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 administration of chlorisondamine was investigated in vitro. Nicotine-induced [3H]-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 killed, responses to (-)-nicotine (10(-6) M) were blocked. 3. In vivo administration of chlorisondamine (10 mg kg-1, s.c.), 7 days before rats were killed, produced a nicotinic blockade in vitro that was insurmountable even with a high concentration of (-)-nicotine (10(-4) M). 4. Both in vitro and in vivo administration of chlorisondamine blocked nicotinic responses to acetylcholine (10(-4) M). In contrast, neither in vitro nor in vivo administration of chlorisondamine reduced [3H]-dopamine release induced by high K+ (20 x 10(-3) M) or (+)-amphetamine (10(-6) M). 5. Nicotinic blockade resulting from in vitro administration of chlorisondamine (10(-5) M) recovered partially after 60 min wash-out, and completely by 90 min. In contrast, no recovery was seen in synaptosomes 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 receptors. The persistence of this block ex vivo indicates that physical trapping by the blood brain barrier is not solely responsible for the persistent blockade seen in vivo. The resistance of this blockade to prolonged in vitro wash-out suggests that the underlying mechanism differs from that associated with in vitro administration.
el-Bizri
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Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.
Clarke
P B
PB
D000109:Acetylcholine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002714:Chlorisondamine / Q000494:pharmacology*; D003913:Dextroamphetamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D009538:Nicotine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018733:Nicotinic Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*
D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D009538:Nicotine; D002714:Chlorisondamine; D000109:Acetylcholine; D003913:Dextroamphetamine; D004298:Dopamine