Effects of antidepressants on monoamine transporters

027~5846/88 $0.00 + .50 Copyright @ 1988 Pergamon Press plc

Prog. Neuro-Psychophormocol. b Biol. Psychiat. 1988. Vol. 12, pp. 193-216 Printed in Great Britain. All rights reserved

EFFECTS OF ANTIDEPRESSANTS ON MONOAMINE TRANSPORTERS SALOMON

Laboratoires

Z. LANGER and HANS SCHOEMAKER

Department of Biology, d'Etudes et de Recherches Synthelabo Paris, France

(Final form, September

(L.E.R.S.),

1987)

Contents

1. 2. 3. 4. 5. 6.

Abstract Introduction Antidepressant Antidepressant Antidepressant Antidepressant Conclusions Acknowledgements References

binding binding binding binding

sites sites sites sites

associated associated associated associated

with with with with

the the the the

193 193 195 203 205 205 206 206 207

serotonln transporter noradrenaline transporter dopamine transporter adrenaline transporter

Abstract Hans: Effects of antidepressants on Langer. Salomon Z. and Schoemaker. transporters. Prog. Neuro-Psychopharmacol. & 6101. Psychiat.1988, -12:193-216

monoamine

1. Using [3H]antldepressants, high affinity binding sites associated wlth the neuronal transporter for serotonin. noradrenaline. dopamine and adrenaline have been identified. of high affinity [3H]imipramine 2. The association binding with the serotonin transporter In brain and platelets is well established. Although the exact relationship between the [3H]lmipramine recognition site and the serotonin it appears that the [3H]imipramine labelled transporter remains to be elucidated, component of the serotonin transporter represents a novel receptor that functions to modulate serotonin uptake. 3. Most data available to date support the hypothesis that [3H]imipramine binding to platelet represents a biological marker in depression. The majority of studies [3Hlimipramine binding Is lower in depressed, indicate that the Bmax of platelet untreated patients than In the control population and that this finding is relatively s ecific to depression. s 4. Among the [ HIantidepressant binding sites associated with the other monoaminergic transporters. the recent identification of [3H]desipramine binding to the neuronal transporter for adrenaline offers novel Perspectives. Thus, given the high affinity for [3H]desipramlne binding to the adrenaline transporter in the frog heart for not only desipramine but also imipramine and the atypical antidepressants mianserin and lprindol. it Is possible that an interaction with the adrenaline transporter is of significance to the clinical effects of antidepressant drugs. Kev-words:

[3HJantidepressants.

depression,

[3H]imipramlne,

monoamine

transporters

1. Introduction

Most

currently

known

antidepressant

drugs 193

exert

effects

on

monoaminergic

S. 2. Langer and H. Schoemaker

194

neurotransmlsslon, an

observation of

Importance to

the

orlgln of

the

monoamlne

hypothesls of affective dlsorders. Thls hypothesls dictates that a deficiency In monoamlnerg~c neurotransmlsslon, In noradrenallne, plays

an

partjcular of

Important role

depression. Antldepressant drugs

would

monoamlnerglc neurotransmlsslon, thus

In

the

then

the

monoamlnes serotonln and

etlology

or

Increase the

providing

a

pathophyslology of

synaptic efficacy of

treatment

of

depresslon

or

allevlatlng Its symptoms. Indeed, many of the antldepressants known today, lnhlblt the metabollsm of serotonln or noradrenallne (MAO lnhlbitors). or tnhiblt thelr neuronal uptake,

which

Is

the

maln

mechanism

neurotransmltters. Addltlonally, drug a2-adrenerglc

autoreceptors,

of

synaptic

antagonism of

through

which

InactIvatIon

of

these

presynaptlc serotonerglc or

serotonln

and

noradrenallne.

respectively, exert an autolnhlbitory effect on their release from the nerve terminal. may be expected to Increase the synaptic avallablllty of these neurotransmltters.The ldentlflcatlon and characterlzatlon of the primary slte of action of antldepressant drugs Is of conslderable Interest, even though the mechanism of cllnlcal efficacy of these drugs may whereas

the

be more complex and

facllltatlon of

involve neuronal adaptatlon processes. Thus,

monoamlnerglc neurotransmlsslon by

these

drugs may

represent their acute effects, their therapeutic effects In depression are generally believed to require a treatment perlod of at least 1-2 weeks.

Table 1 Monoamlnerglc PlasmolenmnaTransport Systems as Labelled by [3H]Antldepressantsand Other Radlollgands Monoamine

Radlollgands

Serotonln

[3H]lmlpramlne [3H]cyanotmlpramlne [3H]nltrolmlpramine [3H]paroxetlne [3H]indalplne [3H]norzlmelidlne [3H]cttalopram

Noradrenallne

[3H]deslpramlne [3H]mazindol

Dopamlne

[3H]nomlfenslne [3H]threo-(+)-methylphenldate [3H]cocalne [3H]mazlndol [3H]GBR-12783 [3H]GBR-12935

Adrenallne

[3H]deslpramlne

[3H] Antidepressant

Receptor an

btnding

effort

neuronal using

to

elements

In the

drugs

associated

braln

mechanism

of

serotonln address high

the

action

of actlon

Among

the

1981a,b;

flrst

gathered

site

Langer that

for

site

that

also

Prellmlnary labelled

Since

and

complex

data

using

serotonln

to

lndlcate

of

slte

may

1986a). not

serotonln

advanced

1981; Langer et al.,

1981a;

Palkovlts

locallzatlon

to

hlppocampus.

the

and adrenaline

but

associated the

wlth

serotonin

(D'Amato

et

the

High

a novel

afflnlty

serotonln

1987).

marker

Langer,

1984;

substrate presynaptlc

blnding

sites

complex

may

complex.

similarly

[3H]Cyanolmlpramlne

has

et al., 1987). However, the

and

antldepressants

transporter

blnding

in depresslon

the

suggests

[3H]6-nitrolmlpramlne)

[3H]imlpramine,

as a blologlcal

of

evidence the

has

bindlng

part

1984a;

represent

transporter

al.,

evidence

Forms

wlth

and

1980a.b.

[3H]lmlpramlne

[3H]norzlmelldlne)

[3H]lndalplne,

be

al.,

substantlal

ldentlcal

may

et

available

transport.

with

almost

been

and

of and

to be identlfled

see Davis,

be

exclusively

rat

study

Transporter

species

([3H]cyanolmipramlne,

that

dealt

following

the ~111

serotonln

dopamlne

sites

The

research

In the

to

[3H]antldepressant

(Langer

several

(For revleus al.,

transporter,

trlcycllc

[3H]cltalopram

closely

of

revtew

to the

the

of

case

binding

respect with

descrlptlon

In vivo (Wolfe

has

the

present

affinity

site

transporter

has

wlth

blndlng

used to label the serotonln

platelets

or

for these

noradrenaline

In

Its

The

the high afflnlty

et

to modulate

shown

that

platelets

blndlng

the

Its tnltlal

Langer

([3H]paroxetlne. been

and

With The Serotonln

recognition

the hypothesis

1987;

other

nontrlcycllc have

of

Sites Associated

transporter

Functions

several

on

the neuronal

[3H]antldepressant

brain

[3H]imlpramine

recognition

with

Studies

serotonln

sites

particular

associated high

In ulth

In the characterlzatlon

In

drugs

1987).

binding

patlents.

those

by an assoclatlon

1979).

the

Schoemaker.

the

receptor

In

serotonln

and

sites

drugs

of

serotontn

studies

depressed

[3H]lmlpramlne

to support

plasmolemM1

drugs,

addltlon,

afflnlty

the

et al.,

identified

and

cllnlcal

blndlng

Elndlna

hlgh

was

Raisman

the

employed

these

Langer,

reuptake

interest

been

1) ~111 be discussed.

2. Antidepressant

characterized

of

of

and

of hlgh afflnlty

of great

from

have

Interaction

neuronal

of antldepressant

In

sites characterized (Table

the

complex

are

extensive

platelets

transporter.

transporters

direct

see Schoemaker

antidepressant to

[3H]antldepressant

noradrenaltne blndlng

of

In

the mechanism

affinity

tnhlblt

studles

lead

transporter

review.

to

macromolecular

1). Such

have

[3H]lmlpramlne,

(for

195

transporters

antldepressants

the

In the ldentlflcatlon

with

(Table

13H]labelled

characterize

known

resulted

transporters

been

using

and

[3H]antldepressants

noradrenallne.

the

studies

Identify

binding to monoamine

cllnlcal

of

(Langer

be been

which

and

to

Erlley,

1981b, 1982).

human

braln.

the

reglonal

et

al.,

the

clngulate

lateral

and

[3H]lmlpramlne denslty

1981).

blndlng

the

Is

serotonerglc

Autoradlographic

cortex, basal

of

anterlor

amygdalold

nuclei

heterogenously Innervation

studies thalamlc and

djstrlbuted.

(Langer

Indicate nuclei,

a

the

the substantla

et

al.,

selective CA3

n\gra

of

the

(Oawson

S. Z. Langer and H. Schoemaker

196

and

Wamsley,

1983;

Biegon,

1986).

density

of

Fuxe

et al.,

Chemical

[3H]lmipramine

binding.

(Paul

et al.,

1981b;

Sette

Luine

et

1983;

Dawson

binding

al.,

site may also

Fuxe et al., transport

1983;

of

nervous

fractions

In been

addition

al.,

1980;

the

correlated

terminals

et al.,

1986;

tissues

and

Segonzac

serotonin Mellerup

(Kd)

of

most

location

have

and Zube, 1983).

model

Paul et

of

central

0.79

of

carried

out

at

afflnlty

at higher

et al.,

1987a).

Incubation

as

temperatures possible

1983,

the

0°C.

This

1985; blndlng

Plenge Is

hlgh

afflnlty

(Davis

et al.,

in the

the

and

of the

(Habert Mellerup,

et al., 1984;

pseudoirreversible.

However,

In drug

afflnlty

[3H]serotonln (Plenge

and

at

and

of et

of

OY,

[3H]lmipramlne In part,

to an

et al., 1987a).

makes

transporter

complex

transporter and

Langer

Segonzac and

platelet

1983; Schoemaker

selective 1985;

human

1984b; Davis et al.,

serotonln

described,

Laduron,

1987a).

Is due, at least

serotonln

to affect

platelet

of

afflnlty

(Segonzac

a

human

to brain

of

which

labelllng recently

[3H]paroxetlne

lnhibltion bindlng (Davis,

from the receptor

The

al.,

membranes

decrease

for

Inhibits et

peripheral

1980a; to

discrepancies

and

and

drugs

al.,

binds

only

such

temperatures

temperature,

more

but

[3H]Imipramlne

radlollgand

(37°C).

using

Inhibltor

a

Itself

(Segonzac

being

et

Schoemaker

Nevertheless,

individual

(Langer

explain

1987a).

temperature-dependent,

[3H]paroxetlne

nH

1987).

Is

serotonerglc

1980;

in central

of some

nM,

30

or platelets

Into

Paul et al.,

Langer.

imlpramine

brain

transport

similar

and

uptake

llkely

et al.,

unsultable

et al.,

Is very

the ability

IC50

in the

1980a.b.c;

et al., 1984) and platelet

lncreaslng

uptake

and

Thus,

In its rate of dissociation

Is

terminal

et al., 1980b;

peripheral

serotonln

(Schoemaker

between

an

blndlng,

(Segonzac

Is

[3H]lmipramine

0°C.

wlth

Segonzac

physiologlcal

nerve

(80rbe

Langer

binding

of

et al.,

1987a),

1987a).

affinity

lower

with

however,

al.,

an

1984; Reith

increase

central that the

et al., 1984).

retina

accessible

[3H]lmlpramlne

[3H]serotonin

uptake

37Y

1985)

binding

readily

species

and

et

[3H]lmipramine

1986;

1983).

the

Axonal

the

show

of peripheral

et al., 1979;

lnhlbltion

(Langer

conslderatlons

progressively al.,

a

sltes

in

studies

from

1983;

localized.

demonstrated

recovered

1982;

[3H]lmipramlne

and Wamsley,

are

fractlonatlon

Langer,

of

exlsts

binding

thermodynamic

1983,

and

of

et al.,

discrepancy

with

Mellerup,

that

different

Segonzac

at

recently

blndlng

(Brlley

1981).

profile

with

among

[3H]serotonin

uptake

In platelets

or platelets

[3H]imlpramine

for

[3H]lmipramine

et al.,

pharmacological

membranes

(Dawson

structures

et al.,

The

the

nerve terminals.

