Embedded Files
We examine the involvement of signal transduction, particularly, phosphorylation in the mechanism of action of amphetamine. Our long-term goal is to use this information to reduce amphetamine’s reinforcing effects. We found that protein kinase C beta (PKCb) is in dopamine transporter (DAT)-containing dopaminergic cells (Fig. 1) and affects transporter function. Either inhibiting PKCb with specific inhibitors or genetically deleting the enzyme reduces amphetamine-stimulated dopamine efflux and amphetamine-stimulated behaviors (Fig.2.).
Recently we demonstrated that inhibition of PKCb also enhances dopamine autoreceptor function (Fig.3). Either genetic deletion of PKCb or inhibition with a small molecule inhibitor enhanced the exocytosis-inhibiting effects of quinpirole (QP), a dopamine D2-like receptor agonist on exocytosis stimulated by 4-aminopyridine. Again, inhibition of PKCb reduced dopamine overflow.
We reason that inhibition of PKCb should reduce extracellular dopamine in response to amphetamine and thus reduce amphetamine reinforcement. We are now testing this hypothesis. Moreover, we are designing new CNS-permeant agents designed to reduce amphetamine function.
Page updated
Report abuse