Ontogenesis of D-1 and opiate receptors coupled to adenylate cyclase in rat striatum

Pharmacological

RELEASE

Research

Communications,

VITRO

AS A MODEL

IN

Vol. 79, No.

TO

STUDY

di

Cembrano

4,

Farmacologia 16148

NEUROTRANSMITTER

(0)

RECEPTORS

Raiteri

Maurizio

Istituto

927

12, 1987

e Farmacognosia,

Universita

di

Viale

Genova,

Italy.

Genova,

Introduction Several models

microiontophoresis

organs,

binding

modulation exploited in

them

ligands,

to contain of

to

of

various

existence

location,

function

techniques,

such

possess

advantages

the

in vitro

used

those

information

of offer (0)

on the receptors

slices the

is

that

of

possibility

The present the 5th of Inter-Regionale

“Societa

release

possessing

both

0031-6989/87/l

being

to

minireview 1987

20927-l

can

be

and to characterize

can be studied the

in

“push-pull

the

living

by vivo

cannula” animal,

more easily release.

and

synaptosomes

are

and

pitfalls.

The

as I will

release-regulating

originates

properties.

transmitter

from the

Lombardia, di Farmacologia”.

5/$03.00/O

the

in

provide

moreover,

during

release

the

or synaptosomes are more commonly

they

slices

study

the

Although

and

regulating

integrity;

Liguria,

vitro.

the

in

of

release

performed

advantages

October

Italiana

in

Since

involved

and pharmacological

slices

since

etc).

of new receptors

and

with brain

of

measurements

microdialysis

of

in vivo

In studies systems,

vivo

techniques,

methods

neurotransmitter

as the

techniques than

in

(isolated

receptors

number of receptors

the

techniques

study

electraphysiological

release,

In the CNS in particular

to

biochemical

a large

transmitter

discover

terms

available

and other

with radiolabelled

appears

body

presently

are

a First

quantitative

complementary major

show

advantage

later, which

receptors

Lecture Meeting

Piemonte,

given

in

of

the

Valle

01987

they

d’Aosta”

The Italian

are

Pavia

on

"Gruppo

of the

Pharmacological

Society

928 not

Pharmacological sited

on

determine

the

which, way

the

a

located

on

other

the

transmitter

1984a).

Particularly

use

of

Raiteri formation,

the

vicinity

slices) the

their

receptor

with

tool

transmitter

release

on the

release

Serotonergic

in

layer

of

chosen

concerning

the

(Takeuchi

et

acid

al.,

1974;

biophase

the

containing

In

other

systems

often

sometimes

competes

complicating

of the

layer al.,

may

represent

receptors

rat

a

which

a recent

receptor-mediated

study

effects

useful

regulate carried

of

out

serotonin

cerebellum.

considered

granule of

(Sandoval

1982).

to describe

is

(GLU)

varicosities

and

vitro of

in the

cerebellar

(5-HT)

in

of GLU release

acid

Serotonin

cell

appears

minimizes

biophase

study,

characterization

I have

modulation

cerebellum

granule

the

of glutamic

neurotransmitter at

release

how

Glutamic

released

under

et al.,

evaluation.

functional

laboratory

a

of (for

Raiteri

et

released. this

release

compounds

system of

in

possess

receptors

this

transmitter

drugs

the

Raiteri

receptors,

present the

illustrate

in our

the

transmitter

quantitative To

the

transmitter

may also

presynaptic

because

the

autoreceptors

1984;

(see

known,

the

terminal

Chesselet,

superfusion

of of

the

by

is

modulating

studying

mainly

concentrations

(i.e. for

1978)

it

regulating

1981;

in a

represent

As

various

to

receptors)

presynaptic

same

by

for in

Levi, in

unknown

suitable

allow

controlled

the

Langer,

synaptosomes

themselves,

heteroreceptors)

1981;

Vol. 19, No.

