SODIUM-CHANNEL BLOCKERS PARTIALLY INHIBIT NICOTINE-STIMULATED RB-86(-BRAIN SYNAPTOSOMES() EFFLUX FROM MOUSE)

The possible contribution of non-nicotinic cation channels to nicotine -stimulated 86Rb(+) efflux was investigated. Dendrotoxin, charybdotoxi n and apamin did not affect nicotine-stimulated Rb-86(+) efflux. Altho ugh 4-aminopyridine and tetraethylammonium completely inhibited nicoti ne-stimulated Rb-86(+) efflux, the concentrations required to achieve this inhibition differed markedly from those required to inhibit K+-st imulated Rb-86(+) efflux. Cs+ reduced basal Rb-86(+) efflux, but did n ot affect nicotine-stimulated efflux. Tetrodotoxin completely inhibite d veratridine-stimulated Rb-86(+) efflux (IC50 = 3.4 nM) and partially inhibited (about 42%) nicotine-stimulated efflux (IC50 = 1.3 nM). Sax itoxin also completely inhibited veratridine-stimulated efflux (IC50 = 19.5 nM) and partially inhibited (about 47%) nicotine-stimulated effl ux (IC50 = 5.4 nM). Tetrodotoxin had no significant effect on the EC(5 0) for nicotine, but decreased the efflux rate and reduced modestly th e rate of desensitization measured with prolonged exposure to nicotine . Tetrodotoxin (50 nM) also inhibited maximal nicotine-stimulated Rb-8 6(+) efflux to approximately the same extent in each of ten brain regi ons examined. Nicotine-stimulated Rb-86(+) efflux measured in the pres ence or absence of 100 nM tetrodotoxin is correlated with the density of [H-3]nicotine, but not [H-3]saxitoxin, binding sites in 12 regions, suggesting that the density of nicotinic receptors, not the number of Na+ channels, is the rate-limiting step for nicotine-stimulated 86Rb efflux. Therefore, activation of Na+ channels secondary to the stimula tion of nicotinic receptors seems to contribute to the nicotine-stimul ated Rb-86(+) efflux observed in mouse brain synaptosomes, In contrast , no evidence for K+ channel modulation of nicotine-stimulated Rb-86() efflux from thalamic synaptosomes was obtained.