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Persistent nicotinic blockade by chlorisondamine of noradrenergic neurons in rat brain and cultured PC12 cells
Author(s) -
Reuben M,
Louis M,
Clarke P B S
Publication year - 1998
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0702215
Subject(s) - chlorisondamine , nicotine , mecamylamine , endocrinology , locus coeruleus , nicotinic agonist , medicine , cytisine , veratridine , dopamine , chemistry , nomifensine , hexamethonium , methyllycaconitine , ganglionic blocker , dopaminergic , agonist , hippocampal formation , neurotoxin , catecholamine , biology , acetylcholine , nicotinic acetylcholine receptor , receptor , central nervous system , sodium , sodium channel , organic chemistry , blood pressure
1 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 [ 3 H]‐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. 2 Administration of CHL (10 mg kg −1 s.c. or 10 μg i.c.v.), 21 days prior, resulted in a near‐total block of nicotine‐evoked release of hippocampal [ 3 H]‐noradrenaline ([ 3 H]‐NA) from superfused rat synaptosomes; NMDA‐evoked [ 3 H]‐NA release was unaffected. 3 Three weeks after administration of [ 3 H]‐CHL (10 μg 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. 4 In rat pheochromocytoma (PC12) cells, nicotine evoked [ 3 H]‐NA release (EC 50 approximately 30 μ m ). This effect was blocked by co‐incubation with mecamylamine (10 μ m ) or CHL (1 μ m ) but was not affected by α‐bungarotoxin. As in the hippocampus, the nicotinic agonist cytisine was at least as efficacious as nicotine. 5 Acute exposure of PC12 cells to CHL 10 or 100 μ m (but not 1 μ m ), followed by 90 min wash‐out, almost completely blocked release evoked by 30 μ m nicotine. More prolonged (24 h) exposure to CHL 100 μ m (but not 1 or 10 μ m ), 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. 6 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.British Journal of Pharmacology (1998) 125 , 1218–1227; doi: 10.1038/sj.bjp.0702215