(presynaptic

so called

activated

Communications.

process. be

terminal;

synaptosomes

and

release

of the

once

Starke,

receptors

can

activation

hand,

terminals

the

(presynaptic

see

the

of

releasing

reviews

those

transmitter

the

other

releasing

the

given

receptors same

on

of

controllers

of through

On the

location

sited

last

itself

terminals.

exact

being

release

the

nerve

Research

the

the

cells.

molecular

GLU

parallel

and Cotman,

projections

the

fiber

1978;

from

Gallo

raphe

layer

in

nuclei the

excitatory

major is

thought

in

the

et al., reach

cerebellar

to

be

molecular 1982). both

the

cortex

72, 1987

Pharmacological

Research

Communications,

929

Vol. 19, MO. 12, 1987

70 -

.g 2

60 -

A 5

1+ .= -s

50 -

c

40.

n/

/

I .E E

P 30-

/ t

z ii 20s ccl

P/

10 -

0.01

0.1

1

10

Serotonin Fig. 1. Concentration-response K+-evoked release of Experimental details Means r S.E.M. of 6-8

The

interactions

cerebellar

GLU

and

various

rat

cerebellar

have

been

serotonergic

Two

types

recognized

by

Peroutka

to

(Pedigo

be

necessary

of

on

or

slices.

al., to

demonstrate

et

of

into

al.,

whether

of and the

of

5-HT

GLU

from

were

5-HT,,

sites

5-HT,,8

and

Functional

binding

and

multiple 5-HT2

5-HTIA,

1984).

these

endogenous

5-HT., Then

cerebellum effects

existence

(1979).

subdivided

the the

release

termed

Snyder

Pazos

to

studying

the

sites

and

1981;

the

for

binding and

heterogeneous

et

by

accumulating

receptors.

projections

investigated

synaptosomes is

5-HT

agents

1000

of the inhibition by 5-HT of the from rat cerebellar synaptosomes. reported (Raiteri et al., 1986). triplicate are shown.

in

between

Evidence

found

curve GLU

endogenous as previously experiments

100

(nM)

cont.

studies

sites

reflect

5-HT first were 5-HT,C are true

receptors. A

number

selectivity in

for

our

shown

of

study in

Table

on I.

pharmacological

the

various

the

effect

tools 5-Hi

of

sites 5-HT

on

endowed are GLU

now release

with

relatively

available in

and rat

good those

cerebellum

used are

930

PharmacologicalResearch

TABLE

I.

selective

Drugs

for

5-HT

receptor

Communications,

types

and

Vol. 19. No.

subtypes

5-HTl 5-HTIA

Agonists

5-HT2

5-HT.,D

5-HT.,C

8-OH-DPAT

-DOI RU 24969

Antagonists

SPIPERONEa

KETANSERIN

(-~PROPRANOLOL

MESULERGINE

METHYSERGIOE

METHIOTHEPIN

The

receptors;

a at

a)

indicate is a

underlinings 8-OH-DPAT

(i.e.

the relative selectivity of the drugs reported relatively selective agonist at the 5-HT,,A is a non-selective antagonist). concentration (1 uM)

methiothepin

relatively

Studies

low

with

synaptosomes

Depolarization release

of

GLU

that

elicited

5-HT

release

of

(Fig.

1).

spiperone

agonist an

RU

As

would it

(Table

II).

lead should

to

be

was

The the

5-HT

conclude

considered uM)

-dependent

concentration

(1

(-)propranolol

was ineffective

(not

15

release

shown).

putative

selective

to methiothepin

(Table

their belong

that:

1)

routinely

used at the

to

the

spiperone to

block

heteroreceptors

to of

GLU

but

it

(-)propranolol by

agonist

the

5-HT,

8-OH-DPAT,

II).

sensitivity 5-HT,A

caused

Exposure

GLU was reduced

5-HT,A

they

KC1

methiothepin,

by

methysergide, of

mM

inhibition

antagonized

heteroreceptors, that

with

cinanserin,

was sensitive the

to

by

2+

concentration-dependent

effect

ketanserin,

and

Ca

and

This

24969

synaptosomes

totally

to

which

effect

was

a potent

was insensitive and

cerebellar

to subtype.

was

ineffective

the

5-HT,,A at

8-OH-DPAT However,

at sites;-

a concentration

a 2)

12, 1987

Pharmacological

Research

Communications,

Vol. 19, No.

931

12, 1987

Table 11 Effect of 5-HT, RU 24969 and 8-OH-DPAT of the of endogenous GLU from cerebellum synaptosomes. serotonergic receptor blockers.

