that

the receptor could be involved in the pathology of the illness.

In particular, an argument will be developed that the changes

in the 5HT2AR in schizophrenia are reflective of a real or

perceived change in serotonergic tone and that this forms an

important part of the pathology of the illness.

Keywords: antipsychotic drugs, frontal cortex, post-mortem,

serotonin.

J. Neurochem. (2003) 85, 1–13.

It is now 50 years since it was suggested that abnormalities in

serotonergic pathways may be involved in the pathology of

schizophrenia (Wooley and Shaw 1953; Gaddum and Hameed

1954). More recently, it has become widely accepted that

antipsychotic drugs that antagonize both serotonin (5HT) and

dopamine (DA) receptors give improved therapeutic out-

comes compared with those that mainly antagonize the DA

D2-like receptors (Borison et al. 1992). When it became

apparent that the serotonin2A receptor (5HT2AR) was the

critical serotonin receptor targeted by the new generation of

antipsychotic drugs, the dopamine/serotonin hypothesis of

psychoses was formulated (Huttunen 1995). This hypothesis

suggested that antipsychotic drugs should be high-affinity

antagonists at the 5HT2AR with a lower affinity for the DA

D2-like receptors. These clinical neuropharmacological find-

ings also suggested that the 5HT2AR could be closely linked to

the pathology of schizophrenia; this review examines the

considerable body of data that supports this proposition.

Post-mortem studies of the 5HT2AR in schizophrenia

Findings using radioactive lysergic acid

Neurochemical hypotheses of schizophrenia have invariably

been constructed on a foundation of findings in the area of

neuropsychopharmacology (Meltzer 1976). For example, the

hypothesis that over-activation of 5HT receptors plays a role

in the pathology of schizophrenia was partly based on the

observation that the 5HT receptor agonist lysergic acid

diethylamide (LSD) could cause or exacerbate psychotic

symptoms (Vardy and Kay 1983). It is therefore logical that

the first studies on 5HT receptors in post-mortem CNS from

subjects with schizophrenia were carried out using radioact-

ive LSD binding, with non-specific binding being defined

with 5HT, even though this approach was not receptor

specific (Leysen et al. 1982). Hence, the first direct evidence

to implicate changes in the 5HT2AR in the pathology of

schizophrenia came from a study that showed a significant

decrease in the density of [3H]LSD binding in the cortex

from subjects with schizophrenia (Bennett et al. 1979)

Received July 1, 2002; revised manuscript received October 16, 2002;

accepted December 16, 2002.

Address correspondence and reprint requests to Associate Professor

Brian Dean, The Rebecca L. Cooper Research Laboratories, The Mental

Health Research Institute of Victoria, Locked Bag 11, Parkville, Victoria,

3052, Australia. E-mail: [email protected]

Abbreviations used: BA, Broadmann’s area; DA, dopamine; 5HT,

serotonin; 5HT2AR, serotonin2A receptor; LSD lysergic acid diethyl-

amide, PET, positron emission; SNP, single nucleotide polymorphisms.

Journal of Neurochemistry, 2003, 85, 1–13 doi:10.1046/j.1471-4159.2003.01693.x

� 2003 International Society for Neurochemistry, J. Neurochem. (2003) 85, 1–13 1

Tab

le1

Radio

ligand

bin

din

gstu

die

sof

the

sero

tonin

2A

recepto

rin

hum

an

cort

ex

obta

ined

post-

mort

em

from

schiz

ophre

nic

and

contr

olsubje

cts

Refe

rence

Meth

od

Radio

ligand

Conc.

(nM

)

Dis

pla

cin

g

dru

g

Conc.

(lM

)

Cohort

Siz

e(n

)

Dia

gnosis

BA

Outc

om

eS

chiz

o.

Cont.

Bennett

et

al.

1979

Mem

bra

ne

[3H

]LS

D4

LS

D1

12

12

DS

M-I

II-R

6,

8–11,

Decre

ase

indensity

15

944–47

24

10

Whitta

ker

et

al.

1981

Mem

bra

ne

[3H

]LS

D0.8

–10

LS

D1

13

8S

cneid

erian

firs

t

rank

+F

eig

hner

4,

10

&11

Incre

ase

inK

d

No

change

Bm

ax

Joyce

et

al.

(1993)

Tis

sue

section

+

auto

radio

gra

phy

[125I]

LS

D0.2

–1.9

Keta

nserin

110

8D

SM

-III

-R6,

24,

9,

4,

23,

1,

5

&te

mpora

l

No

change

Incre

ase

indensity

Gure

vic

hand

Joyce

(1997)

Tis

sue

section

+

auto

radio

gra

phy

[125I]

LS

D0.2

Keta

nserin

110

12

DS

M-I

II-R

1,

2,

3,

4,

6,

8,

9,

23,

24,

32,

44,

45,

46

Decre

ase

inB

max

inall

regio

ns

insubje

cts

ON

antipsychotic

dru

gs

at

death

Decre

ase

inB

max

inB

A6

and

24

insubje

cts

OF

F

antipsychotic

dru

gs

at

death

Reynold

set

al.

