MARGATOXIN INCREASES DOPAMINE RELEASE IN RAT STRIATUM VIA VOLTAGE-GATED K+ CHANNELS

The distribution of iodinated margatoxin ([I-125]margatoxin) binding s ites in rat was investigated by autoradiography. Rat striatum expresse s a high density of margatoxin binding sites and, therefore, the effec ts of margatoxin, charybdotoxin and iberiotoxin have been studied on [ H-3]dopamine release from rat striatal slices in vitro. Margatoxin (0. 1-100 nM) and charybdotoxin (10-1000 nM), but not iberiotoxin increase d the spontaneous and the electrically evoked [H-3]dopamine release. [ H-3]dopamine release by margatoxin was inhibited by tetrodotoxin and o mega-conotoxin GVIA, but not by atropine, naloxone, N-omega-nitro-L-ar ginine and neurokinin or neurotensin receptor antagonists. In the buff er solution used for release experiments, [I-125]margatoxin labels a m aximum of 0.12 pmol of sites/mg protein in rat striatal membranes with a K-d of 5 pM. [I-125]margatoxin binding was inhibited by margatoxin (K-i of 4 pM), charybdotoxin (K-i of 162 pM) but not by iberiotoxin. W e conclude that inhibition of margatoxin-sensitive voltage-gated K+ ch annels increases [H-3]dopamine release demonstrating their role in rep olarization of nigrostriatal projections. In contrast, iberiotoxin-sen sitive, high-conductance Ca2+-activated K+ channels are not involved i n release of [H-3]dopamine. (C) 1998 Elsevier Science B.V.