Protein Kinase Cβ Is a Critical Regulator of Dopamine Transporter Trafficking and Regulates the Behavioral Response to Amphetamine in Mice

The dopamine transporter (DAT) is a key mediator of dopaminergic neurotransmission and a major target for amphetamine. We found previously that protein kinase C (PKC) beta regulates amphetamine-mediated dopamine efflux. Here, using PKC beta wild-type (WT) and knockout (KO) mice, we report a novel role for PKC beta in amphetamine-induced regulation of DAT trafficking and activity. PKC beta KO mice have less striatal surface DAT, [H-3] dopamine uptake, and amphetamine-stimulated dopamine efflux, yet higher novelty-induced locomotor activity than WT mice. Although a short exposure (<= 90 s) to amphetamine rapidly increases striatal surface DAT and [H-3] dopamine uptake in WT mice, this treatment decreases surface DAT and [H-3] dopamine uptake in KO mice. Increases in surface DAT and [H-3] dopamine uptake are not evident in KO mice until a longer exposure (60 min) to amphetamine, by which time WT mice exhibit decreased surface DAT and dopamine uptake. The slowness of amphetamine-induced striatal DAT trafficking in PKC beta KO mice was mimicked by the use of a specific PKC beta inhibitor, LY379196, in WT mice. Furthermore, PKC beta KO mice exhibit reduced locomotor responsiveness to amphetamine compared with WT, which could be explained by reduced surface DAT and delayed amphetamine-induced DAT trafficking in KO mice. Our results indicate that PKC beta is crucial for proper trafficking of DAT to the surface and for functioning of DAT and amphetamine signaling, providing new insight into the role of PKC beta as an important regulator of dopaminergic homeostasis.