(1983b)

Mem

bra

ne

[3H

]keta

nserin

0.4

,2

LS

D1

11

10

10

No

change

Mita

et

al.

(1986)

Mem

bra

ne

[3H

]keta

nserin

0.2

5–4

Pip

am

pero

ne

111

16

DS

M-I

II9

No

change

inK

d

Decre

ase

inB

max

Laru

elle

et

al.

(1993)

Mem

bra

ne

[3H

]keta

nserin

0.1

25–4

Pip

am

pero

ne

16

13

DS

M-I

II-R

10

No

change

inK

d

Decre

ase

inB

max

in

non-s

uic

ide

psychotics

10

13

17,

18

No

change

inK

d

Decre

ase

inB

max

innon-s

uic

ide

psychotics

Dean

et

al.

1996

Mem

bra

ne

[3H

]keta

nserin

0.2

–2.0

Spip

ero

ne

10

20

20

DS

M-I

II-R

9N

ochange

inK

dor

Bm

ax

Burn

et

et

al.

(1996b)

Tis

sue

section

+

auto

radio

gra

phy

[3H

]keta

nserin

2L-m

eth

yserg

ide

50

13

15

Not

sta

ted

46

Decre

ase

inB

max

17,

22,

24

No

change

Dean

and

Hayes

(1996)

Tis

sue

section

+

auto

radio

gra

phy

[3H

]keta

nserin

10

Spip

ero

ne

10

20

20

DS

M-I

II-R

8,

9,

10

Decre

ase

inB

max

inall

regio

ns

Dean

et

al.

(1998)

Tis

sue

section

+

auto

radio

gra

phy

[3H

]keta

nserin

10

Spip

ero

ne

10

55

55

DS

M-I

II-R

9D

ecre

ase

inB

max

Dean

et

al.

(1999a)

Tis

sue

section

+

auto

radio

gra

phy

[3H

]keta

nserin

10

Spip

ero

ne

10

19

19

DS

M-I

II-R

9D

ecre

ase

inB

max

2 B. Dean

� 2003 International Society for Neurochemistry, J. Neurochem. (2003) 85, 1–13

(Table 1). Whilst the authors of this study argued that the

decrease in radioligand binding they observed was the result

of a decrease in 5HT receptors in schizophrenia, this posit was

not supported by a second study that failed to show a decrease

in cortical [3H]LSD binding associated with the disorder

(Whitaker et al. 1981). The argument was further complicated

by a study using [125I]LSD that reported increased binding in

the middle laminae of the posterior cingulate and temporal

cortices, but not the frontal, anterior cingulate or motor

cortices, from subjects with schizophrenia (Joyce et al. 1993).

These apparently discrepant findings must be balanced

against those from the same group, who later reported a

decrease in [125I]LSD binding in Brodmann’s area (BA) 24

and 6 from subjects with schizophrenia, irrespective of

whether or not they had received antipsychotic drugs until

death (Gurevich and Joyce 1997). Additionally, this study

showed decreased radioligand binding in BA 1, 2, 4, 8, 9, 23,

31, 32, 40, 44, 45 and 46 from subjects with schizophrenia

that were treated with antipsychotic drugs up until death.

Overall, the studies using radioactive LSD favour the

hypothesis that cortical 5HT receptors are decreased in

schizophrenia. In addition, the most recent study using this

radioligand and post-mortem CNS suggests that some of the

changes in the CNS from subjects with schizophrenia may be

the result of a complex mix of pathological and pharmaco-

logical effects.

Findings using 5HT2 receptor selective radioligands

With respect to the 5HT2AR, the problem of radioligand

selectivity was largely overcome with the availability of

[3H]ketanserin, a 5HT2AR/5HT2CR selective antagonist

(Leysen et al. 1982). This is particularly the case for the

human cortex where the extremely high 5HT2AR/5HT2CR

ratio (Pasqualetti et al. 1996, 1999) means that [3H]ketanserin

binding is essentially a measure of the 5HT2AR.

In the first study using [3H]ketanserin and cortical

membranes from subjects with schizophrenia, it was reported

that there was no decrease in 5HT2AR associated with the

disorder (Reynolds et al. 1983b). However, subsequent

studies using the same radioligand have reported decreased

[3H]ketanserin binding in several cortical regions from

subjects with schizophrenia (Table 1, Fig. 1). These latter

findings gain further support from a report that the 5HT2AR-

specific component of [3H]spiperone binding was decreased

in the cortex from subjects with schizophrenia (Arora and

Meltzer 1991). Thus, from radioligand binding studies, there

is a strong body of data to support the hypothesis that there is

a decrease in the density of cortical 5HT2AR in schizophrenia

and that this effect is particularly notable in the dorsolateral

prefrontal cortex.

Whilst pharmacological approaches had suggested that

there were a number of 5HT receptors in the mammalian

CNS (Hoyer et al. 1994), it was not until molecular cloning

techniques were developed that the full diversity of the 5HTPra

long

et

al.

