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PubMed1998

Blockade of the reward-potentiating effects of nicotine on lateral hypothalamic brain stimulation by chlorisondamine.

Chlorisondamine, a quarternary nicotinic antagonist, was given in a dose that crosses the blood-brain barrier, is taken up and concentrated intracellularly by dopaminergic neurons, and induces long-term blockade of the locomotor stimulant and rewarding effects of nicotine. This treatment had no effect on the rewarding effects of lateral hypothalamic brain stimulation, failing to shift the function that relates reward strength to rate of responding (rate-frequency function). That the treatment regimen was sufficient to block nicotinic receptors in the reward system was confirmed by the fact that it completely blocked the ability of normally effective nicotine to potentiate the rewarding effects of stimulation (shift this function to the left). These data add evidence that the direct, endogenous cholinergic contribution to brain stimulation reward is muscarinic and fit with other evidence that the potentiation of brain stimulation reward by exogenous nicotine involves actions on nicotinic receptors native to dopaminergic neurons.

Animals↗
PubMed1998

Persistent nicotinic blockade by chlorisondamine of noradrenergic neurons in rat brain and cultured PC12 cells.

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.

Alkaloids↗