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

Abstract

The present study evaluated the interaction of lobeline with neuronal nicotinic acetylcholine receptors using two in vitro assays, [ 3H] overflow from [ 3H]dopamine ([ 3H]DA)-preloaded rat striatal slices and 86Rb + 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 μM) and lobeline (>1.0 μM) evoked [ 3H] overflow from superfused [ 3H]DA-preloaded striatal slices. However, lobeline-evoked [ 3H] overflow is mecamylamine-insensitive, indicating that this response is not mediated by nicotinic receptors. Moreover, at concentrations (<1.0 μM) which did not evoke [ 3H] overflow, lobeline inhibited S(−)-nicotine (0.1–10 μM)-evoked [ 3H] overflow, shifting the S(−)-nicotine concentration–response curve to the right. S(−)-Nicotine (30 nM–300 μM) increased (EC 50 value=0.2 μM) 86Rb + efflux from thalamic synaptosomes. In contrast, lobeline (1 nM–10 μM) did not evoke 86Rb + efflux, and the lack of intrinsic activity indicates that lobeline is not an agonist at this nicotinic receptor subtype. Lobeline completely inhibited (IC 50 value=0.7 μM) 86Rb + efflux evoked by 1 μM S(−)-nicotine, a concentration which maximally stimulated 86Rb + 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.