Abstract

Biochemical studies showing that lead (Pb++) inhibits cerebellar adenylate cyclase (IC50 = 2 micrometer) prompted us to test the effects of this cation on the depression of spontaneous discharge of Purkinje (P) cells produced by iontophoresis of norepinephrine (NE). Previous studies have suggested that the effects of NE on P cell discharge may be mediated by activation of a NE-sensitive adenylate cyclase. Iontophoresis of Pb++ in situ, and in cerebellar transplants in oculo, reliably antagonized NE responses in over 80% of the P cells studied in both preparations. Blockade was readily seen at iontophoretic currents of 5 to 10 nA. Superfusion of PB++ (5--10 micrometer) into the anterior eye chamber also antagonized NE responses in P neurons of the transplant. Spontaneous discharge rate was either unaffected or slightly elevated at Pb++ levels that almost completely blocked NE. Barium, a heavy metal which does not inhibit adenylate cyclase in vitro, did not block NE effects. Stimulation of parallel fibers or iontophoresis of acetylcholine excited P cells. No antagonism was seen, however, between Pb++ and these acetylcholine or parallel fiber excitations. These results raise the possibility that blockade of brain catecholamine receptors may partially underlie the central nervous system toxicity seen with lead administration.