The tyrosine kinase inhibitor genistein increases endogenous dopamine release from normal and weaver mutant mouse striatal slices.

Protein tyrosine kinases that are known to have major roles in the control of cell growth and transformation are abundant and have numerous phosphoprotein substrates in the adult CNS. Although less well characterized than serine/threonine kinases, tyrosine kinases are also concentrated in the synapse. The effect of genistein, a selective inhibitor of tyrosine kinase activity, was examined on the in vitro release of endogenous dopamine (DA) from superfused mouse striatal slices. Fractional release of DA was significantly increased over basal release levels by genistein (100 and 200 microM). The effect was concentration dependent and rapidly reversible on washout of the kinase inhibitor. No significant change from basal release levels was observed with two structural analogues of genistein that do not inhibit tyrosine kinase activity 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 also observed with genistein stimulation. The total evoked release was 25-50% greater from the wv/wv striatum. These results suggest a modulatory role for tyrosine kinase activity in neurotransmitter release and perhaps an alteration of kinase-regulated mechanisms in the DA-deficient wv/wv striatum.