The

1984a.b;

brain.

Wennogle

significant

was

Subcellular

to these

cell bodies

1982;

decrease

Brunello

1985b).

raphe

et al.,

neurons

1981;

al.,

the dorsal

predominantly

in the lung (Raisman

closely nerve

is

et

serotonerglc

sltes

1985).

Rainbow

localization

et al.,

Hrdina

within

where

1983;

serotonerglc

their

Gross

1985;

blndlng

site

Importantly,

serotonerglc

1986).

of

et al., 1983; Sette et al.. 1983b. Stockert

to

identified

al.,

et al.,

binding

(Rehavl

and, most

et

et al.,

lesions

1981;

be visualized

Blegon,

(Dawson

[3H]lmipramine

Grabowsky

confirming

et al.,

[3H]lmipramine

system

1983;

or electrolytic

thus

at 37OC,

nontricyclic

et al.,

et al.,

at

1984c;

1987a).

unsuitable

At for

[3H]Antidepressant binding to monoamine transporters

equilibrium higher

binding

= (2O'C; Kd 9 ["Hllmipramine

binding

closely

related

into

if

At

37'C,

human

the

at

37'C

1987a).

A comparison

platelet

than

of

and

of chlorimipramine.

tricyclic

drugs

for

serotonin

the

Thus,

of

nW

0.79 with

also

explain

an

IC50

affinity

of tricycllc

nH

95

at

nH)

0°C

for at

for

maximum

the

affinity

blnding

al..

in studies

Several

al.,

arguments

the

may

transport

allosterically

Hellerup.

but

affects

receptor 1985).

) is

site

(Langer

and

for

binding

is not a

and

identical novel

type

Raisman, binding,

Meyerson, has

to

also

1983; been

the

human

values

that

Segonzac advanced

in

its et

its

(Segonzac

at

O"C,

as

of the serotonin

platelets,

recognition

functions

Amongst

decreasing

that

of 37Y.

substrate

1983).

for

membranes

temperature

that,

receptor

its

(Laduron,

to note

determined

temperature

to the

to

noradrenergic

platelet

the density

indicate

inhibits

imipramine

receptors

to

reflect

lmipramine,

similar

of

at

phenomena

at 0°C.

incubation

Bmax

at the physiological

interpreted

to

affinity

a Kd

binding

Imipramine

it is important

of the

accurately

at 0°C with

nH)

binding the

transporter

temperature,

independent

[3H]lmipramlne

hypothesis

Moreover,

[3Hlimipramine

represent

(Wennogle lhls

incubation

be

[3H]mazindol

affinity

[3H]imipramine

inhibitor

58

5HT2-serotonerglc

and

complex

recognition

transporter

of

=

the

Thus,

the transporter

at 0°C.

(K,

largely

by

thermodynamic

uptake

transporter

such as

with

high

['Hlparoxetine

Such

al.,

with

transporter

and

affinity

1984).

disorders.

may

measured

1987a).

for the serotonin

platelet

in affective

an

[3H]imipramine

(Emax

Thus.

macromolecular

[3H]imipramine

serotonin

of

of the

density

1987a).

transporter

with

inhibition et

al.,

serotonin

a,-adrenergic

as a function

et

uptake

et

temperature. their

interaction

serotonin/noradrenaline

the

37OC

(Javitch

as

of their

uptake

is

inhibitors.

derive

to the serotonin

(Segonzac

nontrlcyclics

uptake

and

et al.,

[3H]paroxetine

(Segonzac

by the incubation

platelets

[3H]serotonin

Is lower than its affinity

Although

from

30

uptake

Hl-histamlnergic.

the

human

of

sites

20°C

transporter

5methoxytryptollne

binds

inhibits

radioligand

=

(K,

transporter

e.g.

in

affinity

0°C

and highly

[3H]serotonin of

at

significant

Segonzac

that

at

serotonin

affected

and

of

are

at

1985;

with

but

affinity

binding

highly

binding

binding

the

their

a

et al.,

Inhibition

the

the affinity

lmipramlne

of

[3H]noradrenaline

et

that for

is strongly

that the nonselective

selective

varies

shows

at 2OY.

that

exists

correlated

[3H]lmipramlne

data

transporter

whereas

of

better

of high

[3H]paroxetine

studied

there

(Habert

profile

Indalpine

imipramlne

imipramine

37°C

1984b)

as

both

[3H]paroxetine

at 0°C. from a temperature-dependence

complex.

is a

of

whereas

temperature-independent,

such

of

and

of

indicating

1987a).

al.,

et

reversible

lnhibitlon

1987a).

or the brain

that

these

for

Similarly,

significantly

exception

binding

identical.

Segonzac

membranes,

inhibition

with

1983;

is readily

et al.,

pharmacological is

citalopram

paroxetine,

human

in platelets

platelets

binding

K,

not

al.,

values

Drug

the

uptake

et

binding

(Segonzac

between

[3H]serotonln 1987a).

to

correlated

correlation

(Hellerup

[3H]paroxetlne

0.073nH).

significantly are

assays

temperatures

197

others, rate

al.,

to describe

of

1985a; the

the

site of

to modulate serotontn dissociation Plenge

and

relationship

S. Z. Langer and H. Schoemaker

198

between

[3H]lmlpramlne

Ralsman. and

1983;

for

1985).

a

brain

(Barbaccla Abraham

On

the

basis

Langer

nM), the

of

and

platelets

studies to

a

blndlng).

analysls

ldentlficatlon

of

Such

hlgh

of

over a

afflnlty (cf.

blndlng

(Philips

et

Heterogenejty

the presence 1984,

of

may

[3H]lmipramine 1985).

In

former

sites

observed

of

[3Hllmlpramlne

al.,

1985)

transporter

low

afflnlty may

not

(IC50

=

179

might

slmllarlty

transported

to

be to

blndlng

by the 5HT

1985,

1986)

blndlng

appears

blndlng sltes

protease-

related

to the

afflnlty

serotonerglc blndlng

may

thus

and be

slte with

membranes

used

allows

(Ienl

the

et

al.,

the measurement

nanomolar

Langer,

radlollgand

1987).

In the

Low afflnlty

binding

filtration

a

than [3H]lmlpramlne.

be most

cerebral

assays

equlpment

promlnent

tlssues

and Brunswick.

(Sette

et

al.,

and

blndlng et

Such Tang, more

sites

al.,

phenomena 1983).

speclflc

nor

and

a are

wlth

In

the

further not

for

et

al.,

only

the

It has been braln

after

lndlcatlon observed

[3H]paroxetlne

radlollgand

1982,

Insensltlve

1985).

Finally.

remain

1983b),

of

displace

Harcusson

et al.,

complex.

brain.

lndlcatlve

1985; Hrdlna,

1983a;

(Marcusson

In the

are

lnhlbltors

uptake

transporter

(Sette

heterogeneity.

may

low

the

serotonln

dlstlngulshed

[3H]lmlpramlne

(Dumbrlll-Ross

to

In

(Conway

serotonln

neurons

[3H]lmlpramlne

norzlmelldlne-sensltlve

and

be

and

on

of

platelet

blnding

fllters

dependlng

manner

sites

flber

[3H]lmlpramlne

1986).

low afflnlty

brain

studied

that

concentrations

nM)

Schoemaker

glass

used (Relth,

= 293

In

at

1987a;

et al.,

Thus,

when

blndlng

be due

homogenelty

true.

Interfere

complex

complex

et

blndlng.

[3H]lmlpramlne

demonstrated

[3H]lmlpramlne (Kd

+n a

which

uptake

(Egashlra

braln

structural

slgniflcantly

binding

low

fluid

imlpramjne

the

of

the

extracted

serotonln

5-methoxytryptollne

Its

(I.e.

be

of

several

[3H]cyanolmipramlne et

range

and

being

that

denervation

wide

or

sltes

1986)

blndlng

of

lnhlbltor

assumed

necessarily

[3H]lmlpramlne

and

that

splte

and

In

Hellerup,

(Brusov et al., 1985;

splnal

uptake

and

1986).

through

A factor

and

plasma

blndlng

suggested

Relth,

the

[3H]lmlpramlne

not

Relth,

of

of hlgh

1987;

a

have

[3H]lmlpramlne

analyses

Human

serotonln

competltlve

recognltlon

Segonzac

1984;

al.,

blndlng

and

acting

postulated.

198513) and Is not acttvely

far

blndlng

type and batch of filters

Saturation

a

[3H]lmlpramlne

[3H]lmlpramtne

1985).

In

of

second,

concentrations

1985)

et al.,

may

low afflnlty

was

(Plenge

llgand

1984) and dog cerebral

so

class this

platelets

[3H]lmlpramlne

(Langer

Kim and Relth.

et al., 1987b).

dlscussed

single

However,

saturation

1985).

(Segonzac

transport

factor. Is

In the braln

1985;

endogenous

[3H]lmlpramlne

(1984a.b.

(Segonzac

and

an

to affect

for

lmlpramlne-like

uptake mechanism

Host

afflnlty

coworkers

brain

et al..

Paul,

able

5-methoxytryptollne

In human

blnds

and

transporter

and Hellerup,

of

lnhlblt

1986; Rehavl

Angel

In

serotonln to

substances Its

endogenous

serotonln.

sltes

1983,

Include

serotonln Plenge

existence

reported

1987;

et al.,

the

the

to modulate

was

et al.,

1987)

and

1983a.b;

blndlng

consequence,

receptor

rat

al.,

et al.,

[3H]paroxetlne As

lmlpramlne from

binding

Sette

the

of wlth

(Habert serotonln

[3H] Antidepressant

Impllclt

to

[3H]antldepressant observatlons

blndlng

caution

pharmacologlcal

do

proflle

difference

In the molecular of

Is

In

the

transporter

may

(see

Is highly

that

Habert

The

sensltlve

to

than

related

above).

sensltlve the

binding

to the

1985;

of

(1985)

to

effects

of and

Inhlbltlon 1983a).

to

the

of serotonln

a the

that

[3Hllmlpramlne

[3H]norzimelldlne

lnhjbltory

reported

[3H]lndalplne

et al..

of

the human

Similarly, than

both

Sette

heterogeneity

in

blndlng

[3H]lmlpramine

et al..

to the

Some

whereas

polymers.

of

affinity

transporter.

sodium-ions

binding

of

high

Thus,

coworkers

and

blndlng

and

1985;

be

serotonln

assumption.

respective

1985).

of

[3H]paroxetlne

Mellerup

their

sensltlve

the

this and

more

al.,

et al.,

however,

brain

et

more

(Benavldes

observations,

of

appears

(Benavldes

[3H]paroxetlne serotonln

size

[3H]lndalplne

wlth

lnvalldate

correlated,

homogenelty

a

[3H]imlpramlne

slgnlflcantly

[3H]imlpramine

not

of

Is

1s

associated

sites

but

platelets

blnding

dlscusslon

above

the

199

binding to monoamine transporters

by

These

binding serotonin

(IC50

= 43 nM;

Hall et al., 1982).

