BLOCKADE OF NICOTINIC RECEPTOR-MEDIATED RELEASE OF DOPAMINE FROM STRIATAL SYNAPTOSOMES BY CHLORISONDAMINE ADMINISTERED IN-VIVO

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.