Amphetamine activates non-receptor tyrosine kinase Fyn and stimulates ERK phosphorylation in the rat striatum in vivo

The psychostimulant amphetamine (AMPH) has an impact on a variety of cellular activities in striatal neurons, although underlying signaling mechanisms are incompletely understood. The Src family kinase (SFK) is among key signaling molecules enriched in striatal neurons and is involved in the regulation of a set of discrete downstream targets. Given the likelihood that AMPH may regulate SFKs, we investigated and characterized the effect of AMPH on SFK phosphorylation and enzymatic activity in rat striatal neurons in vivo. We found that AMPH elevated SFK Y416 phosphorylation in striatal slices and the adult rat striatum. This elevation was concentration- and time-dependent and occurred in all subdivisions of the striatum, including the caudate putamen and nucleus accumbens (core and shell). The dopamine D₁ receptor antagonist SCH23390 blocked the effect of AMPH. Between Fyn and Src, AMPH elevated phosphorylation of immunoprecipitated Fyn but not Src and increased Fyn kinase activity in the striatum. In parallel with SFKs, striatal ERK phosphorylation was increased by AMPH. This increase in ERK phosphorylation was reduced by the SFK inhibitor PP2. These results demonstrate that AMPH is able to activate SFKs (mainly Fyn) in striatal neurons via a D₁ receptor-dependent mechanism. Activated SFKs participate in processing the concomitant ERK response to AMPH.