[3H]Imlpramlne a major Thus,

Interest In

binding

a

(Table

increase

In

studies

the

In

the

quantltatlve complex,

dependlng tsolatlon

radloligand

on

The

blologlcal

[3Hllmlpramlne

drug

Interest.

drug

should

volunteers

of

by taking

washout.

binding The

In

after

be

[3H]lmlpramlne

Into

antldepressant of

platelet

(Polrler

Moreover,

high

the

time

al.,

of blood

1984.

and that

varlabillty

(50 B,,

preparation

the

In

and

the

confounding

depresslon

may

In clintcal

and

and

to healthy

by

on

speclflc

evaluatlng

mg/day)

1987).

transporter

more

sampllng

values

affect

may

these

studles

platelet

It is likely

populatjon

admlnlstration

chlorimlpramlne

of

a 10% decrease

bindlng

of

studies

whlle control

agreement,

serotonln

use

36

the aforementloned

circumvent

respect,

drug

and

platelets

afflntty

The

to

[3H]lmlpramlne et

to

the

patients,

density

In

blndlng

the

latter

of

signlflcant

and Its membrane

of the subject

account

this

the

1987).

used.

explored

Out but

qualltatlve

slte

speclftc

In control

to this quantitative

blndlng

protocol

deflnitlon

admlnistratlon

decreases

admlnlstratlon

of

in

vary between

of platelets

afflnlty

that

patients

In depresslon.

contribute

blndlng

deflnltlon

by a better

and

hlgh

B,,

small

1987a).

[3H]lmlpramlne

melancholic

in

1982,

of

value.

a

are

and

and Langer,

flltratlon)

varlablllty

terms, of

healthy

the

(I.e.

be decreased

hlstory

Its

[3H]paroxetlne

variables. further

of

Kd

has attracted

al.,

than

untreated

decrease

Isolation

[3H]lmlpramlne

Its

studies

exist.

varlables

In

et

Bmax

lower

reported

In manic

23

[3H]lmlpramlne

The

the was

between

relative

(cf. Schoemaker

estimates

membrane

blndlng

remalnlng

the

1987).

Importance

(1982)

In depression

and clintcal

low-affinity

changes

al.

complex

(Langer

date,

patients

differences

the

platelet

and Galzln.

are of known

any

In

sites

to

concomitant et

transporter

In depression

depressed

[3H]lmlpramlne

detect

serotonln

published

Mellerup

whereas

experlmental

putatlve

of

to

binding

decrease

(cf. Langer

of

without

of

the

marker

untreated

differences

[3H]lmlpramlne

several

Bmax

However,

quantitative

label

studies

from

only

failed

volunteers.

are

of

2).

publlshed,

to

a blologlcal

to platelets

studles

a 54%

as

majority

populations

12

as a llgand

for 63%

Similarly,

prevlous platelet

volunteers

one at the

week the

to end

acute

S. Z. Langer and H. Shoemaker

200

Table 2

Sumnary

of Cllnlcal

Studies on Platelet

[3H]bmlpramlne

Study

Blndlng

in Depresslon

Percent variation in platelet [3H]lmlpramine binding (8max)

Decreased L3H]lmlpramine bindlng In dzpression Brlley et al., 1980 Asarch et al., 1981 Paul et al., 1981a Raisman et al., 1981 Raisman et al., 1982b Suranyi-Cadotte et al., 1982 Langer and Raisman, 1983 Arora et al., 1985 Lewis and HcChesney, 1985 Schneider et al., 1985 Suranyl-Cadotte et al., 1985b Tanimoto et al., 1985** Wagner et al., 1985 Baron et al., 1986* Knight et al., 1986 Langer et al., 1986b Pecknold and Suranyi-Cadotte. Poirier et al., 1986 Innis et al., 1987 Maj et al., 1987 Roy et al., 1987*** Slotkin et al., 1987 Suranyl-Cadotte et al., 1987

-54% -22% -29% -48% -32% -54% -43% -13% -40% -20% -26% -21% -10% -20% N.R.a -54% -25% -47% -31% -25% -12% N.R. -26%

1986

Increased r3Hlimlpramine binding jn depresslon Hellerup

et al., 1982

No slpnlficant

+9x

dtfferences

Baron et al., 1983 Egrlse et al., 1983 Gentsch et al., 1985 Hrdlna et al., 1985a Huscettola et al., 1986 Tang and Morris, 1985 Whltaker et al., 1984 Baron et al., 1986* Carstens et al., 1986 Georgotas et al., 1987 Kanof et al., 1987 Roy et al., 1987***

Shown

1s

a

sumnary

of

publlshed

studies

In

which

the

8max

of

platelet

[3H]Antidepressant

binding

to monoamine

201

transporters

[3H]lmlpramlne blndlng was measured ln untreated depressed patients In comparison to volunteers. For those studies ln which a slgnlflcant difference In control the percentage change Is llsted. [3H]lmipramlne blndlng B,, values was reported, In 23 out of the 36 studles, a slgnlficant decrease In [3H]lmlpramlne blndlng was reported. * Baron et al. (1986) reported a slgnlflcant decrease in platelet 8,, values for [3H]lmlpramlne In euthymlc blpolar but not In unlpolar depression. ** Tanlmoto et al. (1985) studled [3H]lmlpramlne blndlng at 1 nH only. *** Roy et al. (1987) reported a slgntflcant decrease In platelet 8ma,, values for of women and [3H]lmlpramlne blndlng In women only, but not In the total populatlon men. a N.R.: not reported.

administration

of

[3H]lmipramine

blndlng

drug-dependent. platelet

The

cause

al.,

those

term

longitudinal

In platelets

from

antidepressant Improvement (1985b)

with

a

[3H]lmlpramlne

the control

while range

[3H]lmipramlne

which

depression, probably of

received

human

brain.

the

(Perry

patients

et al.,

levels

a

as

It remains binding

of

are

Stanley

that,

al.,

1987)

for a 4 week or

did

support

blologlcal

and

at

blnding

six

medication, clinical towards

the hypothesis

that

marker

In

improvement,

that the binding

In depression,

those

whether

post-mortem

has

changes

occurlng

controls

but not

during

Increase

established

In the

coworkers

of

clinical

of

trlcyclic

least

biological

marker

reflectlon

binding

values

after

the hypothesls

1982)

with

presence

values

to the appropriate

et al.,

of

of a significant

binding

following

to be fully a

[3H]lmlpramlne

as compared

1983;

treatment

the

Bmax

only

may

serve

values

[3H]lmlpramlne

In spite

state-dependent

Although

support,

B,,,

period

a

be

chlorlmlpramine

antidepressant

In

lhese data would

Is

may

lmlpramlne

et

Suranyl-Cadotte

other

consolidated.

[3H]lmlpramlne In

during

reported

changed

1986b).

of

1981)

hand,

without

follow-up

platelet

Kd

to allow

with

[3H]lmlpramlne

recently

control

platelets

and depressed

two studles

to

change

other

not

platelet

Is well

considerable

platelet

were

et al., In

recovers

to

A decrease

sulcldes

(Langer

remlsslon

[3H]lmlpramlne

thus In

when

sesslons

advisable

et al.,

control

we

an 18 month

blndlng

the

to

Moreover,

values

over

On

and while

(Polrler

medicated

the density

not

B,,,

of

effects

et al., 1984).

that

does

return

therapy 8max

It seems

(Ralsman

ratlng.

delayed

lmlpramlne.

electroconvulslve

Improvement,

patients

such

1984)

amlneptlne

(Polrler

lndlcate

or maprotlllne

psychlatrlc

reported

treatment

depressed

drugs

In

studies

al.,

previously

uptake

decrease

However, Increases

et and

however,

patlents

serotonln

slgnlflcant

amltrlptyllne

maprotlllne

In general,

for

a

1986).

(8raddock

198%).

at all.

period

In

Plenge,

of

blndlng

other drugs that lnhlblt

Short

and

admlnlstratlon

et

no change washout

results

(Hellerup

[3H]lmlpramlne

(Suranyl-Cadotte

drug

chlorlmlpramlne

In brain

was reported

In a third

the of in

study (Owen

et al., 1986).

The been

specificity addressed

platelets

of In

a

[3H]lmlpramlne much

[3H]serotonln

more uptake

binding

limited was

as

number

decreased

a blologlcal of In

studies

marker

In depression

(lable

platelets

from

3).

lhus,

clrrhotlc

has whlle and

S. Z. Langer and H. Schoemaker

202

Table 3 Summary

of Clinical Studies on Platelet [3H]Imipramine in Diseases Other than Depression

Rind1ng

Percent variation in platelet [3Hllmipramine blnding

Study

(Bmax)

Panic disorders Lewis et al., 1985 Rov-Bvrne and Uhde. 1985 Schneider et al., i987 Uhde et al., 1987 Pecknold and Suranyl-Cadotte, Innis et al., 1987

-35% slgnlficant significant slgniflcant stgnificant significant

difference difference difference difference difference

Adolescent affective disorders Rehavi et al., 1984

no significant

difference

Schizophrenia Wood et al., 1983 Weizman et al., 1987 Kanof et al., 1987

no slgnlflcant no slgnfflcant no significant

dtfference difference difference

Autism Anderson et al., 1984 Weizman et al.. 1987

no significant no signiftcant

difference difference

Alzheimer's disease Suranyi-Cadotte et al., 1985a

no signlflcant

difference

Parkinson's disease Suranyi-Cadotte et al., 1985a

no signlflcant

difference

Essential hvpertension Kamal et al., 1984

no slgniflcant

difference

Ctrrhosis Athee et al., 1981

no significant

difference

Obsessive-compulsive disorders Insel et al., 1985 Wetzman et al., 1986a

no significant difference -37, -50%

1986

no no no no no

Anorexia nervosa Welzman et al., 1986b

-29%

Enuresis Weizman Wejzman

-22% -29%

et al., 1985 (children) et al., 1986c (adolescents)

