Correlation between serotonin uptake and imipramine binding in schizophrenic patients

Pmg. NeuroPsychopharmacol printed In Greet Britain.

6 EM. Psychiol. All elghtn meerwd.

COBBElATION

1982. Vol. 6. pp. 5741 Copyright

AVNER 1

Department

of 3

BINDING

SKuOToNmJ UPTAKB AND JMIPBAMBUB scmzoPHRENIc PATmNTS

BETWEEN

ROTMAN’, Membrane

Ness-Ziona

ANAT SHATZl’*

Research, Rehovot, Government

(Final

and

GEORGE

A.

November

IN

SZEKELY’

The Weizmann Institute of Israel, and Hospital, Ness-Ziona, Israel

form,

0384-7722/821010057~)5503.0010 _ 0 1982 Pergamon Press Ltd.

Science,

1981)

Abstract Rotman, binding

Avner, Anat Shatz in schizophrenic

and George A. patients. Prog.

Szekely: Correlation Neuro-Psychophannacol.

between serotonin & Biol. Psychiat.

1. The active uptake of serohonin by platelets of schizophrenic patients and control group was compared with imipramine binding to these platelets. 2. Significant correlation was observed between the Vmax of serotonin uptake mine binding. 3. Serotonin uptake by patients was much lower than that of control group. Keywords

: serotonin

uptake,

imipramine

binding,

platelets

models,

and

imipramine 5:

a healthy and

the

schizophrenic

imipra-

patients.

Introduction The

use

of

(Sneddon,

blood

1973;

studies

of the

from

depressed

uptake

by

their

platelet

membrane et

al., of

Several

(or

serotonin

We

(3-H)

and

In

have

binding binding

been

sites (1979).

here

a different

-imipramine

binding.

fulfilment of Medical School,

from

made

psychotic

the

last

platelets

serotonin

the requirements Jerusalem.

to

by

57

to

(for

review

see

the

by

serotonin

platelets

M.D.

et

quantitate

determined

the

in

(Rotman

serotonin

of

the

of

by

al.

serotonin The

1976).

sites

degree

uptake

number

et

binding

al.

1980b).

the

Boullin

et

patients’

serotonin

Drummond,

hebephrenic

Rotman

the

al.,

of

serotonin

1979; in towards

differences

years

appeared lower

al,,

carriers

in

platelets

1979) have

et

as a tool

a correlation

blood

al,,

receptors

children

determine

towards

the

reported

was

uptake

amine

used

find

in

et

(Modai

of of

few

were

patients

group

membrane

well-documented

to

serotonin

Tuomisto

affinity we also

in

platelets

of

number

other

approach The

control

study

on platelet on human

1976;

is

an attempt

schizophrenic

a lower

decreased

and

sites)

healthy from

another

children

McKean

report

‘In partial Hadassah

than

1979).

attempts

receptors

Schick

rather

autistic

than

blood

uptake

adult

serotonin

with

Tukiainen, acute

for

human people,

serotonin

and

results

model

reason sick

that

platelets uptake

this

decreased

(Tuomisto

blood lower

terminal

mentally

we reported

This

(Rotman

on

patients

1980a).

platelets

For by

Reports

Recently,

a nerve

1980). uptake

disease.

lately.

as

Rotman,

serotonin

with

of

platelets

number

(1978)

and

by

by

use

of

the

schizophrenic

Hebrew

University-

A. Rotman

58

patients the

and

healthy

platelets

of

control these

group

two

was

et

determined

al.

and

compared

to

the

imipramine

binding

to

groups.

Methods Patient age

range

population

(subjects),

was

most

volunteers

20-40,

(8 males

Drug

design.

rmoming)

over

a 3-5

same

the

healthy

control

Serotonin

and

Imipramine

for

and

of

the

to

a further

5 females

were

consisted

one

or

more

of

Thioproperazine,

from

patients

by

volunteers

every

day

of

studied.

of

Their

12 healthy

the

following

drugs

Perphenazine,

the

same

were,

on

study

:

Fluphenazine

person

once

average

included

at

37’C

for

period.

of

The

a week

studied

2 patients

A filters

conditions

was

twice,

and

The

used

for

described (PRP)

one

The

platelets

and

by

at

the

Rotman

the

et

final

were

37’C

for

platelet

separated

al.

desired

cen&fuged,

washing

were

transferred

5 min,

(3H)-

suspension

by

a rapid

filters

by to

counted.

preincubated

were

followed

as plasma

5 min.

3~10-~M

platelets

10 mM EDTA.

out

was

(PRP)

concentration

Type

carried

platelet-rich

accumulated plasma

a final

same

to

incubated

containing the

were

added

radioactivity

Fiber

saline using

studies

was

5 min

Glass

cold

counted

group

by

control

uptake

Platelet-rich

added

Whatman

50 ml

The Usually,

suspension

and

binding. was

incubated through

the

buffer

imipramine

and

patients.

treated

drawn

period. time.

(3H)-serotonin

concentration with

to

were

were

Serotonin

Briefly,

washed

matched

7 males control

volunteer. uptake.

(1980b).

The

Trihexiphenidyl.

samples

of

24-30.

Levomepromazine,

week

period

age

patients

and Blood

patients,

were

4 females) The

Sulpiridine

Study

them

Propericiazine,

Decanoate,

over

and

administration.

Chlorpromazine,

Twelve

of

rapid of

was

filtration the

filters

with

to

counting

vials

3H-serotonin.

Results patients

Averagely,

and

clear

both

at

inset

low

of

ing

the

typical

and

Fig.

1.

