BLOCKADE OF NICOTINIC RECEPTOR-MEDIATED RELEASE OF DOPAMINE FROM STRIATAL SYNAPTOSOMES BY CHLORISONDAMINE AND OTHER NICOTINIC ANTAGONISTS ADMINISTERED IN-VITRO
H. Elbizri et Pbs. Clarke, BLOCKADE OF NICOTINIC RECEPTOR-MEDIATED RELEASE OF DOPAMINE FROM STRIATAL SYNAPTOSOMES BY CHLORISONDAMINE AND OTHER NICOTINIC ANTAGONISTS ADMINISTERED IN-VITRO, British Journal of Pharmacology, 111(2), 1994, pp. 406-413
1 Central nicotinic receptor function examined in vitro, by measuring
nicotine-induced [H-3]-dopamine release from rat striatal synaptosomes
. 2 The agonists (-)-nicotine, acetylcholine, 1,1 -dimethyl-4-phenylpi
perazinium (DMPP) and cytisine (10(-7)-10(-4) M) all increased [H-3]-d
opamine release in a concentration-dependent manner. Cytisine did not
produce a full agonist response, compared to the other agonists. 3 The
actions of nicotine, acetylcholine and cytisine were largely dependen
t on external Ca2+. In contrast, DMPP (10(-5) and 10(-4) M) evoked a m
arked release of [3(H)]-dopamine even in the absence of Ca2+. Neverthe
less, in the presence of external Ca2+, responses to DMPP were complet
ely blocked by the nicotinic antagonists chlorisondamine and mecamylam
ine (5 x 10(5) M); in the absence of external Ca2+, blockade was only
partial. 4 Chlorisondamine, mecamylamine and dihydro-beta-erythroidine
(10(-8)-10(-4) M) produced a concentration-dependent block of respons
es to nicotine (10(-6) M). Approximate IC50 values were 1.6, 0.3 and 0
.2 x 10(-6), respectively. Chlorisondamine and mecamylamine blocked re
sponses to nicotine (10(-7)-10(-4) M) insurmountably, whereas dihydro-
beta-erythroidine behaved in a surmountable fashion. 5 The occurrence
of use-dependent block was tested by briefly pre-exposing the synaptos
omes to nicotine during superfusion with antagonist, and determining t
he response to a subsequent nicotine application. Consistent with a po
ssible channel blocking action, brief pre-exposure to agonist increase
d the antagonist potency of chlorisondamine (approximately 25 fold). N
o significant use-dependent block was detected with dihydro-beta-eryth
roidine.