Post partum Katona et al., 1985 Cushina's disease Bloomfield et al., 1985

Shown is a [3H]\m1pramlne

~~~~~

wi:

no signlftcant

difference

-34%

platelet the Bmax of In which published studies In diseases other than depresston. For those measured

203

[3H] Antidepressant binding to monoamine transporters

studies reported

In uhlch a slgnlflcant difference ln [3H]imlpramlne 8,x values In comparison to control volunteers, the percentage change 1s llsted.

hypertenslve in

these

patients,

patlents

[3H]lmlpramlne et

al.,

platelet

(Ahtee

blndlng

dlsease

(Suranyl-Cadotte

1984).

panic

Schneider et

al.,

1985)

ratlngs

samples known

neurons

Although

these marker

afflnlty

adolescents

Cushlng's

studles

[3H]lmlpramlne et al.,

enuresls. dlsease,

posslbly

females

anorexla

with

slgnlficantly

(1986a)

reported whjle

a

blndlng

the absence

thls

decreased

In

mood

blnding

In post-mortem It Is not leslon

of

that Is encountered

et

al.,

of

a

In

B,,

complex

(see

high

afflnlty

transporter and

perlpheral

follows

1981c).

In

(Kd =

(Langer.

the a

2).

nervous

-

system,

that of noradrenerglc

the

(Ralsman

rat, et

the

al.,

vas

1982a;

1.4

Langer

nM)

et al.,

Langer

Is et

et al.

[3H]lmlpramlne

Transporter

has

al..

since

ldentlfy

uptake

lnhlbltor

been

radlomarker 1981c; of

establlshed the et al.,

[3H]deslpramlne et al., 1981c;

enriched 1984d).

labelled

of

Ralsman

(Langer

most

to

[3H]lmlpramlne

the denslty

lnnervatlon

deferens

is

[3H]serotonin

platelet

noradrenaline

Whereas

[3H]deslpramlne

1.1 1984;

adolescent

Welzman

[3H]lmlpramlne

speclflc

of platelet

denslty

platelet

With The Noradrenallne

radlollgand.

In

In

disorders, of

and

decreased

binding

In

and

differences.

uslng

studles

Flnally,

[3H]lmlpramlne

the

Is

a

familial

modulatlon

1985).

modlflcatlon

as

Platelet

children

between

bjndlng

an adrenocortlcold

Sites Associated

as

[3H]imlpramlne

lnterpretatlon. enuretlc

obsessive-compulsive

decrease

sltes.

of

caution

platelet

Studyjng

evaluated

transporter

sltes

towards

lnltlal

blndlng also

In the central al.,

Blndlns

wlth

was

noradrenallne

et

depression

[3H]lmlpramlne

(Bloomfleld

slgnlflcant

[3H]antldepressant

closely

1986;

see Lewls

depressive

Its density

speclflclty

Insel et al. (1985) found no slgnlflcant

Slmultaneously

sites

In

but did not dlstlngulsh

platelet

nervosa, the

a

was

1986c)

polntlng

In

3. Antldepressant

speclflc

et al.,

[3H]lmlpramlne

pathophyslologlcal

a concurrent

reports

blndlng 1985,

et al., 1986b).

binding.

a

however

(Cash et al., 1985).

primary

Wood

Alzhelmer's

(Rehavl

1985;

Increase

reduced

a

platelet

Suranyl-Cadotte,

platelet

though

modifled

1987;

1987).

disorders and

an

not

et al.,

al.,

and Uhde,

even

was

towards

parameter

decreased

(Welzman

serotonln

with

other

Moreover,

blndlng

deslpramlne

polnt

In depression,

[3H]lmipramlne

uptake

cortex

or Is associated

(Welzman

nonfamlllal

affective

dlsease

1985)

reflects

et

Pecknold

desplte

were

Furthermore,

(Welzman

Welzman

1987; Roy-Byrne

In Parklnson's

observation

1984).

schlzophrenla 1984;

1987;

et al.,

parameters

al.,

disease.

blologlcal high

et

adolescent

al.,

and prefrontal

latter

In Parkinson's

In

post-partum,

1985).

blndlng

Kamal

al.,

Uhde et al.,

(Suranyl-Cadotte

the

serotonerglc

et

lmnedlately

of the putamen If

et

(Innls

et al.,

Is not modified

affected

et al., 1985a).

1987;

and

(Katona

1981;

(Anderson

disorders

et al.,

[3H]lmlpramlne

al.,

1s not

autlsm

1983).

et

was

In

the as

neuronal 1982a). blndlng Ralsman

[3H]deslpramlne

Surgical

(Langer

and

S. 2. Langer and H. Schoemaker

204

Raisman,

or

1983)

noradrenerglc

chemical

neurons

the rat, thus confirming sympathetic decrease et al., PC12

of the

endogenous

1982a).

The the

Finally,

as

well

quantitattvely Harder,

of

1986;

[3H]deslpramine (Lee et al.,

exists with

PC12

binding 1982;

(BBnlsch

and

hypothesis

that

serotonln

transport

(see

label a regulatory

Harder from the

remains

(1986)

observed

Its recognition dissociation

hypotheses

to

and Harder

of

(1986).

At the basis have

only

et al., other with usual

1986c;

temperature transport.

the

of

in a parallel (Ralsman

demonstrated

In the

they

have

Ralsman

et al.,

a qualltatlve and

of these

suggested

In the

(Langer and

as those

of

the

in analogy with may

to the susbstrate

(1982)

Although

nor

of

BBnisch

(see

observed

and

for

2). Alternative

blndlng

by Lee et al.

this

[3H]deslpramlne

as had been

[3Hldesipramlne

advanced

and

1984d).

serotonin

between transport

[3H]deslpramlne

of dissociation

presence

between

transport

associated

coupled

et al.,

of noradrenaltne,

In the

for

correlation

also

coworkers

rate

lnhlbit

KM

receptor

from but allosterically

Lee

et al.,

observations,

that

and shows

poorly

[3H]noradrenaljne

a modulatory

and

(Raisman

only

their

of

inhlbltors. (B8nlsch

1982a),

of oxaprotlline transporter that

tissues

uptake

transporter

bindlng

been

neither

peripheral

site

and

(1982)

or BBnisch

that transporter

substrates

rematn posslble.

to

hypotheses

compete

the

0°C.

[3Hldeslpramine

this

[3H]mazjndol

et al.,

rat,

1987).

questlon blndlng

of 2OY for

However,

(Javltch

at

with the

[3H]mazlndol et al.,

(cf. Raisman

inhlbitlon

even

In

blndlng

0°C

of their

1984,

et al.,

radlollgand affinity

to

respect rat

In the rat sallvary

sodium-dependent

transporter

affinity

js the observation

with

reevaluated

temperature

higher

of

Similarly.

bindlng

noradrenergic

higher

transporter

such

of

from which

although

labels

relationship

transporter,

noradrenaline

fold

1982a).

has

[3H]lm\pramlne

Schoemaker

Incubatton

much

In the presence

recently

of

1984d.

On the basis

proven,

sodium-dependent

tissues the

the

a modification

potency

We

and

al.,

by

noradrenerglc

noradrenaline

of the above

low

transporter. bindlng

et

different

be

and

defined

[3H]lmipramlne

site

define

the noradrenaline

100

to

been

central

the

site of the noradrenaljne

hypothesis

results

in

blndlng

[3H]deslpramlne

receptor

have

1982) tissues

1986).

as

It

al.,

termtnals.

gland

1986)

to the enantlomers

2).

nerve

Harder,

of

1986).

et

[3H]desIpramine

sites

of

Harder,

the

Lee

and

that

et al.,

of

of

binding

(Bdnlsch

concentrations

Raisman

and

respect

at

1981;

In the appropriate

submaxillary

cells,

Langer

substrates

inhibition

recognition

line

to

e.g. with

However,

substrate

in

Hrd'rna, 1982;

stereospeciflclty 1982a).

cell

[3H]desipramine

as

or

levels

[3H]desipramlne

corresponds

et-al., blnding

to noradrenerglc

heart

(Schiimlg and Bonisch,

pharmacology rat

rat

noradrenaline

rat phaeochromocytoma

been solubilized

(Hrdlna

[3H]deslpramlne

its localization

denervation

in

denervatlon

decreases

to

gland,

1985). 1982a).

noradrenallne

[3H]destpramine

salivary

blnding

gland

less

(Langer

as well as In most js

also

As

compared

substrates

blnding was

the

at than

an

associated to the

had up to lncubatlon

their

KW

for

[3H] Antidepressant

4. AntldeDressant

In those human

areas

of the braln

basal ganglla)

antldepressant neuronal 1986).

dopamlnerglc

and

profile correlated

synaptosomes,

as deflned

as

In

the

case

The

et

al.,

al.,

blndlng

1986)

1985).

and

radlollgands. selectlvlty

al.,

the

experlmental

that,

et al., In

compared

most to

radlollgands sympathetic can

be

1985;

be

braln

et

al..

1986).

transmitter Thls

transporter

Is

The

highly

Into

strlatal

1985).

However,

(see

2)

substrates transport

[3H]cocalne

1983).

1985).

and

affect Into

(Kennedy

[3H]mazlndol

[3H]GBR-12783

et

are

the

al.,

of

1985).

hlghest

and

(Javltch

(Bonnet Among

et

those

affinity

and

transporter. that,

[3Hlcocaine

as

had

been

blndlng

patlents

(Plmoule

shown

was

uslng

slgnlflcantly

et al.. 1983,

[3Hlcocalne

that

for

Wlth The Adrenallne

serotonln.

by means

blndlng

1985;

In

the

of the neuronal been

reported

no

reported.

noradrenallne speclflc However,

et al.,

observation.

and

rat braln

1965) the

transporter the

adrenallne In

the

and

In vlvo

(Tessel

et

Is hampered

major

al.,

using

for

as

use as Is

the

of noradrenallne

also

1978)

by

1987b;

by the fact

adrenallne

levels

deslpramlne et al.,

dopamlne

neurotransmltter lnhlbltors

heart,

mlnlmal

that

and

studies

for adrenallne

(Langer

uptake

frog

only

fact

binding

transporter

recently

Is

TransDorter

noradrenallne

of radlollgand

of the adrenallne

tissues.

In the

by

schlzophrenla.

systems

only

The study

(Azuma

and

ganglla.

serotonln

K,, for

In

et al., 1985).

ldentlflcatlon

and

al.,

revealed

Sltes Associated

has

thelr

the

conditions

strlatum uptake

the

et al.,

deseased In

characterized

mammalian

been

However,

transporter

the

1987).

have

human

rat

transporter

(Janowsky

of the dopamlnerglc

(Dubocovlch

1986).

and Zahnlser,

labelled

et

and

et al., 1985,

of the basal

the

wlth

by a decrease

brain

al.,

dopamine

to

rabbit

1985).

i3H]GBR-12935

the

Elndlno

approach

In

