title: Persistent nicotinic blockade by chlorisondamine of noradrenergic neurons in rat brain and cultured PC12 cells.
abstract: Chlorisondamine (CHL) blocks behavioural responses to nicotine for several weeks or months in rats. Persistent blockade has also been demonstrated ex vivo, in assays of nicotine-evoked striatal dopamine release. Central administration of [3H]-CHL leads to long-term retention of radiolabel in nigrostriatal dopaminergic neurons and in few other cell groups. We investigated whether an analogous blockade also occurs in noradrenergic neurons in the brain and in cultured pheochromocytoma (PC12) cells, which have a similar noradrenergic phenotype. Administration of CHL (10 mg kg(-1) s.c. or 10 microg i.c.v.), 21 days prior, resulted in a near-total block of nicotine-evoked release of hippocampal [3H]-noradrenaline ([3H]-NA) from superfused rat synaptosomes; NMDA-evoked [3H]-NA release was unaffected. Three weeks after administration of [3H]-CHL (10 microg i.c.v.), preferential accumulation of radiolabel was observed in the locus coeruleus, which provides the entire noradrenergic innervation to hippocampus, as well as in previously noted structures. In rat pheochromocytoma (PC12) cells, nicotine evoked [3H]-NA release (EC50 approximately 30 microM). This effect was blocked by co-incubation with mecamylamine (10 microM) or CHL (1 microM) but was not affected by alpha-bungarotoxin. As in the hippocampus, the nicotinic agonist cytisine was at least as efficacious as nicotine. Acute exposure of PC12 cells to CHL 10 or 100 microM (but not 1 microM), followed by 90 min wash-out, almost completely blocked release evoked by 30 microM nicotine. More prolonged (24 h) exposure to CHL 100 microM (but not 1 or 10 microM), followed by 3 days of wash-out, partially inhibited release evoked by nicotine, leaving responses to high K+ unchanged. A significant (30%) reduction was also seen 5 days after exposure. We conclude that persistent nicotinic blockade by CHL is neither restricted to mesostriatal dopamine neurons, nor to the CNS, nor to neurons possessing the same nicotinic receptor pharmacology. In addition, the persistent blockade does not appear to result from an acute blocking action, but may be dependent upon intracellular accumulation of the antagonist.
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Reuben
authors.forename: M
authors.initials: M
authors.lastname: Louis
authors.forename: P B
authors.initials: PB
authors.lastname: Clarke
mesh_terms: D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001392:Azocines; D002478:Cells, Cultured; D002714:Chlorisondamine / Q000493:pharmacokinetics / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007700:Kinetics; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism*; D016716:PC12 Cells; D011807:Quinolizines; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014316:Tritium; D000093843:Quinolizidine Alkaloids
chemical_list: D000470:Alkaloids; D001392:Azocines; D002714:Chlorisondamine; D016291:Dizocilpine Maleate; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D016202:N-Methylaspartate; D018696:Neuroprotective Agents; D018733:Nicotinic Antagonists; D009638:Norepinephrine; D011807:Quinolizines; D016194:Receptors, N-Methyl-D-Aspartate; D014316:Tritium; C004712:cytisine; D000093843:Quinolizidine Alkaloids