Lobeline inhibits nicotine-evoked [3H]dopamine overflow from rat striatal slices and nicotine-evoked 86Rb+ efflux from thalamic synaptosomes

The present study evaluated the interaction of lobeline with neuronal nicotinic acetylcholine receptors using two in vitro assays, [H-3] overflow from [H-3]dopamine ([H-3]DA)-preloaded rat striatal slices and Rb-86(+) efflux from rat thalamic synaptosomes. To assess agonist interactions, the effect of lobeline was determined and compared to S(-)-nicotine. To assess antagonist interactions, the ability of lobeline to inhibit the effect of S(-)-nicotine was determined. Both S(-)-nicotine (0.1-1 muM) and lobeline (>1.0 muM) evoked [H-3] overflow from superfused [H-3]DA-preloaded striatal slices. However, lobeline-evoked [H-3] overflow is mecamylamine-insensitive, indicating that this response is not mediated by nicotinic receptors. Moreover, at concentrations (<1.0 <mu>M) which did not evoke [H-3] overflow, lobeline inhibited S(-)-nicotine (0.1-10 muM)-evoked [H-3] overflow, shifting the S(-)-nicotine concentration-response curve to the right. S(-)-Nicotine (30 nM-300 muM) increased (EC50 value=0.2 muM) Rb-86(+) efflux from thalamic synaptosomes. In contrast, lobeline (1 nM-10 muM) did not evoke Rb-86+ efflux, and the lack of intrinsic activity indicates that lobeline is not an agonist at this nicotinic receptor subtype. Lobeline completely inhibited (IC50 value=0.7 muM) Rb-86(+) efflux evoked by 1 muM S(-)-nicotine, a concentration which maximally stimulated Rb-86(+) efflux. Thus, the results of these in vitro experiments demonstrate that lobeline inhibits the effects of S(-)-nicotine, and suggest that lobeline acts as a nicotinic receptor antagonist. (C) 2000 Elsevier Science Ltd. All rights reserved.