K+(15 mM)-evoked Antagonism

release of inhibition)

K*-evoked

Drugs

(%

+ 3.12 i: 2.01 + 3.57

(16) ( 5) ( 3)

spiperone

49.7 51.6 52.0 49.7

+ + + k

2.99 4.03 4.73 3.72

( ( ( (

3) 3) 4) 41

42 52 29 44 9

t 2 + + 2

3.81 3.93 1.78 3.15 1.37

( ( ( ( (

5) 4) 4) 6) 5)

5-HT 5-HT

+

10 10 10 10

nM nM nM nM

5-HT 5-HT 5-HT 5-HT

+ 1000 + 1000 + 1000 + 1000

nM nM ketanserin nM methysergide nM (-)propranolol

10

nM

5-HT

+ 1000

nM

10

nM RU 24969

100 10 100 100

nM nM nM nM

RU 24969 8-OH-DPAT 8-OH-DPAT 8-OH-DPAT

The data Experimental S.E.M.

+ 100

reported details

of

nM methiothepin

represent as in experiments

several

GLU

50.9 10.5 47.0

nM nM

nM

of

methiothepin cinanserin

10 10

10

release various

by

the

percent 1. Each

changes value

(number

in

Fig.

release.

of K+-evoked represents

parenthesis)

the

mean

+

in

performed

triplicate.

(I

uM)

to

expected

heteroreceptors 5-HTIA

receptor.

fact, and

contrast

high to

ln

and

an

located

on

5-HTIA

for

to

the

sites

to

inhibitory terminals.

GLU way

Thus,

(Pazos

required 5-HT.,G

cerebellar

through receptors

the

al.,

1984), GLU

a

in

activation to

in

release.

endings

nerve

appear

for

respectively,

have, et

the

subtype;

regulating

from

These

the

to

heteroreceptors of

sites.

criteria

reported

5-HTIC

the

5-HTIB

belong

were

release

GLU

all

appear

the at

and

satisfy

methysergide

the

in

to

they

observed

conclusion,

both

seem

affinity what

regulated

receptors

not

Neither

8-OH-DPAT

low

be

do

block

of represent

can 5-HT

932

Pharmacological

Research

Communications,

Vol. 19, No.

P / P n/ /P

80-

70 c .g z 60E .E

b 50 ae -I

10 t

0.1

100

&otonin

Fig. 2. Ki-evoked

Concentration-response (35 mM KC11

slices. (Maura (S2).

et The

Slices al.,

release

(nM)

curve of the of endogenous

were prepared and 1988a). Agonists were presented are means

data

co,',".

inhibition

by rat

5-HT

of

the

cerebellar superfused as previously described added concomitantly with high K+ 2 S.E.M. of 3-7 experiments in GLU

from

duplicate.

a

novel

subtype

concentrations but

insensitive

propose

to In

exist the

of

on 5-HT,D

5-HT,

to

RU

receptor to

cerebellar

subtype,

5-HT.,

8-OH-DPAT

nanomolar

to methiothepin,

or to methysergide.

We

autoreceptors

to

5-HT,D. the

synaptosomes

et al.,

(Bonanno

to what

1984; Engel

to

and

spiperone

to

heteroreceptors,

similarly

(Middlemiss

to

subtype

the

sensitive

receptor

24969,

(-)propranolol,

this

contrast

of the brain

the

to

term

5-HT

of

has et

been

al.,

reportd 1986;

found

1986) belong for

Maura

et

various

areas

al.,

1986).

to

12, 1987

Pharmacological

Research

Communications,

Vol. 19, No.

60

60 * g2 u .r_

P 7/

50

50

s 40 ae

40

8 30 9 E ~ 20 %i

30

E ,m 1 cl

933

12, 1987

P/

20 10

10

I

I

I

I

10

100

1000

10000

I

I

I

I

10

100

1000

10000

8-OH-OPAT cone. (nM) Fig.

3. of

DOI

Concentration-response the K+-evoked

slices.

was

2 shows

superfusion

to to

experiments

using release receptor

5-HT.

the

slices.

cerebellar GLU

in

mediating

release

found

of

fig.

Fig.

of to

be

(Fig.

3) of

GLU

3

and

cerebellar 2.