than

Plmoule

(Berger

of Parklnson's

well

adrenallne

detected.

adrenaline

slmllarly

(Plmoule

neuronal

relatlvely

[3H]antldepressants.

Plmoule

lower

and Zahniser,

and

1985).

5. AntldeDressant

thls

may

(Scatton

putamen was not affected

been

an afflnlty

et al.,

In

In the putamen

Whereas

3),

rat et

(Dubocovlch

[3Hlthreo-(+)-methylphenldate

[3H]nomlfensine

have

(see

[3H]GBR-12935

studies

et

lnhlbltors

the

of

blndlng

for the labelllng

Schoemaker

blndlng

lnhlbltlon

dopamlne

[3HlGBR-12783

Post-mortem

for

(Dubocovlch

1985; Scatton

innervation

[3H]antldepressant

wlth

Schoemaker

1984,

that

In

rat,

associated

Is evidenced

(Scatton

complex

transporter

1983;

decreased

for

nerve ending

dopamlne

Hanbauer.

[3H]nomlfenslne

by uptake

transporter

[3H]nomlfenslne dopamlnerglc

leslons

(e.g.

appear

and Zahniser,

dlsease

Transporter

sites for the nontrlcycllc

that

nerve termlnals

In the dopamlnergic

with

lnnervatlon blnding

ldenttfled,

(Oubocovlch

Parklnson's

of

slgnlflcantly

noradrenaline

been

6-hydroxydopamlne In

by a decrease

pharmacologlcal

in dopamlnerglc

have

205

transporters

Wlth The DoDamjne

sodlum-dependent

to dopamlnerglc

followlng

1985)

characterized

and

rich

transporter

locallzatlon

denslty

Zahnlser,

Sites Assoctated

hlgh afflnlty,

[3H]nomlfens1ne

Thelr

thetr

Blndlnq

binding to monoamine

lnhlbits

prompted

the

Langer

S. 2. Langer and H. Schoemaker

206

and

coworkers

blndlng high

frog

affinity

fmol/mg heart to

(Langer

in the

(Kd

protein, =

(E,,

the

uptake

184

inhibitors

the

noradrenaljne

the

adrenallne

the

atypical

excluded,

lnhlbltor

more

mlanserln, attractive

and

the

the

also

the

the

transporter

additional

the

adrenaline hypothesis

brain

contributes

816 rat

bindtng

btnding

and

$prindol

and

bindlng

of to

transporter

induced

decrease

may

Is

In and

be a specific

that the affinity

imlpramlne. thelr

to

can not be

In vivo (VonVoigtlander iprindol

to

imipramine

is substantiated

The hypothesis

affinity

of the

to that for

differences

6-hydroxydopa

for adrenaline.

preferential

by

[3H]desipramlne

jn the mannralian brain

transporter and

similar

of

species

ts of

noradrenaline

[3H]desipramlne

This

In the mouse

the

imlpramlne.

of

transporter.

In

Thus.

Although

pharmacology

levels

by

be differentiated

lnhibltors

antagonlzes

adrenaline

and deserves

as

(Emax)

[3H]Desipramlne

an affinity

However,

may

heart

binding

inhibited

with

[3H]desipramine

frog

density

1982a).

Is

mlanserin.

potent

study

In the

bindlng

al.,

heart.

transporter.

that

that

antidepressants, for

rat

iprlndol

iprindol

of the neuronal

some

the

of the noradrenaline

jndicating

et

to

[3H]desipramlne

heart

transporter

noradrenerglc

that

for

frog

1987) binding

ma~1mal

(+)oxaprotillne,

but not noradrenaline

1978).

the

In

50 times

et al.,

a

Raisman

in

and

appear

shows

protein;

noradrenaline

would

report

and

observed

transporter

than

Plmoule

[3H]Deslpramine

that

nisoxetlne

20 to

It

the

Losey,

of

fmol/mg

from that

adrenallne

nH) than

antidepressants

are

dlfferent

1.94

transporter

and

the adrenerglc

by

=

1987b;

In vitro.

greater

adrenaline

mlanserln

et al., heart

lprlndol

clinical

and

effects

Is

evaluation.

6. Conclusions

Since

the

transporter

lnltial

description

in

braln

the

and

[3H]antldepressant

binding

dopamine

noradrenallne, of

such

[3H]antidepressant are associated.

such regulatory

and

Horeover.

sites

uptake

the question

the

remains

study

only

not

to

radlollgand

the

a better and

[3H]imipramine

tissues,

within

include

and whether

of

allowed

adrenaline

studies

use

peripheral

sites

recognition

sites may be subject

the

have

antidepressants

[3H]labelled

perspectives

of

the

binding

serotonin

assays

but

transporters.

Undoubtedly,

definition

the

respective

of

transporters

endogenous

using

wfth

ligands

of

also the

relationship

open as to the regulation

so far unidentified

serotonin

characterization

and

the

label

the

future of

which

to which

the they

these

partlclpate

in

processes.

Acknowledgements

The

authors

assistance

gratefully

In the preparation

acknowledge

Francoise

of this manuscript.

Pechoux

for

expert

secretarial

[3H] Antidepressant

binding

to monoamine

transporters

207

References IENI, J.R. and MEYERSON, L.R. (1987) Purlflcatlon and propertles of a ABRAHAM, K.I.. endogenous modulator for the platelet tricycllc blnding/serotonln human plasma transport complex. Blochim. Blophys. Acta 923: B-21. AHTEE, L., BRILEY, M.S., RAISHAN. R., LEBREC, 3H-lmlpramlne of serotonln but unchanged patients. Llfe Scl. 29: 2323-2329.

D. and LANGER, S.Z. (19Bl) Reduced uptake binding In the platelets from cirrhotic

ANDERSON, G.H., HINDERAA, R.B., VAN BENTHEH, P.P.G., VOLKHAR, R. and COHEN, D.J. Platelet lmlpramlne binding In autistic subjects. Psychiatry Res. 11: 133-141. ANGEL, I. and PAUL, S.H. (1984) uptake by endogenous factor(s)

(1984)

Inhibition of synaptosornal 5-[3H]-hydroxytryptamlne In human blood. FEBS Lett. 171: 280-284.

ASARCH, K.B., SHIH. J.C. and KUBESAR, depressed males and females. Comnun.

A. (19Bl) Decreased 3H-lmlpramlne Psychopharmacol. 4: 425-432.

AZUMA, T., BINIA, A. and VISSCHER, H.B. (1965) and turtle. Am. J. Physlol. 209: 1287-1294.

Adrenerglc

mechanisms

In

blndlng

In

the bullfrog

BARBACCIA, H.L., GANDOLFI, 0.. CHUANG, D.M. and COSTA, E. (1983) Modulation of neuronal serotonin uptake by a putative endogenous llgand of Imlpramlne recognition sites. Proc. Natl. Acad. Scl. U.S.A. a: 5134-5138. BARBACCIA, H.L., HELLONI, P., POZZI, 0. and COSTA, E. (1986) [3H]Imlpramlne dlsplaceand 5HT uptake Inhlbltlon by tryptollne derlvatlves : In rat braln ment 5-methoxytryptollne is not the autacold for [3H]lmlpramlne recognltlon sites. Eur. J. Pharmacol. 123: 45-52. BARON, H., BARKAI, A., GRUEN, R., KOWALIK, S. and QUITKIN, F. (1983) 3H-Imlpramine platelet binding sites In unipolar depression. Blol. Psychiatry u: 1403-1409. BARON, H., BARKAI. A., GRUEN, R., PESELOW. M.D., FIEVE. R.R. and QUITKIN, F. (1986) versus Platelet [3Hllmlpramlne binding In affective disorders: trait state characteristics. Am. J. Psychiatry 143: 711-717. BENAVIDES. J., SAVAKI. H.E.. MALGOURIS, C., LAPLACE C.. MARGELIDON. C., DANIEL, H., COURTEIX, J.. UZAN, A., GUEREMY, C. and LE FUR, 6. (1985) Quantltatlve autoradiography of [3Hl-indalplne binding sites In the rat braln : I. Pharmacological characterization. J. Neurochem. 45: 514-520. BERGER, P.. JANOWSKY. A., VOCCI. F., SKOLNICK. P., SCHWERI, M.M. and PAUL, S.M. (1985) [3H]-GBR-12935 : a specific high affinity llgand for labelllng the dopamlne transport complex. Eur. J. Pharmacol. 107: 289-290. BIEGON, A. (1986) Effect of chronic deslpramlne treatment on dihydroalprenolol, lmlpramlne and deslpramlne binding sites : a quantitative autoradlographlc study the rat braln. J. Neurochem. 41: 77-80. BLOOMFIELD. J.G.. ELLIOlT, A.M. and EVANS. [3Hl-yohlmbine binding are reduced In 402P. BANISH, H. and HARDER, R. (1986) Binding nallne carrier of rat phaeochromocytoma Arch. Pharmacol. 334: 403-411.

In

D.J. (1985) Platelet [3H]-lmlpramlne and Cushlng's disease. Br. J. Pharmacol. &.

of 3H-deslpramlne to the neuronal noradrecells (PC-12 cells). Naunyn-Schmledebergls

BONNEI, J.J., PROTAIS. P., CHAGRAOUI. A. and COSTENTIN. J. (1986) High-afflnlty dopamlne t3H]GBR 12783 blndlng to a speclflc site associated wlth the neuronal uptake complex in the central nervous system. Eur. J. Pharmacol. 126: 211-222. BORBE. H.O. and ZUBE.

I. (1983) The detection

of specific

[3H]lmlpramlne

blndlng

in

S. Z. Langer and H. Schoemaker

208

bovine

retina.

Brain Res. 264: 178-180.

BRADDOCK. L.E., COWEN, P.J.. ELIOTT, J.H., FRASER, S. and STUMP, K. (1984) Changes ln the blndlng to platelets of [3H]lmlpramlne and [3H]yohlmblne In normal subjects taking amltrlptyllne. Neuropharmacology 23: 285-286. BRILEY. H.S.. RAISHAN, R. and LANGER. S.Z. (1979) Human platelets possess binding sltes for 3H-lmlpramlne. Eur. J. Pharmacol. 58: 347-348.

high-affinity

BRILEY, H.S., LANGER, S.Z., RAISHAN, R.. SECHTER, D. and ZARIFIAN, E. (1980) Trltlated lmlpramlne blndlng sltes are decreased In platelets of untreated depressed patients. Science 209: 303-305. BRUNELLO, M., CHUANG, 0. mlanserln and lmlpramlne

and COSTA, E. (1982) blndlng sites. Science

Dlfferent synaptic 215: 1112-1115.

locallzatlons

of

CARSTENS. M.E., ENGELBRECHT, A.H., RUSSEL, V.A., AALBERS, C.. GAGIANO. C.A., CHALTON, D.O. and TALJAARD, J.J.F. (1986) Imlpramlne blndlng sites on platelets of patlents wlth major depressive dlsorder. Psychiatry Res. la: 333-342. CASH, R., RAISMAN, pramlne blndlng 71-80.

R.. PLOSKA, A. and AGID, Y. (1985) sites In control and parklnsonlan

CONWAY, P.G. and BRUNSWICK, D.J. (1985) [3H]-lmlpramlne In rat cerebral cortex.

High and low affinity [3H]lmibralns. Eur. J. Pharmacol. 117:

High and low-afflnlty blndlng J. Neurochem. 45: 206-209.

components

for

D'AMATO, R.J., LARGENT. B.L., SNOWMAN, A.M. and SNYDER, S.H. (1987) Selective labellng of serotonln uptake sites In rat brain by [3H]cltalopram contrasted to labeling of multiple sites by [3H]lmlpramlne. J. Pharmacol. Exp. Ther. 242: 364-371. DAVIS, A. 782-794.

(1984a)