(2000)

Mem

bra

ne

[3H

]keta

nserin

0.2

–4

Spip

ero

ne

10

10

10

DS

M-I

VP

lanum

tem

pora

le

Incre

ase

inK

din

subje

cts

treate

dw

ith

phenoth

iazib

es

Decre

ase

inB

max

inall

subje

cts

Tis

sue

section

+

auto

radio

gra

phy

10

10

20

20

Decre

ase

inB

max

Aro

raand

Meltzer

(1991)

Mem

bra

ne

[3H

]spip

ero

ne

0.5

–7

Cin

anserin

10

11

11

Not

sta

ted

8,

9N

ochange

inK

d

Decre

ase

inB

max

Serotonin2A receptor in schizophrenia 3


receptors was understood. The cloning approach has revealed

the serotonin receptor family to be made up of at least 15

receptors, of which 13 have been identified in the CNS

(Kroeze and Roth 1998). In elucidating the sequence of the

5HT2AR (Saltzman et al. 1991; Stam et al. 1992), which is

present on the long arm of chromosome 13, it became

possible to study the receptor at the level of mRNA as well as

protein. In the first study using both in situ radioligand

binding with autoradiography and in situ hybridization, it

was shown that [3H]ketanserin binding to the 5HT2AR was

decreased in BA 46 and the parahippocampal gyrus from

subjects with schizophrenia (Burnet et al. 1996b). There was

also a strong trend to a decrease in radioligand binding in

BA 24 from subjects with schizophrenia, but binding was not

different in either BA 17 or BA 22. Significantly, in parallel

measurements, mRNA for the receptor was decreased in all

cortical regions but was not altered in the parahippocampal

gyrus from the schizophrenic subjects. This study adds

complexity to the mechanism(s) that underlie changes in

cortical 5HT2AR in CNS from subjects with schizophrenia,

as it would appear that in some regions changes in the levels

of receptor expression do not result in changes in the levels

of receptor density.

Studies from this Laboratory have highlighted other issues

regarding findings on cortical 5HT2AR in schizophrenia.

Firstly, we reported a decrease in [3H]ketanserin binding to the

5HT2AR in BA 8, 9 and 10 from subjects with schizophrenia

using in situ radioligand binding with autoradiography (Dean

and Hayes 1996), a finding we could not replicate using BA 9

cortical membrane preparations from what was essentially the

same cohorts of subjects (Dean et al. 1996). At the time, these

two sets of data seemed contradictory but recent studies on the

cellular distribution of the 5HT2AR offer an explanation for

our findings (see below). Additionally, we have shown that

changes in 5HT2AR in BA 9 are not associated with extensive

changes in either other serotonin receptors (Dean et al.

1999b) or receptors for other neurotransmitters (Dean et al.

1999a). These data suggest that changes in cortical 5HT2AR

are not part of widespread changes in neurochemical markers

in the CNS of subjects with schizophrenia, making it more

likely that such changes are associated with the pathology of

the illness. Finally, we have failed to show a decrease in

cortical 5HT2AR in subjects with bipolar disorder who were

psychotic close to death (Dean et al. 2001). This finding

suggests that the change in cortical 5HT2AR in schizophrenia

is disease specific.

Decreased cortical 5HT2AR in schizophrenia:

a pathological or pharmacological effect?

A study reporting that treating rats with a high dose of

clozapine (25.5 mg/kg) for 12 months markedly decreased

[3H]ketanserin binding to frontal cortical membranes (Rey-

nolds et al. 1983a) led to the concern that decreases in

cortical 5HT2AR in post-mortem CNS from subjects with

18

17

12

312324

3210

9

6

17

12

40

44

22

10

9

6

Fig. 1 The regions of the human cortex in which 5HT2AR have been

reported to be decreased in association with the pathology of schi-

zophrenia unchanged in subjects with the disorder or decreased

because of antipsychotic drug effects .

4 B. Dean


schizophrenia was a result of drug treatment. Against this

hypothesis was an early finding that there were decreases in

[3H]ketanserin binding in BA 9 from subjects with schizo-

phrenia, whether or not they had received antipsychotic

drugs up until death (Mita et al. 1986). Importantly, one

consistent finding in subsequent studies in rats was that

treatment by antipsychotic drugs with little or no affinity for

the 5HT2AR, such as haloperidol, does not affect the density

of the receptor in rat cortex (Andree et al. 1986; Wilmot and

Szczepanik 1989; O’Dell et al. 1990). This is contrary to a

finding from the study of a large cohort of subjects with

schizophrenia (n ¼ 55) and age- and sex-matched controls

that showed the largest decrease in 5HT2AR was in BA 9

from schizophrenic subjects who had only received halo-

peridol before death (Dean et al. 1998). Finally, the absence

of changes in cortical 5HT2AR in a cohort of subjects with

bipolar disorder who had received antipsychotic drugs (Dean

et al. 2001) would again argue that changes in these

receptors in the human CNS are not simply an effect of

such drug treatment.