The

on can

(a

suggesting

release

be

provoked were

show

present

DO1

GLU

slices

cerebellar

Moreover,

inhibition

to

8-OH-DPAT rat

data

in duplicate.

endogenous

synaptosomes

slices

by from

slices

results

cerebellar

GLU

see legend experiments

3-7

when

The

8-OH-DPAT with

of

that

inhibited

potently

sensitive

of

inhibition

of the endogenous

details

+ S.E.M.

with cerebellar

Experiments Figure

K'

means

001 cont. (nM)

curve of

release

experimental

For are

presented

b)

A l

P/

that

GLU

nerve

by

agonist) the

through

presence

mM

exposed the

in

receptor endings

demonstrated

5-HT2

35

in

also

when

inhibited of

a

the 5-HT2

a mechanism that

is

934

Pharmacological

Table

Communications,

Vol. 19, No.

III

Effect of

Research

of the

5-HT

antagonists

K+-evoked

release

on of

inhibition

the

GLU

from

by

5-HT,

8-OH-DPAT

K+-evoked

Drugs

release

(% of

IO IO 10 IO

nM nM nM nM

5-HT 5-HT 5-HT 5-HT

+ + +

100 300 1000

IO

nM 5-HT

+

300

IO

nM

IO IO IO

nM 8-OH-DPAT nM 8-OH-DPAT nM 8-OH-DPAT

100 100

nM DO1 nM DO1

nM methiothepin

nM ketanserin nM ketanserin nM methiothepin

nM ketanserin

during

the

therefore,

in

activation

of As

(100-1000 of for

IO

suggested

a) the

could The

activation by

5-HT1/5-HT2

in

and

effect

view

is of

III,

GLU

(5) (3) (3) (3)

f

2.73

(3)

21.4 19.1

+ 2.10 ?I 1.50

(4)

21.0 1.5 39.2 1.7

2 + t i:

only

release

pure about

ketanserin-insensitive the

behavior

further

receptors

of

methiothepin abolished

8-OH-DPAT,

supported a 5-HT,

by

5-HT2

conclusion,

be

inhibited

antagonist

half

of

part

was

the

by

on

likely GLU

which,

agonist

findings that

terminals,

the shown

activates

effect accounted

being

completely the

ketanserin

inhibitory

most

sited

5-HT,

antagonist,

can

(3)

release. The antagonists details see of several

a first

As

(4) (4) (41 (3)

1.22 2.10 2.14 2.30

receptors. the

antagonize

receptor

This

5-HT2

Table

of

the

synaptosomes.

slices

5-HT1

shown

nM 5-HT. the

of

cerebellar both

nM)

by

5-HT.

preparation

GLU

4.05 3.02 3.51 4.75

The data reported represent the percent of the K+-evoked agonists were added concomitantly with high K+ at 52 and the were present throughout the experiment. For experimental Legend to Fig. 2. Each value represents the mean + S.E.M. experiments (number in parenthesis) performed in duplicate.

lost

of

+ t 2 zi

1.3

8-OH-DPAT

+ IO

DOI

inhibition)

63.8 30.6 27.4 37.5

nM ketanserin nM ketanserin nM ketanserin

+ 300 + 1000 + 300

and

slices

cerebellar

a

as mixed

effect in the

Table receptors

of

III:

72, 1987

Pharmacological sited

Research

on

GLU

blocked

by

nerve

on

results,

the

glutamate

system

the

the

The

serotonergic

terminals

of

these

et

of

the

the

5-HTTA

(possibly

of

a

non-A,

of

as

-the

soma

receptors

and/or

also

be

lost

leads the

reports

have

et

5-HT

onto

receptors

subtype)

c)

a

fibers release

5-HT

dendrites

of

granule

decrease

of

GLU

preparation

of

The

1985)

studies,

that

the

are

of

granular 5-HT2

reach

the

5-HT,

type on

an

synaptosomes

layer localized of

effect but

axons

cell

Activation

release,

and

5-HT

receptors

cells.