Molecular

aspects

of

DAVIS, A. (1984b) Temperature-sensitive blndlng sites and the Involvement of 102: 341-341. DAVIS, A., MORRIS, J.M. and changes In membrane-bound Pharmacol. 88: 407-410.

the Imlpramlne

"receptor".

Experlentla

40:

conformational changes In [3H]lmipramlne sulphur-contalnlng bonds. Eur. J. Pharmacol.

TANG, S.W. (1983) Temperature-sensitive and solublllzed [3H]lmlpramlne blndlng

conformatlonal sites. Eur. J.

DAVIS, A., MORRIS, J.M. and TANG. S.W. (1985) Partlal characterlzatlon of solublllzed platelet lmlpramlne binding sltes new probe. [3H]3-.cyanolmlpramlne ([3H]Ro 11-2465). Eur. J. Pharmacol. ,Psi?104a. DAWSON, T.M. and WAMSLEY. J.K. (1983) Autoradlographlc localization of [3H]-lmlpramlne binding sites : assoclatlon with serotonerglc neurons. Brain Res. Bull. 1: 325-334. DAWSON, T.M.. GEHLERT, D.R., SNOWHILL, E.W. and WAMSLEY, J.K. radlographlc evidence for axonal transport of Imlpramlne nervous system of the rat. Neuroscl. Lett. 55: 261-266. DUBOCOVICH, H.L. and ZAHNISER, lnhlbltor [3H]-nomifenslne 1137-1144.

(1985) Quantitative autoreceptors In the central

N. (1985) Blndlng characterlstlcs of the dopamine uptake to strlatal membranes. Blochem. Pharmacol. 2:

DUHBRLLLE-ROSS, A. and TANG, S.W. (1983) Blndlng to a subpopulation of 3H-lmlpramlne blndlng sites by 3H-Ro 11-2465, a posslble lrreverslble llgand. Molec. Pharmac. 607-613.

23:

EGASHIRA. T.. TAKANO, R. and YAMANAKA, Y. (1987) Modulatlon of neuronal MAO actlvlty. 5-HT uptake and Imlpramlne blndlng by endogenous substances In dog cerebrosplnal fluld. Blochem. Pharmacol. 36: 1781-1785.

[3H]Antidepressant binding to monoamine transporters

EGRISE,

in

the

D., DESMEDT,

density

Neuropsychobiology

of

D., SCHOIJTENS, A. and

trltlated

lmlpramlne

209

HENDLEWICZ, J. (1983) Circannual varlatlons blndlng sites on blood platelets In man.

10: 101-102.

FUXE, K., CALZA, L., BENFENATI, F. ZINI, I. and AGNATI, L.F. (1983) Puantltative autoblndlng sites In the braln of the radlographlc locallzatlon of [ 5 HI-lmlpramlne neuron systems. Proc. Natl. Acad. rat : relatlonshlp to ascendlng 5-hydroxytryptamlne U.S.A. a: 3836-3840. GENTSCH, C., LICHTSTEINER, H., GASTPAR, H., GASTPAR, 6. and FEER, H. (1985) 3H-Imlpramine blndlng sites In platelets of hospltallzed psychlatrlc patients. Psychiatry Res. 14: 177-187. GRABDWSKY, K.L.. MCCABE, R.T. and WAMSLEY. binding sltes In rat brain by light 2355-2361.

(1983) Locallzatlon of [3Hl-lmlpramlne mlcroscoplc autoradlography. Life Scl. 32:

J.K.

GROSS, G., GDTHERT. M., ENDER, H.C. and SCHDHANN, H.J. (1981) 3H-lmlpramlne blndlng sites In the rat brain : selective locallzatlon on serotonlnerglc neurons. Naunyn-Schmledeberg's Arch. Pharmacol. 317: 310-314. HABERT, E., GRAHAM, D., TAHRAOUI, L., CLAUSTRE, Y. and LANGER. tlon of [3H]paroxetlne blndlng to rat cortical membranes. 107-114. R., OGREN, S.O. and GAWELL, L. (1982) Blndlng HALL, H., ROSS 3H-norzlmelldlne, lnhlbltor, to rat brain homogenates. 281-282.

S.Z. (1985) CharacterlzaEur. J. Pharmacol. 118:

of a speclflc SHT uptake Eur. J. Pharmacol. a:

HRDINA, P.D. (1982) Trlcycllc antidepressants : differences In hlgh afflnlty binding of [3H]-deslpramlne and [3H]-lmlpramlne In the braln. In: Advances In the Biosciences. S.Z. Langer. R. Takahashl and M. Brlley (Eds), pp 125-132. Pergamon Press, Oxford. HRDINA. P.D. (1984) Differentiation of two components of speclflc binding In rat braln. Eur. J. Pharmacol. 102: 481-488.

[3H]-lmlpramlne

HRDINA, P.D. (1987) Regulation of hlgh- and low-affinity [3H]lmlpramlne recognition sites In rat brain by chronic treatment with antldepressants. Eur. J. Pharmacol. 138: 159-168. HRDINA, P.D. ELSON-HARTMAN, K., ROBERTS, 0. and PAPPAS, 8. (1981) High afflnlty [3H]-deslpramlne binding In rat cerebral cortex decreases after selective lesion noradrenerglc neurons with 6-hydroxydopamlne. Eur. J. Pharmacol. 73: 375-376.

of

HRDINA, P.D., LAPIERRE, Y.D., HORN, E.R. and BAKISH, D. (1985a) Platelet 3H-lmlpramlne blndlng : a possible predlctor of response to antidepressant treatment. Prog. Neuro-Psychopharmacol. Blol. Psychiat. 9: 619-623. HRDINA, P.D., PAPPAS. B.A., ROBERTS, D.C.S.. between Relattonshlp levels [3H]-lmlpramlne recognltlon sltes'ydn thu,P% 1239-1244.

BIALIK,

R.J. and RYAN, C.L. (1985b) serotonln and hlgh affinity bro61n. Can. J. Physlol. Pharmacol. a.:

IENI, J.R.. ZUKIN, S.R. and VAN PRAAG. H.H. (1985) Human platelets [3Hllmlpramlne blndlng sltes. Eur. J. Pharmacol. m: 669-672. INNIS. R.8.. CHARNEY. D.S. and HENINGER. G.R. (1987) Dlfferentlal platelet blndlng In patients wlth panic dlsorder and depression. 33-41.

possess

multiple

3H-imlpramlne Psychiatry Res. 21:

INSEL, T.R.. MUELLER, E.A., ALTERMAN, I., LINNOILA. H. and MURPHY, D.L. (1985) Obsessive compulsive dlsorder and serotonln: Is there a connectlon? Blol. Psychiatry 20: 1174-1188.

210

S. Z. Langer and H. Schoemaker

JANOWSKY, A., SCHWERI, M.M., BERGER, P.. LONG, R., SKOLNICK, lP;s;;;s PAUL, S.M. (1985) The effects surgical and chemical on strlatal [3H]-threo-(+)-methy$hentdate binding : correlation with [3H]-dopamlne uptake. Eur. J. Pha&acol. 108: 187-191. JAVITCH, J.A.. BLAUSTEIN. R.O. and SNYDER, S.H. (1984) [3H]Hazlndol binding associated with neuronal dopamlne and noreplnephrlne uptake sites. Holec. Pharmacol. a: 35-44. JAVITCH, J.A., STRITTMATTER, S.H. and SNYDER, S.H. (1985) Dlfferentlal vlsuallzatton of dopamlne and noreplnephrlne uptake sites In rat brain using [3H]-mazlndol autoradlography. J. Neuroscl. 3: 1513-1521. KANAL. L.A.. RAISHAN, R., MEYER, P. and LANGER, S.Z. (1984) Reduced V,, of 3H-serotonin uptake but unchanged 3H-lmipramlne blndlng In the platelets of untreated hypertenslve subjects. Life Sci. 3: 2083-2088. KATONA. C.L.E.. THEODOROU, A.E.. MISSOURIS, C.G., EOURKE. M.P.. HORTON, R.W., MONCRIEFF. D PAYKEL, E.S. and KELLY, J.S. (1985) Platelet 3H-lmlpramlne blndlng In pregnancy ani the puerperjum. Psychiatry Res. II: 33-37. KENNEDY, L.T. and HANEAUER, I. (1983) Sodlum-sensitive membrane : possible relatlonshlp to dopamlne uptake

cocaine bindfng to rat strlatal sites. J. Neurochem. 1: 172-178.

KIM, S.S. and REITH, H.E.A. (1986) Effect of serotonin on the dlssociatlon of hlghafflnlty blndlng of [3H]-lmipramlne ln mouse cerebral cortex. Neuroscl. Lett. 123-128. KNIGHT, D.L., KRISHNAN, K.R.R.. BLAZER, D.G. and NEMEROFF, C.B. (1986) Trlated lmlpramlne binding to platelets Is markedly reduced jn elderly depressed Sot. Neuroscl. Abst. 12, 1251. LADURON,

P.R. (1984a)

LADURON. P.M. (1984b) col. 33: 833-839.

In reply to S.Z. Langer. Crlterla

for receptor

Trends

Pharmacol.

sites In blndlng

67:

patients.

Scl. 5: 52-53.

studies.

LANGER, S.Z. (1984) [3H]Imlpramlne and [3H]deslpramlne blnding : olaceable sites or ohvsloloalcallv relevant sites associated serotonln and noradrenailne ?-Trend; Pharmacol. Scl. 5: 51-52.

Blochem.

Pharma-

non-specific diswith the uotake

LANGER, S.Z. and BRILEY, H.S. (1981) High afflnlty 3H-lmlpramlne blndlng logical tool for studies In depression. Trends Neurosci. 3: 28-31.

of

: a new bio-

LANGER, S.Z. and RAISMAN, R. (1983) BInding of [3H]-lmipramlne and [3H]-deslpramlne as biochemical tools for studies in depresslon. Neuropharmacology 2: 407-413. LANGER, S.Z. and GALZIN. Experientia. In press.

A.M. (1987) Studles

on the serotonjn

transporter

in platelets.

LANGER. S.Z. and SCHOEMAKER. H. (1987) Platelet lmlpramine bindlng In depression. In : Receptors and Llgands In Psychiatry and Neurology, A.K. Sen and T. Lee (Eds.). Cambrldge Unlverslty Press, Cambrldge, in press. LANGER, S.Z.. MORET. C.. RAISHAN, R.. DUBOCOVICH. H.L. and BRILEY. M.S. (1980a) Highafflnlty 3H-imipramine blndlng In rat hypothalamus is associated with the uptake of serotonjn but not norepinephrlne. Science 210: 1133-1135. LANGER. S.Z.. BRILEY. M.S., RAISHAN, R.. HENRY, J.F. and MORSLLLI, Influence 3H-lmlpramlne blndlng In human platelets : Naunyn-Schmiedeberg's Arch. Pharmacol. 313: 189-194.

P.L. (1980b) Speclflc of and sex. age

LANGER, S.Z., RAISMAN, R. and ERILEY. H.S. (198Oc) Stereoselectlve lnhlbltlon of 3H-tmlpramlne binding by antidepressant drugs and their derlvatlves. Eur. J. Pharmacol. 61: 89-90.

211

[3H] Antidepressant binding to monoamine transporters

LANGER, S.Z., JAVOY-AGID, F., RAISHAN, R., BRILEY, M.S. and AGID, Y. (19Bla) Distributlon of speclflc high-afflnlty Neurochem. 37: 267-271.

blndlng

sites

for

imlpramlne

In

human

brain.

J.

RAISMAN, R. and SECHTER D. (19Blb) HlghLANGER. S.Z.. ZARIFIAN. E., BRILEY, M.S., afflnlty blndlng of 3H-lmlpramlne In braln and platelets and Its relevance to the biochemistry of affective dlsorders. Llfe Sci. 29: 211-218. [3H]-DMI blndlng is LANGER, S.Z., RAISMAN, R. and BRILEY, M.S. (19Blc) High-afflnlty associated with neuronal noradrenallne uptake in the perlphery and the central nervous system. Eur. J. Pharmacol. 72: 423-424. LANGER, S.Z.. ZARIFIAN, E., BRILEY. M.S., RAISMAN, new 3H-lmlpramine blndlng : a afflnlty Pharmacopsychlatry. 15: 3-10.

R. and SECHTER, D. (1982) HlghIn depresslon. blologlcal marker