More recent post-mortem studies have added further

weight to the hypothesis that changes in 5HT2AR are

involved with the pathology of schizophrenia. For example,

one study has shown that levels of mRNA encoding the

5HT2AR were decreased in the superior temporal gyrus from

subjects with schizophrenia who were not receiving antipsy-

chotic drugs until death (Hernandez and Sokolov 2000).

Moreover, the levels of mRNA for the 5HT2AR were

inversely related to the time since antipsychotic drug

treatment had ceased. These data suggest that, at least at

the level of mRNA, changes in the 5HT2AR are associated

with the pathology of the illness and not a drug treatment

effect. Similarly, decreases in the density of 5HT2AR binding

reported in the planum temporale from subjects with

schizophrenia could not be fully accounted for by antipsy-

chotic drug treatment before death (Pralong et al. 2000). In

particular, these data showed that adding exogenous anti-

psychotic drug to planum temporale from non-schizophrenic

subjects at extremely high concentrations did not cause the

decrease in 5HT2AR observed in tissue from subjects with

schizophrenia. Moreover, the decrease in 5HT2AR was not

consistent across laminae, an unexpected outcome if the

decreases observed were a simple drug effect.

Whilst at present the weight of argument favours the view

that changes in cortical 5HT2AR in schizophrenia is related,

at least in some part, to a pathological process it must be

acknowledged that treating rats with antipsychotic drugs that

antagonize the 5HT2AR decreases the density of that receptor

in the cortex (Mikuni and Meltzer 1984; Andree et al. 1986;

Wilmot and Szczepanik 1989; O’Dell et al. 1990). The

decrease in 5HT2AR following treatment with such drugs

appears to be related to decreased levels of expression of the

receptor as it has been shown that clozapine treatment

(25 mg/kg) for 14 days decreased [3H]ketanserin binding

and mRNA for the 5HT2AR in the cingulate and frontal, but

not piriform, cortex of the rat (Burnet et al. 1996a). By

contrast, haloperidol (2 mg/kg/day) had no effect on either

[3H]ketanserin binding or levels of mRNA for the 5HT2AR.

Whilst the hypothesis that antipsychotic drugs with affinity

for 5HT2AR decrease levels of cortical receptor is compel-

ling, evidence against this model is given in another study

that reported on the effects of treating rats for 4 (clozapine

only at 30 mg/kg/day) or 32 days [haloperidol (3 mg/kg/

day), sulpride (100 mg/kg/day) or clozapine (10 mg/kg/day)]

on levels of mRNA for the 5HT2AR (Buckland et al. 1997).

In this study, rats treated with clozapine for 4 days had

a significant decrease in mRNA for the 5HT2AR in the

brainstem but not hippocampus, midbrain, cerebellum,

striatum, nucleus accumbens, cortex or prefrontal cortex.

Treatment with clozapine for 32 days decreased levels of

mRNA in the hippocampus and brainstem. By contrast,

32 days treatment with haloperidol decreased mRNA for the

5HT2AR only in the hippocampus, brainstem and midbrain

whereas sulpride only caused this effect in the hippocampus.

This finding was somewhat surprising given the absence of

haloperidol-induced changes in 5HT2AR density in studies

using radioligand binding to measure receptor density. Thus,

at present it cannot be concluded that changes in cortical

5HT2AR necessarily occur after treatment with antipsychotic

drugs that bind to the 5HT2AR. However, it is important to

acknowledge this effect as a confounding factor in the study

of the 5HT2AR in schizophrenia because of the increasing

use of these atypical antipsychotics, some of which bind to

the 5HT2AR, in the treatment of psychoses in some countries

(Ashcroft et al. 2002).

In summarizing data on the study of post-mortem tissue

there is a strong body of evidence to suggest that decreased

cortical 5HT2AR are associated with the pathology of

schizophrenia, particularly in the dorsolateral prefrontal

cortex of subjects with the disorder (Fig. 1). Many different

approaches suggest that the functioning of this region of the

CNS is markedly affected by the pathological processes

underlying schizophrenia (Weinberger and Berman 1996)

adding further weight to the argument that changes in the

5HT2AR in this region of the CNS are likely to be of

pathological consequence.

Neuroimaging studies

The availability of suitably selective radioligands has meant

that positron emission tomography (PET) could be used to

measure 5HT2AR in the CNS (Ito et al. 1998). Significantly,

the majority of studies have thus far failed to demonstrate

any changes in the density of the cortical 5HT2AR in

schizophrenia (Trichard et al. 1998; Lewis et al. 1999;

Okubo et al. 2000; Verhoeff et al. 2000). Thus, these studies

do not support findings from studies of post-mortem tissue

that generally report a decrease in cortical 5HT2AR in

schizophrenia. In contrast, one study did agree with findings



in post-mortem brain tissue, reporting a decrease in the

density of cortical 5HT2AR in schizophrenia (Ngan et al.

