H. Elbizri et Pbs. Clarke, BLOCKADE OF NICOTINIC RECEPTOR-MEDIATED RELEASE OF DOPAMINE FROM STRIATAL SYNAPTOSOMES BY CHLORISONDAMINE ADMINISTERED IN-VIVO, British Journal of Pharmacology, 111(2), 1994, pp. 414-418
1 The chronic nicotinic blockade produced following in vivo administra
tion of chlorisondamine was investigated in vitro. Nicotine-induced [H
-3]-dopamine release from striatal synaptosomes was used as a measure
of central nicotinic receptor function. 2 In synaptosomal preparations
from rats pretreated with a single administration of chlorisondamine
(10 mg kg(-1), s.c.), 1, 7, 21, 42, 63 or 84 days before they were kil
led, responses to (-)-nicotine (10(-6) M) were blocked. 3 In vivo admi
nistration of chlorisondamine (10 mg kg-L, s.c.), 7 days before rats w
ere killed, produced a nicotinic blockade in vitro that was insurmount
able even with a high concentration of (-)-nicotine (10(-4) M). 4 Both
in vitro and in live administration of chlorisondamine blocked nicoti
nic responses to acetylcholine (10(-4) M). In contrast, neither in vit
ro nor in vivo administration of chlorisondamine reduced [H-3]-dopamin
e release induced by high K+ (20 x 10(-3) M) or (+)-amphetamine (10(-6
) M). 5 Nicotinic blockade resulting from in vitro administration of c
hlorisondamine (10(-5) M) recovered partially after 60 min wash-out, a
nd completely by 90 min. In contrast, no recovery was seen in synaptos
omes prepared from rats pretreated with chlorisondamine (10 mg kg(-1),
s.c.) in vivo. 6 Thus, in vivo treatment with chlorisondamine results
in a quasi-irreversible, insurmountable block of CNS nicotinic recept
ors. The persistence of this block ex vivo indicates that physical tra
pping by the blood brain barrier is not solely responsible for the per
sisent blockade seen in vivo. The resistance of this blockade to prolo
nged iii vitro wash-out suggests that the underlying mechanism differs
from that associated with in vitro administration.