The

hyperbolic

serotonin

uptake

in

Table

platelets/min

This

is

and

and

a significant the

0.68+0.14 imipramine/lOB

two p.mol

the

of

imipramine/lO* platelets/min

The

control

for group

(~~0.014). average

imipramin

platelets/min (p
is

uptake

There

were

p.mol is

that

to of

is in

a function

the

maximum

observed

shown

in

line

is:

represent-

patients control

from of

from

imipramine 16.5

the

the

amine

velocity

calculated

as the

significant

the

A

is

the

as

serotonin/lO*

no

(Fig.1).

groups

concentration

calculated

binding and

and

as well

64.7

two

(especially

(Km)

patients

group

the

serotonin

volunteer

parameters,

V,,,

low

serotonin

constant

these

average

difference groups.

of

control

analysis

point

at

control

Michaelis-Menten

The that

of

and

one

uptake

drawings

patient

the between

Lineweaver-Burke at

of

than

uptake

linearity

deviation

Similar each

Results 1.

uptake

serotonin The

from from

for

the

concentration.

curve. made

serotonin

in

deviation

analysis,

summarized

between

amine

results

weaver-Burke

IO*

high

were

a lower

difference

patients)

centration of

showed

significant

con(Vmax)

the

Line-

binding,

p.mol

are

serotonin/

platelets/min. difference

in

platelets group

the

membrane is:

1.88+0.31

Km is: p.mol.

Serotonin

-$ \

uptake

and

imipramine

binding

in

I

I

t

I

I

12345678

I

L3H] -serotonin Fig. 1. of serotonin

59

80

*m Uptake

schizophrenics

of serotonin concentration.

I

I

( xIO-~M)

by blood platelets Inset: Lineweaver-Burke

of

patients analysis.

(0)

and

control

(m)

as

a function

Discussion The

binding

of

3H-imipramine

patients

and

average

patient’s

control

group

contain

inhibitor

of

serotonin

Stacey,

1961;

Todrick

that

will

that

these

in

the

lets

of

drugs

list 150

in

they lo-GM

et

by

did of

not each

of

by

our these

groups. and

the

are will

and

as

uptake drugs

as

sites. brain

and

Carlsson

the

carrier

imipramine

All

the

result

in drugs

tested

of

used

to

were

used

us

and

the none

treat

of

the

5x10-‘M doses,

inhibition

of

them

could

the

of

a competitive 1971;

al.,

of

serotonin

1967),

carriers

to

plate-

1976)

a fact

we can

human

attributed

to

studied

patients

Knowing

that

in

lower

that that

Saarnivaara,

be

uptake. of

at

be

binding

cannot

serotonin

a concentration

Nevertheless, by

serotonin

calculate

in

et al.,

number

binding

drugs

inhibitors

other

for

and

et

the

carriers

while to

Blackburn

(Boullin

values

and

known

(Ahtee

1969;

can

imipramine is

represent

Similar

serotonin

one

for

platelets al.,

uptake

assay. was

its

actually

of

number,

imipramine

in et

to

number

sites

As

(1979).

poor

the

Avogadro

McKean

patients,

section)

1976)

affect

binding

calculate

binding

serotonin

serotonin

taken

Methods

two

in

1969; of

Schick

in

al.,

binding both

mg chlorpromazine/day

Calimlin

4.09x103

imipramine these

differences

effect

of

of

obtained

6.02~10~~

Tait,

binding of

to

using

uptake and

us

contain

11.3~103

the

numbers

platelets

These

Thus, platelets

reduce

were

(see

control.

allowed

the

blood

we can serotonin

inhibit

the

assume

the

a dose (Rivera-

assume

that

uptake

by

uptake

by

A. Rotman

60

et al.

Table

1

of Serotonin Uptake and Values Km* v,, by Platelets of Schizophrenic Patients

of Imipramine and Control Control

Patients N0' 1

2 3 4 5 6 7 8 9 10 11 12

Km

"mar

0.63 1.14 6.60 1.16 1.09 0.41 1.41 0.40 0.40 6.22 2.10 1.92

11.2 8.9 58.8 20.8 16.2 10.0 18.8 4.4 3.3 5.7 25.0 29.4

Binding Group

Imipramine

binding

Km

V max

0.79

1.36

0.74 1.25

0.80 N.D. N.D. N.D. 6.30 1.30 1.40 N.D. 1.50 22.20 0.70

55.5 21.9 N.D. N.D. N.D. 125.0 25.0 27.8 N.D. 28.9

1.03 0.49 1.24 0.55 0.67 0.29 1.06 0.48 0.86

. Km is. in 0.1~~; Vmax is in p.mol/lOe in p.mol/108 platelets/min.

Imipramine N.D. N.D. 3.02 2.28 1.86 1.92 1.48 0.76 1.84 1.39 2.88 1.41

500 19.2

platelets/min;

binding

imipramine

binding

more than 5%. Therefore, we feel that there is full justification to assume that represent true and significant differences between the number of serotonin carriers schizophrenic patients and control group.

results

OUT

in

Conclusions 1. There are differences in platelet serotonin uptake between schizophrenic patients healthy controls. 2. There is a good correlation between imipramine binding and serotonin uptake both individuals and between two groups of schizophrenics and healthy people.

and among

Acknowledgement The generous

financial

support

of the Gatsby Foundation

(London,

England)

is highly

acknow-

Career

Development

Chair.

ledged. Avner Rotman is the incumbent

of the Samuel and Isabelle

Friedman

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61

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Dr. Avner Rotman Department of Membrane Research, The Weizmann Institute of Science, 76100 Rehovot, Israel.

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