2000). There is no obvious reason why this study should

differ from other studies because they all used a very similar

methodological design. However the study showing a

decrease in 5HT2AR in schizophrenia only included antipsy-

chotic drug naive schizophrenics, whereas the others inclu-

ded some drug-treated individuals. Thus, whilst it would

seem that PET studies do not support the hypothesis that

there are changes in 5HT2AR in schizophrenia, it remains

possible that future studies of drug naive subjects may be

required to ensure that the effects of antipsychotic drug

treatment do not confound the results from PET. Further-

more, recent data on the distribution of the 5HT2AR within a

cell (see below) may provide a more plausible reason as to

why PET and post-mortem tissue studies have produced

apparently discrepant outcomes.

Genetic studies on the 5HT2AR

Clearly, dysregulation of the 5HT2AR in the CNS could

result from mutations in the gene encoding the receptor if

such mutations were of higher than normal prevalence in

schizophrenia. Elucidating the sequence of the gene enco-

ding the 5HT2AR led to the identification of a number of

single nucleotide polymorphisms (SNP) in the gene

sequence. The evidence implicating the 5HT2AR in post-

mortem CNS was a key factor in making this gene an early

candidate gene that has now been extensively studied in

relation to schizophrenia (Table 2).

Two early studies on a T to C polymorphism at position

102 in the 5HT2AR gene have reported an increased incidence

of the C variant associated with schizophrenia (Erdmann

et al. 1996; Williams et al. 1996). There was significant

debate concerning the interpretation of results from the study

on the T102C SNP in schizophrenia, as such a mutation

would not impact on the amino-acid sequence of the receptor

protein (Erdmann et al. 1996). One suggestion was that such

an amino-acid neutral mutation, if truly associated with

schizophrenia, must be in a linkage disequilibrium with a

causative mutation (Clifford and Nunez 1996; Crow 1996;

Malhotra et al. 1996a). Another argument was that the

association was arrived at by chance because of the study of

particular populations that are disparate for allelic distribu-

tion. This arose from a multinational study where an allelic

association was reported as a result of a particularly strong

effect in subjects recruited in France and Germany overriding

the negative findings from subjects in Britain, Austria, Italy

and Sweden (Jonsson et al. 1996; Malhotra et al. 1996a).

Whatever the explanation for the variation in early

findings on the T102C SNP, an increasing number of studies

have failed to replicate the finding that a particular allelic

variant of the T102C SNP is associated with schizophrenia

(Arranz et al. 1996b; Ishigaki et al. 1996; Jonsson et al.

1996; Malhotra et al. 1996a; Sasaki et al. 1996; Chen et al.

1997; Hawi et al. 1997; Kouzmenko et al. 1997; Shinkai

et al. 1998; Spurlock et al. 1998; Yoshihara et al. 2000;

Chen et al. 2001; Virgos et al. 2001) whilst one study

showed an excess of T allele in a population of Chinese

males with the disorder (Tay et al. 1997). Thus, it would

appear that the T102C SNP is not of great significance in

transmitting susceptibility for schizophrenia. However, a

meta-analysis of the studies on the T102C SNP has

suggested that a minor contribution to the aetiology of

schizophrenia may be attributable to this SNP (Williams

et al. 1997). Thus, a study of larger sample size may be

necessary to finally determine whether a particular variant of

the T102C SNP does infer increased susceptibility for

schizophrenia.

Since the initial studies that attempted to link the T102C

SNP to schizophrenia were carried out there have been a

number of studies that looked at this SNP in relation to

physiological outcomes. For example, one study has sug-

gested that the functional outcome of an excessive represen-

tation of the C variant of the T102C SNP in schizophrenia is

an altered N100 amplitude (Yu et al. 2001). N100 is an

event-related potential following an auditory stimuli that had

been reported as abnormal in subjects with schizophrenia.

One novel approach, which looked at the translation of the

T102C SNP at the level of mRNA sequence, reported an

increase in the expression of the C allele in the temporal

cortex from subjects with schizophrenia (Polesskaya and

Sokolov 2002). However, interpreting this finding is difficult

as it would have no affect on the amino-acid sequence of the

receptor, an outcome supported by data from a post-mortem

CNS study showing that allelic variations at T102C SNP are

not altered in schizophrenia and do not change receptor

binding dynamics in the human cortex (Kouzmenko et al.

1997).

Another approach to studying variation at the T102C SNP

was to examine pharmacologically related outcomes. Two

such studies have suggested the altered allelic frequency of

the T102C SNP was associated with antipsychotic drug-

induced tardive dyskinesia (Segman et al. 2001; Tan et al.

2001), a finding not confirmed by a third study focusing on

this side-effect of antipsychotic drug treatment (Basile et al.

2001). In addition to studies on antipsychotic drug side-

effects it has also been suggested that the T102C SNP may

confer differential outcomes following treatment with cloza-

pine, the archetypal atypical antipsychotic drug (Baldessarini

and Frankenburg 1991). Clozapine is unique in that it can

improve symptoms in individuals who have not responded to

treatment with other antipsychotic drugs (Meltzer 1997).