GLU

fibers)

group

onto

of

sited

parallel

the

the

autoreceptors

of

different

axon

subtype

terminals

the

in

tentatively

5-HT,B

with

axon

of

be

subtypes

neurophysiological

al.,

endowed

varicosities

cerebellar and

the

to

5-HT

might

to

during

be

non-C

mossy

and

of

was

present

cerebellum.

of

release;

classical 1977)

may

non-B,

GLU

the

(Verge

the

could

according

group

the

4)

DOI

the

types

autoreceptors

release

(probably

(Chan-Palay,

to

new

and and

(Fig.

totally

agonist

involve

innervate

lesion

a

they

inhibition

terminate

on

b)

where

endings

mediate

and

to

scheme

neurons

subtype; layer

nerve

1984)

5-HT2

neurons

Interestingly,

but

literature

and

possess

serotonergic

molecular

complex

ketanserin

the

5-HT

neurons

al.,

of

existing

following

1986).

et

the

be

neurons

al.,

Montigny

soma

of

between

receptor. a)

(de

basis

to

to

effect

ketanserin.

appears

proposed:

the

935

12, 1987

insensitive

by

interaction

5-HT

(Bonanno

was b)

antagonized

Therefore

Vol. 19, No.

endings

methiothepin;

completely

of

Communications,

that is

these appears

measurable

in

slices. Recent GLU-containing (which

mossy

are

also

multisynaptic this fiber

terminals

mossy

fibers

to

the

labeling

(Somogyi the

granular

classical

point

be

(see c),

5-HT2

on

(Beitz revealed

al.,

fibers

of

receptors

the

1986).

In of

cerebellar

might

in

cortex

be

present

on

mossy of

are of

1965).

to

endings

because

Whittaker,

a

support

GLU the

synaptosomes and

cells

constituting

Interestingly,

of Israel

al.,

as

granule thus

enrichement

1986). layer

et

project

cerebellar

glutamatergic)

preparation

properties to

et

pontocerebellar

synapse

pathway

immunogold

sedimentation alternative

to

considered

from

that

fibers

glutamatergic

idea,

during

proposed

lost their

Thus,

as

the

endings

an

936

Pharmacological

Research

Communications,

Vol. 19, No.

MF

b

5HTv, neurons

neurons

Fig. 4. Schematic cerebellum. 5-HT, serotonin;

model

GLU, fibers; MF, mossy fibers. Two alternatives have 1) serotonin-containing 1976, 1977; Shinnar

gigantocellularis, nucleus reticularis 2)

on 5-HT2 receptors 5-HT2 receptors

fibers

projecting

of

possible

glutamic

5-HT

acid;

and GR,

GLU granule

interactions cell;

been considered concerning the 5-HT2 fibers arising from raphe nuclei 1975) or/and nucleus et al., nuleus reticularis paragigantocellularis

pontis

oralis

in PF,

the

rat

parallel

receptors: (Ghan Palay

reticularis

(Bishop and Ho, 1985) release sited on granule cells; are sited on the terminals of glutamatergic to the cerebellar cortex (Beitz et al., 1986).

and 5-HT mossy

12, 1987

Pharmacological

Research

Table TV. This this laboratory. proposed to exist

Communications,

table summarizes They include by others on

Vol. 19, No.

Presynaptic

Effect

receptor

Noradrenaline

a2A

Serotonin

a2B

GABA

a2B

GABA

al

GABA

GABAs

Serotonin

5-HT,B

Acetylcholine

S-HTTB

Glutamate

5-HT

ID(?)

Glutamatea

5-HT2

Acetylcholine

(M,)

Dopamine

(MEI

Serotonin

(M,)

a Result obtained sited on GLU t facilitation;

with nerve c

for for

which we terminal; the first

on

cerebellar terminals.

inhibition

+ c I t t + t I + 1 + t t slices.

studied already with

in been brain

have determined b) presynaptic time in this

References

release

a2

Noradrenaline

937

the presynaptic receptors a) receptors which had the basis of results obtained

tissues more complex than synaptosomes and unequivocally the location on a presynaptic receptors which have been shown to exist laboratory. Nerve terminal

12, 1987

Langer Raiteri

1977, et al.

Starke 19B3a

Raiteri

et

1983a,b

al.

Maura et al.

et al. 1983a,b

Pittaluga Maura

et

1982,

Raiteri

and Raiteri al. 19BBb

Pittaluga

and

Pittaluga

et

1987;

Raiteri

1988

al.,

1987

Bonanno et a1.1986, al. 1986, Maura et Maura

and

Raiteri Maura

Engel et al. 1986

Raiteri et

et

al. al.