LANGER, S.Z., LEE, C.R.. SEGONZAC, A.. TATEISHI. T.. ESNAUD, H., SCHOEMAKER, H. and WINBLAD B. (1984a) Posslble endocrine role of the plneal gland for C-methoxytetraneuromodulator of the [3H]lmlpramlne hydro+carboline, a putatlve endogenous recognltlon site. Eur. J. Pharmacol. 102: 379-380. LANGER. S.Z., RAISMAN, R., TAHRAOUI, L., SCATTON, B.. NIDDAM. R.. LEE, C.R. and CLAUSTRE, Y. (1984b) Substltuted tetrahydro-&carbollnes are posslble candidates as endogenous llgand of the [3H]lmlpramlne recognition slte. Eur. J. Pharmacol. 98: 153-154. SCHOEMAKER, H. and SEGONZAC. A. (1984c) Comparatlve studies on LANGER, S.Z., [3H]-paroxetlne and [3H]-lmlpramlne blnding to human platelets. Br. J. Pharmacol. 84: 59P. LANGER, S.Z., TAHRAOUI, L., RAISHAN, R., ARBILLA, S., NAJAR, M. 3H-Deslpramlne labels a site associated with the neuronal in the perlpheral and central nervous system. In : Neuronal In autonomic pharmacology, W.W. Flemlng et al. (Eds.), pp York.

and DEDEK. J. (19844) uptake of noradrenallne and extraneuronal events 37-49. Raven Press, New

LANGER. S.Z., LEE C.R., SCHOEMAKER, H., SEGONZAC, A. and ESNAUD, H. (1985) 5-Hethoxytryptollne and close analogs as candidates for the endogenous llgand of the 3H-lmlpramine recognltlon site. In : Endocolds, H. Lal, F. Labella and J. Lane (Eds.), pp 441-455. Alan R, Llss, New York. LANGER, S.Z., GALZIN, A.M., LEE, C.R. and SCHOEMAKER. H. (1986a) Antidepressant blndlng sltes in braln and platelets. In : Antidepressants and receptor function, Clba Foundation Symposium 123: John Wiley and Sons, pp. 3-29. LANGER, S.Z., SECHTER, D.. LOO, H., RAISMAN. R. and ZARIFIAN. E. (1986b) Electroconvulslve shock therapy and maxlmum bindlng of platelet trltlated imlpramlne blnding In depresslon. Arch. Gen. Psychiatry. 43: 949-952. DE OLIVEIRA A.M.> and _ LANGER, S.Z., SCHOEMAKER, H. (1986c) substrate lnteractlon wlth H mazlndol binding to the Br. J. Pharmacol. a: 63DP.

Temperature-dependence of noradrenallne transporter.

LANGER. S.Z., GALZIN. A.M., POIRIER, H.F., LOO H., SECHTER, D.b;nrjnzgARI\I,;Nh, Eth(d987a) [3H]-Imlpramlne Association of and [iH]-paroxetlne 5HT transporter In braln and platelets : relevance to studles In depresslon. J. Recept. Res. 1: 499-521. LANGER, S.Z., PIMOULE, C. and SCHOEHAKER, H. (1987b) In the frog heart, [3H]-deslpramine labels the neuronal transporter for adrenallne. 8r. J. Pharmacol. 9: 285P. LEE, C.M., JAVIICH. J.A. and SNYDER. S.H. (1982) Characterization of [3H]-desipramine binding associated wlth neuronal noreplnephrlne uptake sltes In rat brain membranes. J. Neurosci. 2: 1515-1525.

212

S. Z. Langer and H. Schoemaker

LEWIS, D.A. and McCHESNEY, C. (1985) Trltlated lmlpramlne blndlng subtypes of depresslon. Arch. Gen. Psychiatry 42: 485-488. LEWIS, D.A., NOYES, R., CORYELL. W. and CLANCY. J. (1985) Trlated platelets Is decreased In patlents with agoraphobla. Psychiatry

dlstlngulshes

among

lmlpramine blndlng Res. la: l-9.

to

LUINE, V.N., FRANKFURT, H., RAINBOW, T.C., BIEGON, A. and AZMITIA, E. (1983) Intrahypothalamlc 5,7-dlhydroxytryptamlne facllltates femlnlne sexual behavlor and decreases [3H]-lmlpramlne blndlng and 5-HT uptake. Braln Res. 264: 344-348.

HAJ, M., MASTRONARDI,

P., CERRETA, A., ROHANO, M., MAZZARELLA, 8. and KEMALI. Changes In platelets 3H-lmlpramlne blndlng In depressed patlents electroconvulslve therapy. Blol. Psychiatry, In press.

MARCUSSON. J., FOWLER, C.J., HALL, H., ROSS, S.B. and WINBLAD, B. (1985) blndlng of [3H]-lmlpramlne to protease-sensltlve and protease-resistant Neurochem. 44: 705-711. MELLERUP, E.T., PLENGE, P. and ROSENBERG, R. (1982) 3H-Imlpramlne blndlng platelets from psychlatrlc patlents. Psychiatry Res. 1: 221-227. HELLERUP, E.T., PLENGE and ENGELSTOFT. M. (1983) [3H]paroxetlne and [aH]!t&pramlne to human platelet 96: 303-309.

Chlorlmlpramlne, human platelet

MUSCELLOTA, G., DI LAURO, A. and GIANINI, C.P. (1986) In blpolar patlents. Psychiatry Res. j&: 343-353. OWEN, F., CHAMBERS, D.R., COOPER, POULTER, M. (1986) Serotonerglc 362: 185-188.

"Specific* sites. J.

sltes

In

High affinity btndlng of Eur. J. Pharmacol. membranes.

MELLERUP, E.T., PLENGE, P. and NIELSEN, M. (1985) Slze determlnatlon for [3H]lmlpramlne and [3H]paroxetlne In human membranes. Eur. 411-413. MELLERUP, E.T. and PLENGE, P. (1986) reduces [3H]-lmlpramlne blndlng In m: 155-158.

D. (1987) recelvlng

of blndlng polymers J. Pharmacol. m:

but not lmlpramlne. membranes. Eur. J.

Platelet

3H-lmlpramlne

S.J., CROW, T.J., JOHNSON, J.A., mechanisms In bralns of sulclde

rapidly Pharmacol.

blndlng

LOFTHOUSE, R. vlctlms. Braln

PALKOVITS. M., RAISMAN, R., BRILEY, M.S. and LANGER, S.Z. (1981) Reglonal of [3H]-lmlpramlne blndlng In rat braln. Brain Res. 210: 493-498.

and Res.

distribution

PAUL, S.M., REHAVI. H., SKOLNICK, P. and GOODWIN, F.K. (1980) Demonstratlon of speclflc "high afflnlty" blndlng sltes for [3H]lmlpramlne on human platelets. Llfe Scl. 26: 953-959. PAUL, S.M., Depressed serotonln

REHAVI. M., SKOLNICK, P., BALLENGER, J.C. and GOODWIN, F.K. (1981a) patlents have decreased blndlng of 3H-lmlpramlne to the platelets "transporter". Arch. Gen. Psychiatry 38: 1315-1317.

PAUL. S.M.. REHAVI, M., RICE, K.C., affinity [3H]-lmlpramlne bindlng platelet ? Life Scl. 28: 2753-2760.

ITTAH. Y. and SKOLNICK. P. (1981b) Does hlghlabel serotonln reuptake sites In brain and

PECKNOLD. J.C. and SURANYI-CADOTTE. B.E. (1986) Panic dlsorder and depression: lmlpramlne blndlng studles. Clln. Neuropharmacol. 9 (suppl.4): 46-48.

5HT and

PERRY, E.K.. MARSHALL, E.F.. BLESSED, 6.. TOHLINSON, 8.E. and PERRY, R.H. (1983) Decreased Imlpramtne blndlng In the braln of patlents wlth depresslve Illness. Br, J. Psychiatry 142: 188-192. PHILLIPS, O.H., WOOD, K.M. and WILLIAMS, D.C. (1984) Blndlng human platelet membranes wlth compensation for saturable

of [3H]-lmlpramlne to blndlng to fllters and

Its

[3H] Antidepressant

lmpllcatlon

for blndlng

studles wlth

binding

to monoamine

brain membranes.

213

transporters

J, Neurochem.

43: 479-486.

PIMOULE. C., SCHOEHAKER H. JAVOY-AGID. F., SCATTON. 6.. AGID, Y. and (1983) Decrease In [3H]-cocalne bIndIng to the dopamlne transporter disease. Eur. J. Pharmacol. 95: 145-146. PIHOULE, C., SCHOEMAKER, H., REYNOLDS, G.P. and LANGER, S.Z. (1985) labeled 01 dopamlne receptors are unchanged In schlzophrenla dlsease. Eur. J. Pharmacol. 114: 235-237. PIHOULE. C.. SCHOEHAKER. H. and LANGER, afflnlty the neuronal transporter Pharmacol., 137: 277-280.

LANGER, S.Z. In Parkinson's

3H-SCH 23390 and Parklnsonls

S.Z. (1987) [3HlDeslpramine labels wlth high for adrenaline In the frog heart. Eur.

J.

PLENGE, P. and HELLERUP, E.T. (1984) Imlpramine blndlng site. Temperature dependence of the blnding of f3Hl-labeled lmlpramine and [3Hl-labeled paroxetlne to human platelet membrane. Blochem. Blophys. Acta 770: 22-28. PLENGE, P. and HELLERUP, E.T. (1985) Antidepressive [3H]-imlpramlne and [3H]-paroxetine blndjng to Eur. J. Pharmacol. 119: l-8.

drugs can platelet

change the afflnlty of and neuronal membranes.

POIRIER. H.F.. LOO, H., BENKELFAT C., SECHTER, D., ZARIFIAN, E.. GALZIN, A.M., SCHOEHAKER, H., SEGONZAC, A. and LANGER. S.Z. (1984) [3HlImlpamine binding and [3H]5HT uptake in human blood platelets : changes after one week chlorlmipramlne treatment. Eur. J. Pharmacol. m: 629-633. POIRIER, H.F., BENKELFAT, C., LOO, H.. SECHTER, D., ZARIFIAN. E., GALZIN. A.M. and LANGER, S.Z. (1986) Reduced Bmax of [3H]-lmipramlne blndlng to platelets of medlcatlon with 5HT uptake depressed patients free of previous inhibitors. Psychopharmacology 8: 456-461. POIRIER, H.F., GALZIN, A.M., LOO, H., PIMOULE, C., SEGONZAC, A., BENKELFAT, C., SECHTER, H. and LANGER, S.Z. (1987) D ZARIFIAN, E., SCHOEHAKER, Changes In [3H]-5-HT u$ake and [3Hl-lmlpramine blnding In platelets after chlorlmlpramine In healthy volunteers : comparison with maprotlline and amlneptine. 8101. Psychiatry 22: 287-302. RAINBOW, T.C., BIEGON, A. and McEWEN, B.S. (1982) Autoradlographlc pramlne blndtng jn rat brain. Eur. J. Pharmacol. x: 363-364. and LANGER, S.Z. (1979) RAISMAN. R.. BRILEY. W.S. binding sites In rat brain. Nature 281: 148-150.

Speclflc

localization

trlcycllc

of iml-

antidepressant

High RAISMAN, R., SECHTER, D.. BRILEY, M.S., ZARIFIAN, E. and LANGER. S.Z. (1981) affinity 3H-lmlpramlne blndlng In platelets from untreated and treated depressed patients compared to healthy volunteers. Psychopharmacology 75: 368-371. RAISMAN, R., SETTE M., PIMOULE, C., BRILEY, M. and LANGER. S.Z. (1982a) High-affinity [3H]-deslpramlne blndlng In the perlpheral and central nervous system : a specific site associated with the neuronal uptake of noradrenallne. Eur. J. Pharmacol. 78: 345-351. BOUCHAMI. F., SECHTER, D., ZARIFIAN. E. and LANGER. S.Z. RAISMAN, R. BRILEY, M.S.. gH-Imlpramlne bindlng and serotonln uptake In platelets from untreated (1982b) depressed patients and control volunteers. Psychopharmacology n: 332-335. RAISHAN. R. and LANGER, S.Z. (1983) Specific hlgh-affinity in rat lung are related wlth a non-neuronal uptake Pharmacol. H: 345-348.

3H-lmipramlne bjndtng sites site for serotonln. Eur. J.

REHAVI. M., TRACER, H., RICE, K., SKOLNICK, P. and PAUL, S.M. (1983) [3H]2-Nitrolmlprobe of the lmlpramlne blndlng slte pramlne : a selective "slowly-dlssociatlng" ("serotonln transporter") In platelets and brain. Life Sci. 2: 645-653.

S. Z. Langer and H. Schoemaker

214

REHAVI,

M.,

WEIZMAN,

R.,

CAREL,

C.,

APTER,

A.

3H-lmlpramlne blndlng In platelets of children disorders. Psychtatry Res. 13: 31-39.

and TYANO, S. (1984) Hlgh-affinity and adolescents with major affective

Demonstration REHAVI, M., VENTURA, I. and SARNE. Y. (1985) like" materlal In rat braln. Life Scl. 36: 687-693.

of endogenous

REITH, M.E.A. 661.

assays.

(1985)

Posslble

artefacts

in Imlpramlne