Initially it was suggested that a therapeutic response to

clozapine was associated with the C allele of the T102C SNP

(Arranz et al. 1995). Unfortunately, the publication of three

further studies that did not confirm a relationship between the

T102C SNP and clozapine responsiveness (Masellis et al.

1995; Nothen et al. 1995; Malhotra et al. 1996b) placed the

6 B. Dean


Table 2 Studies on single nucleotide polymorphisms in the sequence of the serotonin2A receptor gene and its promoter in schizophrenia

SNP Study Focus Cohorts size n Outcome Reference

T102C Diagnosis Schizophrenia 571 Allele 102C more

frequent in schizophrenia

Williams et al. (1996)

Controls 639

Schizophrenia 45 Allele 102C more


Erdmann et al. (1996)

Controls 46

Schizophrenia 50 No differences Malhotra et al. (1996a)

Parents 158

Schizophrenia 118 No differences Jonsson et al. (1996)

Controls 99

Schizophrenia 74 No differences Arranz et al. (1996b)

Controls 183

Schizophrenia 121 No differences Sasaki et al. (1996)

Controls 162

Schizophrenia 150 No differences Ishigaki et al. (1996)

Controls 158

Schizophrenia 247 No differences Hawi et al. (1997)

Controls 249

Schizophrenia 177 No differences Chen et al. (1997)

Controls 98

Schizophrenia 101 Allele T102 more


Tay et al. (1997)

Controls 103

Schizophrenics,

parents and offspring

63 trios Allele T102 more


Spurlock et al. (1998)

Schizophrenia 106 No differences Shinkai et al. (1998)

Controls 109

Schizophrenia 31 No differences Yoshihara et al. (2000)

Controls 55

Schizophrenia 471 No differences Chen et al. (2001)

Controls 523

Schizophrenia 262 No differences Virgos et al. (2001)

Controls 278

Clozapine response Schizophrenia +response 92 No difference with diagnosis but Arranz et al. (1995)

Schizophrenia ) response 57 homozygous C genotype more

frequent in non-responders

Schizophrenia + response 105 No differences Nothen et al. (1995)

Schizophrenia ) response 41

Schizophrenia + response 74 No differences Masellis et al. (1995)


Schizophrenia + response 42 No differences Malhotra et al. (1996b)


Control 140

Tardive dyskanesia Schizophrenia + TD 59 No differences in schizophrenia but Segman et al. (2001)

(TD) Schizophrenia ) TD 62 increased frequency of C allele in

subjects with tardive dyskanesia

Controls 96

Schizophrenia + TD 87 No differences in schizophrenia but Tan et al. (2001)

Schizophrenia ) TD 134 increased frequency of T allele in

subjects with no tardive dyskinesia

Controls 97

Schizophrenia + TD 82 No differences Basile et al. (2001)



initial findings in doubt. The subsequent failure to further

elucidate the mechanisms by which certain allelic variants at

the T102C SNP affect antipsychotic drug responsiveness

would seem to suggest that there is no clear-cut relationship

between specific allelic variants and clozapine responsive-

ness.

Further exploration of the 5HT2AR gene resulted in the

identification of three other SNPs, one of which (C516T) is

Table 2 (Continued)

SNP Study Focus Cohorts size n Outcome Reference

Schizophrenia ) TD 54

Post-mortem

CNS

Schizophrenia 63 No differences with diagnosis

or in receptor density

Kouzmenko et al. (1997)

DNA Controls 62

A()1438)G Diagnosis Schizophrenia 119 No differences Ohara et al. (1997)

Control 106

Clozapine response Schizophrenia + response 181 Frequency of G-1438

higher in no responders

Arranz et al. (1998)


Control 178

Peripheral DNA –

tardive dyskinesia

Schizophrenia + TD 59 No differences

in schizophrenia but increased

frequency of G allele in subjects

with tardive dyskinesia

Segman et al. (2001)


Controls 96



Post-mortem CNS Schizophrenia 58 No difference Kouzmenko et al. (1999)

DNA Controls 64

His452Tyr Diagnosis Schizophrenia 45 No difference Erdmann et al. (1996)

Controls 46

Clozapine response Schizophrenia + response 105 No differences Nothen et al. (1995)


Schizophrenia + response 99 Frequency of Tyr

452 higher in no responders

Arranz et al. (1996a)


Control 178

Schizophrenia + response 181 Frequency of Tyr

452 higher in no responders

Arranz et al. (1998)


Control 178

Schizophrenia + response 42 No differences Malhotra et al. (1996b)


Control 140

Peripheral DNA – Schizophrenia + TD 59 No differences Segman et al. (2001)

tardive dyskinesia Schizophrenia ) TD 62

Controls 96


Schizophrenia – TD 54

Thr25Asn Diagnosis Schizophrenia 45 No difference Erdmann et al. (1996)

Controls 46

Clozapine response Schizophrenia + response 105 No differences Nothen et al. (1995)


