THE TYROSINE KINASE INHIBITOR GENISTEIN INCREASES ENDOGENOUS DOPAMINERELEASE FROM NORMAL AND WEAVER MUTANT MOUSE STRIATAL SLICES

Protein tyrosine kinases that are known to have major roles in the con trol of cell growth and transformation are abundant and have numerous phosphoprotein substrates in the adult CNS. Although less well charact erized than serine/threonine kinases, tyrosine kinases are also concen trated in the synapse, The effect of genistein, a selective inhibitor of tyrosine kinase activity, was examined on the in vitro release of e ndogenous dopamine (DA) from superfused mouse striatal slices, Fractio nal release of DA was significantly increased over basal release level s by genistein (100 and 200 mu M). The effect was concentration depend ent and rapidly reversible on washout of the kinase inhibitor. No sign ificant change from basal release levels was observed with two structu ral analogues of genistein that do not inhibit tyrosine kinase activit y at the same concentration, We have previously described alterations in basal and evoked DA release from the striatum of the weaver (wv/wv) mutant mouse, and genotypic differences in fractional release were al so observed with genistein stimulation. The total evoked release was 2 5-50% greater from the wv/wv striatum. These results suggest a modulat ory role for tyrosine kinase activity in neurotransmitter release and perhaps an alteration of kinase-regulated mechanisms in the DA-deficie nt wv/wv striatum.