NICOTINE-INDUCED ACTIVATION OF LOCUS-COERULEUS NEURONS AN ANALYSIS OF PERIPHERAL VERSUS CENTRAL INDUCTION

Previous electrophysiological experiments have shown that the marked but short-lasting excitation of locus coeruleus (LC) neurons seen after systemic administration of low doses of nicotine is of a peripheral origin. In addition, nicotine induces a weak but more long-lasting activation of LC neurons which is preferentially observed following administration of high doses of the drug. In the present study this latter activation was pharmacologically analysed. Whereas low intravenous doses of nicotine caused a marked but short-lasting excitation of most LC cells recorded from, higher doses of nicotine were associated with a moderate but durable (>20 min) activation. In contrast to the short-lasting activation of the LC, the long-lasting effect of the drug was not counteracted by chlorisondamine (0.3 mg/kg, i.v.; n = 5). On the other hand, administration of mecamylamine (4 mg/ kg, i.v.; n = 5) rapidly and effectively decreased the elevated spontaneous firing rate of LC neurons (as observed following repeated nicotine injections) to the original baseline firing rate. Intravenous administration of tetramethylammonium (TMA, 50-800 mg/kg, i.v.), activated most LC neurons in a manner resembling that of nicotine at low doses, i.e. a marked but short-lasting excitation with no tachyphylaxis. However, in contrast to nicotine, TMA administered in higher dose's did not affect the baseline firing rate of LC neurons. The results reveal that LC activation following administration of nicotine is the result of two distinct, separable actions of nicotine, one (observed at low doses) linked to activation of peripheral nicotinic receptors, the other (observed at higher doses) mediated by central nicotinic receptors which may be located on the LC neurons themselves.