8 B. Dean


amino acid neutral (Erdmann et al. 1996). Significantly, the

other two polymorphisms (C74A and C1354T) both cause

changes in the amino acid sequence, Thr25 to Asp and

His452 to Tyr, respectively. Importantly, in the study

reporting the presence of the additional SNPs, none of the

variants at these three polymorphisms were linked to

schizophrenia. Further study of these SNPs have suggested

that Tyr452 may (Arranz et al. 1996a, 1998) or may not

(Nothen et al. 1995; Malhotra et al. 1996b) be associated

with non-response to antipsychotic drugs, but not the

presence of tardive dyskinesia (Basile et al. 2001; Segman

et al. 2001). This raises the possibility that a His to Tyr

substitution at amino acid 452 in the 5HT2AR may be

associated with antipsychotic drug resistance and subsequent

clozapine responsiveness.

A study of the T102C SNP that failed to show any

association with that polymorphism reported a SNP in the

promoter region of the 5HT2AR (A-1438G) that was in

complete linkage disequilibrium with the T102C SNP (Spur-

lock et al. 1998). The complete linkage disequilibrium with

the T102C SNP meant that the A-1438G SNP was also a

candidate for linkage with schizophrenia. Subsequent studies

have suggested that there is no association between A-1438G

and schizophrenia (Ohara et al. 1997). It has also been

debated as to whether (Segman et al. 2001) or not (Basile

et al. 2001) an excess of the G allele is associated with tardive

dyskinesia. In addition, one study suggested that homozyg-

osity for the G allele was associated with clozapine respon-

siveness (Arranz et al. 1998), a finding that was not replicated

in a second study on genetic variance and clozapine

responsiveness (Masellis et al. 1998). Finally, a study using

DNA from post-mortem CNS, confirming there was no

association between the A-1438G SNP and schizophrenia,

showed there was no relationship between allelic variance and

either the disorder or the density of the cortical 5HT2AR

(Kouzmenko et al. 1999). This finding confirmed, at the level

of protein expression, an earlier study using luciferase

activation (Spurlock et al. 1998) that showed neither the A

nor G variant of the SNP affected the promoter activity.

The conclusion on the studies of the 5HT2AR and

schizophrenia is that there is no convincing data to support

a particular allelic variant of the receptor being a cause of the

illness. Thus, it would seem reasonable to conclude that the

changes affecting the levels of the receptor in post-mortem

CNS are more likely to be related to either control of

expression or an increase in the rate of degradation rather

than the presence of a particular nucleotide sequence.

However, a study in a large number of individuals to

identify whether any of the SNPs in the 5HT2AR might

confer a slight increase in the risk of developing schizo-

phrenia is still warranted. In addition, the 5HT2AR has been

shown to be one of a number of receptors that undergo

polymorphic imprinting in humans (Bunzel et al. 1998).

With such receptors, although one copy of a gene is inherited

from both parents only the copy from one parent is

expressed. Imprinting can be tissue specific, and possibly

CNS regionally specific, as well as being dependent on

developmental factors (Bunzel et al. 1998). Hence, it was

necessary to determine if the level of imprinting had been

altered in a disease-specific manner as this would be import-

ant in understanding the possible consequences of the T102C

SNP in schizophrenia. One study examining the T102C SNP

in schizophrenics and in their parents and children (Spurlock

et al. 1998) has shown that there is no significant difference

between allelic transmission between mothers and fathers,

arguing against imprinting being an important factor when

studying the genetics of the 5HT2AR. However, given the

potential for the tissue-specific nature of this effect, studies

within the CNS need to be completed to ensure that

peripheral data gives a true reflection of genetic transmission

throughout the whole body.

Possible involvement of the 5HT2AR in the pathology

of schizophrenia

It is now widely accepted that antagonizing the 5HT2AR is a

critical feature of atypical antipsychotic drugs (Huttunen

1995). Importantly, the failure of the 5HT2AR receptor

antagonist MDL 100 907 as an effective treatment for

schizophrenia (de Paulis 2001) indicates that the receptor

per se is not a ‘stand alone’ therapeutic site of action and

therefore the benefits of the atypical antipsychotic drugs must

come from their combined pharmacology. This outcome

might have been expected given that treatment with the

5HT2A/2C receptor antagonist ritanserin, either alone (Wiesel

et al. 1994) or in conjunction with antipsychotic drugs

(Duinkerke et al. 1993), failed to show any clear therapeutic

benefits. This would suggest that the 5HT2AR is not central

to the pathological processes that precipitate psychoses but

may be involved in processes generating some of the

symptoms associated with schizophrenia.