blndlng

REITH, H.E.A. (1986) Blndlng of [3H]-lmlpramlne to mouse to glass fiber ftlters. J. Neurochem. 46: 760-766.

"lmlpramine

J. Neurochem.

cerebrocortlcal

membranes

45:

and

REITH, R.E.A., SERSHEN, H. and LAJTHA, A. (1984) Thermodynamics of the Interactions of tricycllc drugs with binding sltes for [3H]lmlpramlne In mouse cerebral cortex. Blochem. Pharmacol. 33: 4101-4104. ROY-BYRNE, P. and UHDE, T.W. (1985) Panic dlsorder relationships. Psychopharmacol. Bull. 21: 551-554.

and major depression:

Elologlcal

SCATTON, 8.. DUEOIS, A., DUEOCOVICH. H.L.. ZAHNISER. N.R. and FAGE, D. (1985) Quantitative autoradiography of 3H-nomifenslne blndlng sites In rat braln. Scl. 36: 815-822.

Llfe

SCATTON, 8.. DUEOIS, A., CAHUS. A., ZAHNISER. N.R.. DUEOCOVICH, M.L.. AGID, Y. and CUDENNEC, A. (1986) Autoradlographlc vlsuallzation and quantlflcatlon of dopamlne receptors and uptake sites In the rat and human C.N.S. In : Dopamlnerglc Systems and their Regulation. G.N. Woodruff, J.A. Poat and P.G. Roberts (Eds.), pp 111-130. Macmillan Press, London. SCHNEIDER, L.S.. SEVERSON, J.A. and SLOANE, R.8. (1985) Platelet in depressed elderly patlents. 8101. Psychiatry 20: 1234-1237.

3H-lmlpramlne

bindlng

PALMER, R. (1987) Platelet SCHNEIDER, L.S.. HUNJACK, D., SEVERSON, J.A. and [3H]Imlpramlne bindlng in generalized anxlety disorder. panic disorder, agarophobla with panic attacks. 8101. Psychiatry 2: 59-66. SCHOEHAKER. H. and LANGER. S.Z. (1987) High affinity bindlng of antidepressants platelets and braln tissue. In: Neuromethods lo. A.A. Eoulton, G.8. Baker, Coutts. (Eds.). Humana Press, In press.

and

to R.T.

SCHOEMAKER, H., PIMOULE. C., AREILLA, S., SCATTON E., JAVOY-AGID, F. and LANGER. S.Z. (1985) Sodium-dependent [3H]-cocalne binding associated with dopamine uptake sites tn the rat strlatum and human putamen : decrease after dopaminerglc denervatlon and in Parkinson's dlsease. Naunyn-Schmledeberg's Arch. Pharmacol. 329: 227-235. of 3H-paroxeSCHOEHAKER, H.. SEGONZAC, A. and LANGER, S.Z. (1986) Characterization tlne blndlng to the 5HT transportrer In human platelets. Symposla in Neuroscience ; "Modulation of central and peripheral transmitter function". G. Elgglo. P.F. Spano, G. Toffano and G.L. Gessa (Eds). pp 419-422. Llvlana Press, Padova. SCHOEMAKER, H., PIMOULE. C., de OLIVEIRA, A.-M. and LANGER, S.Z. (1987) Radlollgand blndlng to the neuronal adrenergic and noradrenerglc transporter. In: Proceedings 6th International Catecholamine Symposium, Jerusalem, In press, SCHBMIG. E. and 86NISCH. H. (1986) Solublllzation and characterization of the [3H]deslpramlne binding site of rat phaeochromocytoma cells (PC-12 cells). Naunyn-Schmledeberg's Arch. Pharmacol. 334: 412-417. SEiONZAC, A ., RAISMAN. R.. TAlEISHI. T.. SCHOEHAKER. H., HICKS, P.E. and LANGER, S.Z. (1985a) Tryptamlne. a substrate for the serotonln transporter In human platelets, modifies the dissociation kinetics of [3H]lmlpramlne blndlng : possible allosterlc interaction. J. Neurochem. 3: 349-356.

[3H] Antidepressant binding to monoamine transporters

215

SEGONZAC, A., SCHOEMAKER, H., TATEISHI, T. and LANGER, S.Z. (1985b) 5-Methoxytryptollne, a endocold acting at competitive [3H]lm+pramine recognition sites in human platelets. J. Neurochem. 45: 249-256. SEGONZAC, A., SCHOEMAKER, H. and LANGER, S.Z. (1987a) Temperature-dependence of drug lnteractlon with the platelet 5HT transporter : a clue to the imipramlne selectlvlty paradox. J. Neurochem. 48: 331-339. SEGONZAC, A., SCHOEHAKER, H., LEE, C.R. and LANGER, S.Z. (1987b) [3H]-5-Hethoxytryptoline is not actively accumulated by rabbit platelets. Naunyn-Schmledeberg's Arch. Pharmacol. 336: l-4. SETTE, M., RAISMAN, R., ERILEY, H.S. and LANGER, S.Z. (1981) Localization of trjcyclic antidepressant blndlng sites on serotonln nerve terminals In rat hypothalamus. J. Neurochem. 31: 40-42. SETTE, H.. ERILEY, M.S. and LANGER, S.Z. (1983a) Complex lnhlbltlon of 3H-lmlpramlne binding by serotonln and non-trlcycllc serotonln uptake blockers. J. Neurochem. 622-628.

40:

SETTE. M., RUBERG H.. RAISHAN. R., SCATTON. 8.. ZIVKOVIC. 8.. AGIO, Y. and LANGER. S.Z. (1983b) [5H]-lmlpramlne blndlng In subcellular fractions of the rat cerebral cortex after chemical lesion of serotonlnerglc neurons. Eur. J. Pharmacol. 95: 41-51. SLOTKIN, T.A.. BARNES, G.A.. BLAZER, O.G., KNIGHT, D.L., KRISHNAN, K.R.R., WHITMORE, W.L. and NEMEROFF. C.8. (1987) Elogenic amlne uptake and [3H]lmlpramlne binding In evidence for biological differences from platelets of depressed elderly patlents: depresslon in a younger cohort. 6th International Catecholamlne Symposlum, Jerusalem, p. 131. STANLEY. H., VIRGILIO, S. and GERSHON, S. (1982) Trltlated decreased in the frontal cortex of suicides. Science a:

lmlpramlne blndlng 1337-1339.

sites are

STOCKERT, M., VEIGA A., BUTMAN. S. and DE ROBERTIS, E. (1984) Pre- and postsynaptic locallzatlon of i H - lmlpramine binding sites In rat cerebral cortex. J. Recept. Res. 3: 755-771. SURANYI-CADOTTE, 6.. WOOD, platelet (3H)lmlpramlne Pharmacol. 85: 357-358.

P.L., NAIR. N.P.V. and SCHWARTZ, bjndlng In depressed patients

G. (1982) Normalization of during remlsslon. Eur. J.

SIJRANYI-CADOTTE. E.E., GAUTHIER, S., LAFAILLE. F., DEFLORES, N.P.V. and QUIRION, R. (1985a) Platelet 3H-lmlpramlne depression from Alzhelmer dementla. Llfe Scl. 31: 2305-2311.

S., DAM, T.V., NAIR, blndtng dlstlngulshes

SURANYI-CADOTTE. E.E., QUIRION, R., NAIR. N.P.V.. LAFAILLE. F. and SCHWARTZ. 6. (1985b) Imipramlne treatment differentially affects platelets 3H-lmlpramlne blndlng and serotonln uptake In depressed patlents. Ltfe Scl. 36: 795-799. SURANYI-CADOTTE, 8.. LAFAILLE, F., SCHWARTZ, 6.. NAIR, N.P.V. and QUIRIDN, R. (1985c) Unchanged platelet 3H-lmlpramlne blndlng In normal subjects after Imlpramlne admlnlstratlon. Biol. Psychiatry 20: 1237-1240. SURANYI-CADOTTE. B., DEFLORES, S.. LAFAILLE. F.. DAM. T.V., DALPE. H. and QUIRION. R. (1987) Platelet 3H-lmipramlne binding and the dexamethasone suppression test In patients with major depressive dlsorder. Canadlan Coll. Neuropsychopharmacol., Ottawa, W-10. TANG, S.W. and MORRIS, J.M. (1985) Varlatlon Psychiatry Res. 16: 141-146.

In human platelet

3H-lmlpramlne

Alteration of platelet TANIROTO, K., MAEDA. K. and TERADA. T. (1985) blndlng In mtldly depressed patients correlates wlth dlsease Psychiatry 20: 340-343.

blnding.

[3H]lmlpramlne severlty. Blol

S. Z. Langer and H. Schoemaker

216

TESSEL, R.E., KENNEDY, E., hypothalamus: antagonlsm Res. 153: 615-617.

BURGESS, S.K. and BORCHARDT, R.T. (1978) Eplnephrlne In rat by deslpramlne of 6-hydroxydopamlne-Induced depletion. Brain

BERRETTINI, W.H., ROY-BYRNE, P.P., BOULENGER. J.P. and POST R.M. (1987) UHDE, T.W., [3H]Imlpramlne blndlng In patients wlth panic dlsorders. Blol. Psychiatry 22: 52-58. VONVOIGTLANDER, P.F. and LOSEY, E.G. (1978) C-hydroxydopa depletes both braln eplnephrlne and noreplnephrlne : lnteractlons wlth antldepressants. Llfe Scl. 2: 147-150. WAGNER, A., ABERG-WISTEOT, A., ASBERG. M., EKQWIST, B., MBRTENSSON. B. and MONTERO, 0. (1985) Lower 3H-lmlpramlne blndlng In platelets from untreated depressed patients compared to healthy controls. Psychiatry Res. 16: 131-139. WEIZHAN, R., CAREL, C., TYANO, S. and REHAVI. M. (1985) 3H-lmlpramlne binding ln platelets of enuretlc children Res. 14: 39-46.

Oecreased high afflnlty and adolescents. Psychiatry

WEIZHAN, R., CARMI, M., HERMESH, H., SHAHAR. A., APTER, A., TYANO, S. and REHAVI, H. (1986a) High-afflnlty ImlDramlne binding and serotonln uDtake In Dlatelets of elaht adolescent-and ten- adult obsesslve-compulsive patlents. Am. J: Psychiatry j&3: 335-339. WEIZMAN, R., CARMI, M., TYANO, S., APTER, A. and REHAVI. 74. (1986b) Hlgh afflnlty [3H]lmlpramlne blndlng and serotonln uptake to platelets of adolescent females suffering from anorexla nervosa. Llfe Scl. a: 1235-1242. WEIZMAN, R., CAREL. C.. TYANO, S. and REHAVI, H. (1986c) Reduced 3H-lmlpramlne blndlng but unaltered 3H-serotonln uptake In platelets of adolescent enuretlcs. Psychiatry Res. 19: 37-42. WEIZMAN, A., GONEN. N., TYANO. S.. SZEKELY, G.A. and REHAVI. H. (1987) Platelet [3H]lmlpramlne binding In autism and schizophrenia. Psychopharmacology 91: 101-103. WENNOGLE, L.P., BEER, 8. and MEYERSON, recosnltlon sltes : blochemlcal Blochem. Behav. 12: 975-982.

L.R. (1981) Human platelet lmlpramlne and Dharmacologlcal characterization.

Pharmac.

WENNOGLE. L.P. and MEYERSON. L.R. (1983) Serotonln modulates the dlssoclatlon of [3H]-lmlpramlne from human platelets recognltlon sites. Eur. J. Pharmacol. 303-307. WHITAKER, P.M., WARSH, J.J., STANCER, H.C., PERSAD. E. and VINT, C.K (1984) Seasonal varlatlon In platelet 3H-lmlpramlne blndlng : comparable values In control depressed populations. Psychiatry Res. 1: 127-131. WOLFE, J., KREIOER, M.S.. GOODMAN, C. and BRUNSWICK, D.J. (1987) L$bellng In vlvo of serotonln uptake sltes in rat braln after admlnlstratlon of [JH]cyanolmlpramlne. Pharmacol. Exp. Ther. 241: 196-203.

and

J.

WOOD, P.L., SURANYI-CADOTTE, B.E.. NAIR, N.P.V., LAFAILLE, F. and SCHWARTZ, 6. (1983) Lack of assoclatlon between [3H]lmlpramlne blndlng sites and uptake of serotonln in control, depressed and schizophrenic patients. Neuropharmacology 22: 1211-1214. Inquiries

and reprints

requests

should be addressed

Dr. S. Z. Langer Department of Biology Laboratoires d'Etudes et de Recherches 58, rue de la Glaciere 75013 Paris, France

Synthelabo

to:

(L.E.R.S.)