1986 1986

1988a

Raiteri et and Raiteri

al. 1984b, 1985

Marchi

Raiteri et and Raiteri

al. 1984b, 1985

Marchi

Marchi

The

1977,

5-HT2

et

al.

receptor

1986

may

not

be

938

PharmacologicalResearch

of

glutamatergic

cells.

mossy

The

technique

cerebellar Finally,

the

association et

by

summarized

Table

below:

a)

There

seem

brain

which

exist we

are

endings.

They

the

IV.

to

alpha-28

the

it drugs do

b)

The

lead

are

to

significant

isolation

latter

of

possibility. regression

patients

after

of

long

alone inhibitor

more

of

receptors

dicyclomine

and

term or

in

benserazide

alpha-2 and

their

drugs

the

do

alpha-2A

and

not

basis of

those

presently

(MT,

sensitive

to

atropine,

helpful

and to

alleviate

of

so

far are these

with on

5-HT

equally results alpha-2 which

alpha-2B.

pharmacologically

function

rat

available

of

to

the

nerve

synthesizing

existence

only

are

interact

of

the

sensitive

which

The

receptors

the

are

(+)enantiomer

found

alpha-2

possibility

in

the

been

On

than

obtained

noradrenergic

by

have

been

respectively.

they

These

have

results

alpha-2B, on

(-jmianserin.

release

adrenoceptors

whereas

the

GLU

considerations

blocked

selective

M2, of

major

located

between

on The

some

terminals.

of

new

that

5-HT

alpha-28

consider

discriminate

determination

the

model.

subtypes

to

to

demonstration

prepare

They

of

adrenoceptors

and

muscarinic

to

release

nerve

logical

not

verify

the

granule

release

that

mianserin,

(+I

which

for

human

stereoselectively

GABAergic

seems

onto

5-hydroxytryptophan

autoreceptors

are

to

(1985)

several

the

Alpha-28

sensitive

release

decarboxylase

termed

antidepressant

on

mention

transmitter

two

have

(-Jmianserin. and

to

than

exploiting

reported

to

peripheral

other

in

help

GLU

Vol. 19, No.

1982).

Interactions studied

of

in

regulating

receptors

al.

precursor

the

al.,

regulate et

observed 5-HT

with

(Trouillas

like

was

with

be

would

ataxia

to

Terrian

could

we

cerebellar

Other

by

glomeruli

therapy

fibers

Communications,

pirenzepine

atropine)

localization the

distinct

together , symptoms

may

pave of

and with

the

the

way

dementia

of

72, 1987

Pharmacological the

Research

Alzheimer's

type.

autoreceptor

may

prove

The

adrenoceptors

to

not

suggest

yet in

(a,

sensitive

are

that

to

tonic

the

cholinergic

on

active

be

due

of

the

M2

a selective acetylcholine

of

M,-agonist

disease.

a2B)

the

of

Also a selective

Alzheimer's

present

to clonidine

some

release

the

degenerated.

and

activation

terminals,

nerve

should increase

terminals

the

939

Vol. 19, No. 12, 1987

fact,

antagonist

from

which

In

located

autoreceptors

c)

Communications,

on

GABAergic

(Pittaluga

and

several

activities

short

review,

terminals

and

19BB)

may

Raiteri,

of

clonidine

are

GABA-mediated.

Conclusions The

results

in this

reported

considerations,

allow

neurotransmitter

release

release-regulating a

small

considers

that

the

be

through

several

likely not

to

only

family

and

between

GABAergic

pre-

A and

selective

transmitters

(including

number

the

pharmacological

so

of

same on)

type

in

do

fact,

peptides)

is

each

receptors

if

probably

suggest

but

several

that

new

not one

likely

are

regulated

is

receptors

existing

also

example muscarinic

(for

study

receptors

heterogeneities

postsynaptic

the

B and

of

to

release-regulating

the

and of

release

other a)

model

release-regulating

the

some

conclusions:

valuable

a

receptors:

the

c)

be

of particular

that

relevant;

receptors

more

a)

receptors,

be

presynaptic *2' for

50

to

with

following

the

appears

putative

than

more

draw

receptors;

represent

to

to

together

between M,

targets

and

exist

drugs.

Acknowledgements This Education,

work from

was the

supported

Italian

by C.N.R.

grants and

from from

the Italian

Regione Liguria.

Ministry

of

940

Pharmacological

Research

Communications.

Vol. 79, No.

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