The failure to show that mutations of the 5HT2AR are

associated with schizophrenia is still further evidence to

support the argument that the receptor may only be

considered an ‘accessory after the fact’ in the pathological

processes of schizophrenia. However, understanding the role

of the 5HT2AR in these processes could provide insight into

factors that are central to the illness. This would especially

seem to be the case as the 5HT2AR has now been implicated

in neuronal branching, terminal sprouting, synaptogenesis,

mitogenesis and glycogen breakdown to glucose (Azmitia

2001). Changes in any of these functions could have

profound effects in the CNS, which may precipitate the

symptoms of schizophrenia. Equally intriguing is the hypo-

thesis that the 5HT2AR is one of a number of receptors that

are termed ‘programmable receptor’, these receptors are

thought to be able to be affected during development so that

their function remains within certain constraints in the adult

CNS (Meaney et al. 1994). This means that the changes in



the 5HT2AR in subjects with schizophrenia that origin-

ated during neurodevelopment may only have discernable

consequences later in life. If this is the case, then the

decreased 5HT2AR in schizophrenia would be consistent

with the proposal that schizophrenia results from derange-

ments of neurodevelopmental processes (Woods 1998).

It is becoming clear that the 5HT2AR has some unique

properties that are not common to all seven-transmembrane

domain receptors. For example, the 5HT2AR undergoes both

agonist and antagonist-induced down-regulation (Gray and

Roth 2001). The balance between these two effects could

account for the difficulties in delineating between patholo-

gical and pharmacological changes in the CNS of subjects

with schizophrenia. This means the complexity of the

decreases in 5HT2AR in post-mortem CNS from subjects

with schizophrenia could have arisen from a combination of

antipsychotic drug treatment and a prevailing hyperseroto-

nergic state, as has been suggested as being important in the

hippocampus of subjects with the disorder (Scarr et al.

2001). This new understanding of the complexity of control

exerted on the 5HT2AR make it necessary to identify

differences that must presumably exist between the mecha-

nisms causing agonist- and antagonist-induced receptor

down-regulation.

The recent discovery that the majority of 5HT2AR in the

human cerebellum are in cytosol, rather than the cellular

membrane (Eastwood et al. 2001), confirms findings on the

cellular distribution of the 5HT2AR in rat CNS (Cornea-

Hebert et al. 1999; Doherty and Pickel 2000). Moreover, if

these data can be extrapolated to humans a high cytosol/

membrane ratio of the 5HT2AR will be widespread through-

out the human CNS. Importantly, there is evidence to suggest

that the 5HT2AR receptor on the cell membrane is present in

a high-affinity form, whereas the non-cellular membrane

associated receptor is in a low-affinity state (Cornea-Hebert

et al. 1999). Given that the high-affinity membrane receptor

is the receptor population most likely to be imaged in PET,

the results from the use of PET could indicate that only the

low-affinity receptor not associated with the cellular mem-

brane is altered in schizophrenia. Apparently discrepant data

from our studies support this hypothesis as we failed to show

a decrease in membrane-associated 5HT2AR in the cortex

from subjects with schizophrenia (Dean et al. 1996) but

showed these receptors to be decreased in frozen sections

(Dean and Hayes 1996) where, presumably, both cytosolic

and membrane receptors are involved in binding the

radioligand.

It has been suggested that the membrane : cytosolic ratio

of the 5HT2AR is a sensor of ambient 5HT levels (Cornea-

Hebert et al. 1999), with the receptor being internalized in

proportion to the level of 5HT stimulation. If that is the case,

then a change in the level of non-membrane-associated

5HT2AR could either result from a change in prevailing

levels of 5HT or result from a change in the 5HT monitoring

mechanisms themselves. In either case, the changes in

5HT2AR observed in schizophrenia would indicate that there

is either a real or apparent change in 5HT tone associated

with the illness. Given that such a change in real or perceived

serotonergic tone would be expected to cause changes in

motor control, appetite, mood and aggression as well as

in cognition, there is little doubt such a change could result in

the symptoms associated with schizophrenia (Breier 1995).

In conclusion, whilst the role of the 5HT2AR in the

pathology of schizophrenia has yet to be understood, new

data on the distribution of the 5HT2AR raise questions that

must be answered in post-mortem human CNS, rat brain and

model systems. In particular, whether there are changes in the

cellular distribution of the 5HT2AR in the CNS of subjects

with schizophrenia needs to be determined. In addition, the

mechanisms underlying agonist and antagonist down-

regulation of the 5HT2AR need to be understood. Then it

will be possible to determine which regions of the cortex

from subjects with schizophrenia show down-regulation

clearly not associated with antipsychotic drug effects.

Moreover, given the growing understanding of the direct

involvement of the 5HT2AR in critical CNS functions such as

working memory (Williams et al. 2002), a CNS function that

is affected in schizophrenia (Cameron et al. 2002), it would

seem particularly important to increase the basic understand-

ing of the physiological roles of this important CNS receptor.

Acknowledgements

This work was supported in part by NH & MRC grant #114253 and

the State Government of Victoria. The author would like to

acknowledge the Paul Leonard Caroll Trust for support in

investigating the pathology of bipolar disorder. In addition, thanks

are given to Dr Elizabeth Scarr for her editorial assistance with this

manuscript.

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The cortical serotonin2A receptor and the pathology of schizophrenia: a likely accomplice