The modulation of neurotransmitter release by muscarinic presynaptic receptors is not directly mediated by the activation of PI turnover

Pharmaco~g~alResea~h Commun~ation~VoL 20 Supplements 1988

223

THE MODULATION OF NEUROTRANSMITTER RELEASE BY MUSCAR1NIC PRESYNAPT1C RECEPTORS IS NOT DIRECTLY MEDIATED BY THE ACTIVATEON OF PI TURNOVER M. Marchi, P. Paudice, G. Fontana and M. R a i t e r i di Farmacologia e Farmacognosia, Viale Cembrano 4, 16148 GENOVA

[stituto

Key words: presynaptic muscarinic receptors, P1 turnover The effects of various muscarinic agonists were comparatively studied in the

rat

cerebral

cortex

3H-acetylcholine

(3H-ACh)

on

the

and

release

of

3H-dopamine

3H-5-hydroxytryptamine

(3H-DA),

(3H-5-HT)

from

superfused nerve endings and on phosphatidylinositol (PI) turnover. ACh was found to be the most potent among the agonists tested on a l l

three

systems

examined.

concentration-effect

Oxotremorine

curves q u a l i t a t i v e l y

and

carbachol

the

produced

s i m i l a r to those obtained with

ACh, but were less potent. Bethanechol, tested at 100 pH, had no e f f e c t on the K+-induced release of 3H-ACh, 3H-DA or 3H-S-HT. The e f f e c t s some cholinergic

agonists on P1 turnover

were studied

both with

of the

medium containing normal concentrations of K+ ions and in conditions of K -depolar~zatlon similar to those used in the experiments of release. In the presence of 15 mH K+ the e f f e c t s of a l l

the agonists tested were

enhanced;

however,

the

rank

PI

modified.

ACh was

the

m~st

of

potency

on

effective

hydrolysis

agonist.

For

was

not

instance,

the

enhancement of P1 turnover caused by 1 pM ACh was barely reached by 100

pM oxotremorine or bethanechgl. The l a t t e r

two compounds were in

r e l a t i v e l y weak agonists since they produced a s i g n i f i c a n t turnover only at the highest concentration

tested.

was found to be the most potent among the agonists three

release

turnover.

systems examined as well

Oxotremorine and bethanechol

tested as stimulators effective

as

ineffective.

a

of

release

Our data

PI turnover, modulator

therefore

as on the were very

suggest

turnover does not seem to be d i r e c t l y

e f f e c t on P1

In conclusion,

activation

the

involved in

of

weak agonists

bethanechol that

ACh

tested on ~11 the

however oxotremorine

while

fact

was

P1 when

was very completely

activation

of

P1

the modulation

of

neurotransmitter release mediated by presynaptic muscarinic receptors.